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A diagnosis of exclusion or by exclusion (per exclusionem) is a diagnosis of a medical condition reached by a process of elimination, which may be necessary if presence cannot be established with complete confidence from history, examination or testing. Such elimination of other reasonable possibilities is a major component in performing a differential diagnosis.
Diagnosis by exclusion tends to occur where scientific knowledge is scarce, specifically where the means to verify a diagnosis by an objective method is absent. It can also commonly occur where objective diagnostic tests do exist, but extensive diagnostic testing or sufficient exploration of differential diagnosis by a multidisciplinary team is not undertaken due to financial constraints or assessment bias (health inequity).
The largest category of diagnosis by exclusion is seen among psychiatric disorders where the presence of physical or organic disease must be excluded as a prerequisite for making a functional diagnosis.
== Examples ==
An example of such a diagnosis is "fever of unknown origin": to explain the cause of elevated temperature the most common causes of unexplained fever (infection, neoplasm, or collagen vascular disease) must be ruled out.
Other examples include:
Fibromyalgia
Adult-onset Still's disease
Behçet's disease
Bell's palsy
Burning mouth syndrome
Chronic recurrent multifocal osteomyelitis
Long COVID
Inappropriate sinus tachycardia
Psychogenic polydipsia
Schizophrenia
Somatic symptom disorder
Sudden infant death syndrome
Tolosa–Hunt syndrome
Systemic-onset juvenile idiopathic arthritis
== See also ==
Idiopathic
Wastebasket diagnosis
== References == | Wikipedia/Diagnosis_of_exclusion |
Prenatal testing is a tool that can be used to detect some birth defects at various stages prior to birth. Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problems with the pregnancy as early as possible. These may be anatomic and physiologic problems with the health of the zygote, embryo, or fetus, either before gestation even starts (as in preimplantation genetic diagnosis) or as early in gestation as practicable. Screening can detect problems such as neural tube defects, chromosome abnormalities, and gene mutations that would lead to genetic disorders and birth defects such as spina bifida, cleft palate, Down syndrome, trisomy 18, Tay–Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, muscular dystrophy, and fragile X syndrome. Some tests are designed to discover problems which primarily affect the health of the mother, such as PAPP-A to detect pre-eclampsia or glucose tolerance tests to diagnose gestational diabetes. Screening can also detect anatomical defects such as hydrocephalus, anencephaly, heart defects, and amniotic band syndrome.
Prenatal screening focuses on finding problems among a large population with affordable and noninvasive methods. Prenatal diagnosis focuses on pursuing additional detailed information once a particular problem has been found, and can sometimes be more invasive. The most common screening procedures are routine ultrasounds, blood tests, and blood pressure measurement. Common diagnosis procedures include amniocentesis and chorionic villus sampling. In some cases, the tests are administered to determine if the fetus will be aborted, though physicians and patients also find it useful to diagnose high-risk pregnancies early so that delivery can be scheduled in a tertiary care hospital where the baby can receive appropriate care.
Prenatal testing in recent years has been moving towards non-invasive methods to determine the fetal risk for genetic disorders. The rapid advancement of modern high-performance molecular technologies along with the discovery of cell-free fetal DNA (cffDNA) in maternal plasma has led to new methods for the determination of fetal chromosomal aneuploidies. This type of testing is referred to as non-invasive prenatal testing (NIPT) or as non-invasive prenatal screening. Invasive procedures remain important, though, especially for their diagnostic value in confirming positive non-invasive findings and detecting genetic disorders. Birth defects have an occurrence between 1 and 6%.
== Purpose ==
There are three purposes of prenatal diagnosis: (1) to enable timely medical or surgical treatment of a condition before or after birth, (2) to give the parents the chance to abort a fetus with the diagnosed condition, and (3) to give parents the chance to prepare psychologically, socially, financially, and medically for a baby with a health problem or disability, or for the likelihood of a stillbirth. Prior information about problems in pregnancy means that healthcare staff as well as parents can better prepare themselves for the delivery of a child with a health problem. For example, Down syndrome is associated with cardiac defects that may need intervention immediately upon birth.
=== Prenatal screening ===
==== Maternal serum screening ====
First-trimester maternal serum screening can check levels of free β-hCG, PAPP-A, intact or beta hCG, or h-hCG in the woman's serum, and combine these with the measurement of nuchal translucency (NT). Some institutions also look for the presence of a fetal nasalbone on the ultrasound.
Second-trimester maternal serum screening (AFP screening, triple screen, quad screen, or penta screen) can check levels of alpha fetoprotein, β-hCG, inhibin-A, estriol, and h-hCG (hyperglycosolated hCG) in the woman's serum.
The triple test measures serum levels of AFP, estriol, and beta-hCG, with a 70% sensitivity and 5% false-positive rate. It is complemented in some regions of the United States, as the Quad test (adding inhibin A to the panel, resulting in an 81% sensitivity and 5% false-positive rate for detecting Down syndrome when taken at 15–18 weeks of gestational age).
The biomarkers PAPP-A and β-hCG seem to be altered for pregnancies resulting from ICSI, causing a higher false-positive rate. Correction factors have been developed and
should be used when screening for Down's syndrome in singleton pregnancies after ICSI, but in twin pregnancies such correction factors have not been fully elucidated. In vanishing twin pregnancies with a second gestational sac with a dead fetus, first-trimester screening should be based solely on the maternal age and the nuchal translucency scan as biomarkers are altered in these cases.
==== Advances in prenatal screening ====
Measurement of fetal proteins in maternal serum is a part of standard prenatal screening for fetal aneuploidy and neural tube defects. Computational predictive model shows that extensive and diverse feto-maternal protein trafficking occurs during pregnancy and can be readily detected non-invasively in maternal whole blood. This computational approach circumvented a major limitation, the abundance of maternal proteins interfering with the detection of fetal proteins, to fetal proteomic analysis of maternal blood. Entering fetal gene transcripts previously identified in maternal whole blood into a computational predictive model helped develop a comprehensive proteomic network of the term neonate. It also shows that the fetal proteins detected in pregnant woman's blood originate from a diverse group of tissues and organs from the developing fetus. Development proteomic networks dominate the functional characterization of the predicted proteins, illustrating the potential clinical application of this technology as a way to monitor normal and abnormal fetal development.
The difference in methylation of specific DNA sequences between mother and fetus can be used to identify fetal-specific DNA in the blood circulation of the mother. In a study published in the March 6, 2011, online issue of Nature, using this non-invasive technique a group of investigators from Greece and UK achieved correct diagnosis of 14 trisomy 21 (Down syndrome) and 26 normal cases. Using massive parallel sequencing, a study testing for trisomy 21 only, successfully detected 209 of 212 cases (98.6%) with 3 false-positives in 1,471 pregnancies (0.2%). With commercially available non-invasive (blood) testing for Down syndrome having become available to patients in the United States and already available in China, in October 2011, the International Society for Prenatal Diagnosis created some guidance. Based on its sensitivity and specificity, it constitutes an advanced screening test and that positive results require confirmation by an invasive test, and that while effective in the diagnosis of Down syndrome, it cannot assess half the abnormalities detected by invasive testing. The test is not recommended for general use until results from broader studies have been reported, but may be useful in high-risk patients in conjunction with genetic counseling.
A study in 2012 found that the maternal plasma cell-free DNA test was also able to detect trisomy 18 (Edwards syndrome) in 100% of the cases (59/59) at a false-positive rate of 0.28%, and trisomy 13 (Patau syndrome) in 91.7% of the cases (11/12) at a false-positive rate of 0.97%. The test interpreted 99.1% of samples (1,971/1,988); among the 17 samples without an interpretation, three were trisomy 18. The study stated that if z-score cutoffs for trisomy 18 and 13 were raised slightly, the overall false-positive rates for the three aneuploidies could be as low as 0.1% (2/1,688) at an overall detection rate of 98.9% (280/283) for common aneuploidies (this includes all three trisomies: Down, Edwards and Patau).
=== Prenatal genetic testing ===
The goal of prenatal genetic testing is to identify pregnancies at high risk of abnormalities, allowing for early intervention, termination or appropriate management and preparation measures. Prenatal genetic testing can be subdivided into two categories: screening and diagnostic testing. Screening informs an individual of the potential for certain abnormalities occurring, whereas, diagnostic testing is used to confirm/diagnose that specific abnormalities exist within the fetus. Prenatal screens are typically less invasive than prenatal diagnostic tests. Screening comes with much lower risks, however, the results are not as definitive as diagnostic tests. Providers often recommend following up with a diagnostic test upon receipt of a positive result from a specific screen.
Medically invasive techniques are those in which a tool is used to access something inside the body. There are varying degrees of invasiveness, depending on what specimen is required to complete the test. The typical blood draw administered by a healthcare professional is one of the most common invasive medical practices. Since it causes minimal discomfort and there is very low risk associated with the sample collection, a blood draw is considered less invasive. Chorionic villus sampling (CVS) and Amniocentesis are the most invasive prenatal tests because there is greater associated risk and the sample is more difficult to access. These procedures are done via needle insertion into the abdomen to collect a sample within the uterus, meaning exceptional care/precision is required.
Prenatal genetic testing can identify various chromosomal abnormalities, autosomal conditions, various birth defects, and some fetal blood disorders.
Chromosomal abnormalities are when the chromosomes differ in either structure or number when compared to a typical reference genome. This includes chromosomal deletions, duplications, inversions, and translocations. Some examples of chromosomal abnormalities include:
Down syndrome (trisomy 21)
Edwards syndrome (trisomy 18)
Patau syndrome (trisomy 13)
Turner syndrome (monosomy X)
Klinefelter syndrome (XXY)
Trisomy X (XXX)
Jacobs syndrome (XYY)
Pallister–Killian syndrome
Wolf–Hirschhorn syndrome
Cri-du-chat syndrome
WAGR syndrome
DiGeorge syndrome
Fragile X syndrome
– Prader-Willi/Angelman syndrome
Autosomal recessive conditions occur when both parents pass on a mutation within an autosomal (non-sex) chromosome. Some examples of autosomal recessive conditions are:
Cystic fibrosis
Sickle cell anemia
Tay–Sachs disease
Spinal muscular atrophy
Autosomal recessive polycystic kidney disease
Phenylketonuria
Neural tube defects are a type of birth defect that occurs when the neural tube of a fetus does not form/close properly, potentially effecting other systems throughout the body. Some examples of neural tube defects are:
Spina bifida
Anencephaly
Encephalocele
Tethered spinal cord syndrome
Abdominal wall defects are a type of birth defect that occur when the abdominal wall of a fetus does not form properly, potentially effecting other organs throughout the body. Some examples of abdominal wall defects are:
Gastroschisis
Omphalocele
Bladder exstrophy
Cloacal exstrophy
Ectopia cordis
Pentalogy of Cantrell
Body-stalk anomaly
Blood disorders can occur from a negative interaction between the maternal blood and the fetal blood. An example of a fetal blood disorder is Hemolytic disease of the fetus.
=== Ultrasound imaging and serum markers as indications for genetic testing ===
Ultrasound imaging provides the opportunity to conduct a nuchal translucency (NT) scan screening for chromosomal abnormalities such as Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), and Patau syndrome (trisomy 13). Using the information from the NT scan the mother can be offered an invasive diagnostic test for fetal chromosomal abnormalities. Serum markers are used in a similar fashion to identify gestations that should be recommended for further testing. When the NT scan or serum markers arouse suspicion for chromosomal abnormalities the following genetic tests may be conducted on fetal or placental tissue samples: Interphase-fluorescence in situ hybridization (FISH), quantitative PCR and direct preparation of chromosomes from chorionic villi.
=== Screens ===
==== Carrier screening ====
Carrier screening is a general DNA test that uses a blood or cheek swab sample to determine if the parents carry certain genetic conditions. This test can be done anytime, whether the individual(s) are considering starting a family or have already become pregnant. Various types of carrier screens are available that test for progressively more genetic abnormalities. The single gene/condition screen will test for a specific condition, whereas, the expanded carrier screen will test for hundreds of different abnormalities that can be inherited by a fetus. There are also three gene/condition and ethnic specific carrier tests. In the case of a positive test result, further testing is often recommended, as the carrier test only determines if the parent(s) is a carrier, not if the gene has definitively been passed to the fetus.
==== Placental acellular DNA (pa-DNA) ====
Placental acellular (fetal cell-free) DNA testing (pa-DNA) allows for the detection of apoptotic placental cells and placental DNA circulating in maternal blood for the noninvasive diagnosis of fetal aneuploidy. A meta-analysis that investigated the success rate of using placental acellular DNA from maternal blood to screen for aneuploidies found that this technique detected trisomy 13 in 99% of the cases, trisomy 18 in 98% of the cases and trisomy 21 in 99% of the cases. Failed tests using placental acellular DNA are more likely to occur in fetuses with trisomy 13 and trisomy 18 but not with trisomy 21. Previous studies found elevated levels of acellular placental DNA for trisomy 13 and 21 from maternal serum when compared to women with euploid pregnancies. However, an elevation of acellular DNA for trisomy 18 was not observed. Circulating placental nucleated cells comprise only three to six percent of maternal blood plasma DNA, reducing the detection rate of fetal developmental abnormalities. Two alternative approaches have been developed for the detection of fetal aneuploidy. The first involves the measuring of the allelic ratio of single nucleotide polymorphisms (SNPs) in the mRNA coding region in the placenta. The next approach is analyzing both maternal and placental DNA and looking for differences in the DNA methylation patterns.
==== First/Second/Third trimester Screen ====
The first, second, combined, and third trimester screens typically consist of an ultrasound (abdominal and/or transvaginal) and maternal blood/serum testing. The ultrasound is used to visually assess the growth, development, and activity of the fetus through imaging observations and measurements. The ultrasound portion of the first trimester screen can include a nuchal translucency screen and a fetal nasal bone determination screen. The available blood tests from the first trimester screen can test for plasma protein A and human chorionic gonadotropin. The second trimester screen looks at specific blood markers, to include the estriol, inhibin and human chorionic gonadotropin hormones and often consists of Alpha-fetoprotein (AFP) screening. Any abnormal results from these screening tests can indicate the possibility of abnormal conditions such as Trisomy 18, Trisomy 21 (Down syndrome), and spina bifida.
==== Alpha-fetoprotein (AFP)/multiple marker test ====
The AFP test is often done in the second trimester using the serum from the maternal blood draw. This test looks at a specific protein that is formed in the liver of the fetus and released into the fluid contents of the womb, which is then absorbed into the mother's blood stream. Multiple determinations stem from the results of AFP testing. Genetically, it can expose chromosomal and neural defects.
=== Diagnostic tests ===
==== Chorionic Villus Sampling (CVS) ====
CVS is an invasive diagnostic test that can be done during the first trimester of pregnancy for individuals that are looking to identify or are at higher risk of passing chromosomal abnormalities. A tissue cell sample of the placenta is obtained abdominally via needle or via vaginal insertion of a catheter/syringe into the cervix in combination with ultrasound to guide the procedure. Positive results from CVS require blood testing for confirmation.
==== Amniocentesis ====
Amniocentesis is an invasive diagnostic test that can be done during the second trimester of pregnancy for individuals that are looking to identify or are at higher risk of passing chromosomal and/or neural tube abnormalities. The procedure is typically done via needle, in combination with ultrasound for guidance, to obtain a sample of the amniotic fluid surrounding the fetus.
==== Cordocentesis/Percutaneous umbilical blood sampling (PUBS) ====
PUBS is an invasive diagnostic test that can be done during the second trimester of pregnancy for individuals that are looking to identify or are at higher risk of passing chromosomal and/or blood abnormalities. The demand for cordocentesis tests is diminishing because it has been replaced with CVS and Amniocentesis, which carry less risk. The procedure is typically done via needle into the mother's abdomen, in combination with ultrasound for guidance, to obtain a blood sample from the umbilical cord of the fetus.
== Prenatal genetic testing analysis techniques ==
=== Digital PCR ===
Recently, it has been proposed that digital PCR analysis can be conducted on fetal cell-free DNA for detection of fetal aneuploidy. Research has shown that digital PCR can be used to differentiate between normal and aneuploid DNA.
A variation of the PCR technique called multiplex ligation-dependent probe amplification (MLPA), targeting DNA, has been successively applied for diagnosing fetal aneuploidy as a chromosome- or gene-specific assay.
=== Shotgun sequencing ===
Fetal cell-free DNA has been directly sequenced using shotgun sequencing technology. In one study, DNA was obtained from the blood plasma of eighteen pregnant women. This was followed by mapping the chromosome using the quantification of fragments. This was done using advanced methods in DNA sequencing resulting in the parallel sequencing of the fetal DNA. The amount of sequence tags mapped to each chromosome was counted. If there was a surplus or deficiency in any of the chromosomes, this meant that there was a fetal aneuploid. Using this method of shotgun sequencing, the successful identification of trisomy 21 (Down syndrome), trisomy 18 (Edward syndrome), and trisomy 13 (Patau syndrome) was possible. This method of noninvasive diagnosis is now starting to be heavily used and researched further.
=== Other techniques ===
Microarray analysis, karyotyping, and different genome sequencing techniques are also used to detect abnormalities. Fetal components in samples from maternal blood plasma can be analyzed by genome-wide techniques not only by total DNA, but also by methylated DNA immunoprecipitation (with tiling array), microRNA (such as with Megaplex) and total RNA (RNA-sequencing).
== By invasiveness ==
Diagnostic prenatal testing can be performed by invasive or non-invasive methods. An invasive method involves probes or needles being inserted into the uterus, e.g. amniocentesis, which can be done from about 14 weeks gestation, and usually up to about 20 weeks, and chorionic villus sampling, which can be done earlier (between 9.5 and 12.5 weeks gestation) but which may be slightly more risky to the fetus. One study comparing transabdominal chorionic villus sampling with second trimester amniocentesis found no significant difference in the total pregnancy loss between the two procedures. However, transcervical chorionic villus sampling carries a significantly higher risk, compared with a second-trimester amniocentesis, of total pregnancy loss (relative risk 1.40; 95% confidence interval 1.09 to 1.81) and spontaneous miscarriage (9.4% risk; relative risk 1.50; 95% confidence interval 1.07 to 2.11).
Non-invasive techniques include examinations of the woman's womb through ultrasonography and maternal serum screens (i.e. Alpha-fetoprotein). Blood tests for select trisomies (Down syndrome in the United States, Down and Edwards syndromes in China) based on detecting cell-free placental DNA present in maternal blood, also known as non-invasive prenatal testing (NIPT), have become available. If an elevated risk of chromosomal or genetic abnormality is indicated by a non-invasive screening test, a more invasive technique may be employed to gather more information. In the case of neural tube defects, a detailed ultrasound can non-invasively provide a definitive diagnosis.
One of the major advantages of the non-invasive prenatal testing is that the chance of a false positive result is very low. This accuracy is very important for the pregnant woman, as due to a high sensitivity and specificity of the testing, especially for Down syndrome, the invasive testing could be avoided, which includes the risk of a miscarriage.
=== Testing guidelines and qualifying risk factors for invasive testing ===
The American College of Obstetricians and Gynecologists (ACOG) guidelines currently recommend that anyone who is pregnant, regardless of age, should discuss and be offered non-invasive prenatal genetic screening and diagnostic testing options. Non-invasive prenatal genetic screening is typically performed at the end of the 1st trimester (11–14 weeks) or during the beginning of the second trimester (15–20 weeks). This involves the pregnant woman receiving a blood draw with a needle and a syringe and an ultrasound of the fetus. Screening tests can then include serum analyte screening or cell-free fetal DNA, and nuchal translucency ultrasound [NT], respectively. It is important to note that screening tests are not diagnostic, and concerning screening results should be followed up with invasive diagnostic testing for a confirmed diagnosis. Invasive diagnostic prenatal genetic testing can involve chronic villus sampling (CVS) or amniocentesis. The ACOG recommends genetic screening before pregnancy to all pregnant women planning to have a family. After comprehensive counseling and discussion that acknowledges residual risks, it is important to respect the patients' right of choosing whether or not to pursue any component of genetic testing.
The following are some reasons why a woman might consider her risk of birth defects already to be high enough to warrant skipping screening and going straight for invasive testing:
Increased risk of fetal aneuploidy based on personal obstetric history or family history affected by aneuploidy
Increased risk for a known genetic or biochemical disease of the fetus
Maternal transmissible infectious disease such as rubella or toxoplasma
Parental request in the context of acute parental anxiety or under exceptional circumstances
==== Patient acceptance ====
Research was conducted to determine how women felt about noninvasive diagnosis of fetal aneuploid using maternal blood. This study was conducted using surveys. It was reported that eighty-two percent of pregnant women and seventy-nine percent of female medical students view this type of diagnosis in a positive light, agreeing that it is important for prenatal care. Overall, women responded optimistically that this form of diagnosis will be available in the future.
== By pregnancy stage ==
=== Pre-conception ===
Prior to conception, couples may elect to have genetic testing done to determine the odds of conceiving a child with a known genetic anomaly. The most common in the Caucasian population are:
Cystic fibrosis
Fragile X syndrome
Blood disorders such as sickle cell disease
Tay-Sachs disease
Spinal muscular atrophy
Hundreds of additional conditions are known and more discovered on a regular basis. However the economic justification for population-wide testing of all known conditions is not well supported, particularly once the cost of possible false positive results and concomitant follow-up testing are taken into account. There are also ethical concerns related to this or any type of genetic testing.
One or both partners may be aware of other family members with these diseases. Testing prior to conception may alleviate concern, prepare the couple for the potential short- or long-term consequences of having a child with the disease, direct the couple toward adoption or foster parenting, or prompt for preimplantation genetic testing during in vitro fertilization. If a genetic disorder is found, professional genetic counseling is usually recommended owing to the host of ethical considerations related to subsequent decisions for the partners and potential impact on their extended families. Most, but not all, of these diseases follow Mendelian inheritance patterns. Fragile X syndrome is related to expansion of certain repeated DNA segments and may change generation-to-generation.
=== First trimester ===
At early presentation of pregnancy at around 6 weeks, early dating ultrasound scan may be offered to help confirm the gestational age of the embryo and check for a single or twin pregnancy, but such a scan is unable to detect common abnormalities. Details of prenatal screening and testing options may be provided.
Around weeks 11–13, nuchal translucency scan (NT) may be offered which can be combined with blood tests for PAPP-A and beta-hCG, two serum markers that correlate with chromosomal abnormalities, in what is called the First Trimester Combined Test. The results of the blood test are then combined with the NT ultrasound measurements, maternal age, and gestational age of the fetus to yield a risk score for Down syndrome, trisomy 18, and trisomy 13. First Trimester Combined Test has a sensitivity (i.e. detection rate for abnormalities) of 82–87% and a false-positive rate of around 5%.
Cell-free fetal DNA is also available during the first trimester of pregnancy.
=== Second trimester ===
The anomaly scan is performed between 18 and 22 weeks of gestational age. The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) recommends that this ultrasound is performed as a matter of routine prenatal care, to measure the fetus so that growth abnormalities can be recognized quickly later in pregnancy, and to assess for congenital malformations and multiple pregnancies (i.e. twins). The scan can detect anencephaly, open spina bifida, cleft lip, diaphragmatic hernia, gastroschisis, omphalocele, congenital heart defect, bilateral renal agenesis, osteochondrodysplasia, Edwards syndrome, and Patau syndrome.
A second-trimester Quad blood test may be taken (the Triple test is widely considered obsolete but in some states, such as Missouri, where Medicaid only covers the Triple test, that's what the patient typically gets). With integrated screening, both a First Trimester Combined Test and a Triple/Quad test is performed, and a report is only produced after both tests have been analyzed. However patients may not wish to wait between these two sets of tests. With sequential screening, a first report is produced after the first trimester sample has been submitted, and a final report after the second sample. With contingent screening, patients at very high or very low risks will get reports after the first-trimester sample has been submitted. Only patients with moderate risk (risk score between 1:50 and 1:2000) will be asked to submit a second-trimester sample, after which they will receive a report combining information from both serum samples and the NT measurement. The First Trimester Combined Test and the Triple/Quad test together have a sensitivity of 88–95% with a 5% false-positive rate for Down syndrome, though they can also be analyzed in such a way as to offer a 90% sensitivity with a 2% false-positive rate. Finally, patients who do not receive an NT ultrasound in the 1st trimester may still receive a Serum Integrated test involving measuring PAPP-A serum levels in the 1st trimester and then doing a Quad test in the 2nd trimester. This offers an 85–88% sensitivity and 5% false-positive rate for Down syndrome. Also, a patient may skip the 1st-trimester screening entirely and receive only a 2nd-trimester Quad test, with an 81% sensitivity for Down syndrome and 5% false-positive rate.
=== Third trimester ===
Third-trimester prenatal testing generally focuses on maternal wellbeing and reducing fetal morbidity/mortality. Group B streptococcal infection (also called Group B strep) may be offered, which is a major cause of neonatal morbidity and mortality. Group B strep is an infection that may be passed to an infant during birth. Vaginal screening for GBS is performed between 34 and 37 weeks of gestational age, so that mothers that are positive for the bacterium can receive treatment before delivery. During the third trimester, some institutions may require evaluations of hemoglobin/hematocrit, syphilis serology, and HIV screening. Also, before delivery, an assessment of fetal position and estimated fetal weight is documented.
== Legislation ==
=== In Europe ===
Prenatal diagnosis (DPN) is permitted throughout Europe, with the exception of Ireland. Eight (8) countries have no legislation on this matter. However, there are differences between states. For instance, in Poland, the deadline for DPN is 22 weeks. In Malta, the Parliamentary Social Affairs Committee specified in its 2005 report that DPN should only be allowed for conditions for which therapeutic options exist. Nevertheless, all countries prohibit DPN for non-medical purposes (such as sex selection), for example.
=== In France ===
Article L2131-1 of the Public Health Code, stemming from the July 2011 bioethics law, states that "prenatal diagnosis refers to medical practices, including obstetric and fetal ultrasound, aimed at detecting, in utero, a particularly severe condition in the embryo or fetus." The law requires that pregnant women receive clear information about these techniques to "assess the risk that the embryo or fetus may have a condition that could alter the course or management of the pregnancy.
== Ethical and practical issues ==
=== Non-genetic prenatal testing ===
Parents need to make informed decisions about screening, diagnosis, and any actions to be taken as a result. Many screening tests are inaccurate, so one worrisome test result frequently leads to additional, more invasive tests. If prenatal testing confirms a serious disability, many parents are forced to decide whether to continue the pregnancy or seek an abortion. The "option" of screening becomes an unexpected requirement to decide.
In some genetic conditions, for instance cystic fibrosis, an abnormality can only be detected if DNA is obtained from the fetus. Usually an invasive method is needed to do this.
Ultrasound of a fetus, which is considered a screening test, can sometimes miss subtle abnormalities. For example, studies show that a detailed 2nd-trimester ultrasound, also called a level 2 ultrasound, can detect about 97% of neural tube defects such as spina bifida . Ultrasound results may also show "soft signs," such as an Echogenic intracardiac focus or a Choroid plexus cyst, which are usually normal, but can be associated with an increased risk for chromosome abnormalities.
Other screening tests, such as the Quad test, can also have false positives and false negatives. Even when the Quad results are positive (or, to be more precise, when the Quad test yields a score that shows at least a 1 in 270 risk of abnormality), usually the pregnancy is normal, but additional diagnostic tests are offered. In fact, consider that Down syndrome affects about 1:400 pregnancies; if you screened 4000 pregnancies with a Quad test, there would probably be 10 Down syndrome pregnancies of which the Quad test, with its 80% sensitivity, would call 8 of them high-risk. The quad test would also tell 5% (~200) of the 3990 normal women that they are high-risk. Therefore, about 208 women would be told they are high-risk, but when they undergo an invasive test, only 8 (or 4% of the high risk pool) will be confirmed as positive and 200 (96%) will be told that their pregnancies are normal. Since amniocentesis has approximately a 0.5% chance of miscarriage, one of those 200 normal pregnancies might result in a miscarriage because of the invasive procedure. Meanwhile, of the 3792 women told they are low-risk by the Quad test, 2 of them will go on to deliver a baby with Down syndrome. The Quad test is therefore said to have a 4% positive predictive value (PPV) because only 4% of women who are told they are "high-risk" by the screening test actually have an affected fetus. The other 96% of the women who are told they are "high-risk" find out that their pregnancy is normal.
By comparison, in the same 4000 women, a screening test that has a 99% sensitivity and a 0.5% false positive rate would detect all 10 positives while telling 20 normal women that they are positive. Therefore, 30 women would undergo a confirmatory invasive procedure and 10 of them (33%) would be confirmed as positive and 20 would be told that they have a normal pregnancy. Of the 3970 women told by the screen that they are negative, none of the women would have an affected pregnancy. Therefore, such a screen would have a 33% positive predictive value.
The real-world false-positive rate for the Quad test (as well as 1st Trimester Combined, Integrated, etc.) is greater than 5%. 5% was the rate quoted in the large clinical studies that were done by the best researchers and physicians, where all the ultrasounds were done by well-trained sonographers and the gestational age of the fetus was calculated as closely as possible. In the real world, where calculating gestational age may be a less precise art, the formulas that generate a patient's risk score are not as accurate and the false-positive rate can be higher, even 10%.
Because of the low accuracy of conventional screening tests, 5–10% of women, often those who are older, will opt for an invasive test even if they received a low-risk score from the screening. A patient who received a 1:330 risk score, while technically low-risk (since the cutoff for high-risk is commonly quoted as 1:270), might be more likely to still opt for a confirmatory invasive test. On the other hand, a patient who receives a 1:1000 risk score is more likely to feel assuaged that her pregnancy is normal.
Both false positives and false negatives will have a large impact on a couple when they are told the result, or when the child is born. Diagnostic tests, such as amniocentesis, are considered to be very accurate for the defects they check for, though even these tests are not perfect, with a reported 0.2% error rate (often due to rare abnormalities such as mosaic Down syndrome where only some of the fetal/placental cells carry the genetic abnormality).
A higher maternal serum AFP level indicates a greater risk for anencephaly and open spina bifida. This screening is 80% and 90% sensitive for spina bifida and anencephaly, respectively.
Amniotic fluid acetylcholinesterase and AFP level are more sensitive and specific than AFP in predicting neural tube defects.
Many maternal-fetal specialists do not bother to even do an AFP test on their patients because they do a detail ultrasound on all of them in the 2nd trimester, which has a 97% detection rate for neural tube defects such as anencephaly and open spina bifida. Performing tests to determine possible birth defects is mandatory in all U.S. states. Failure to detect issues early can have dangerous consequences on both the mother and the baby. OBGYNs may be held culpable. In one case a man who was born with spina bifida was awarded $2 million in settlement, apart from medical expenses, due to the OBGYN's negligence in conducting AFP tests.
No prenatal test can detect all forms of birth defects and abnormalities.
=== Prenatal genetic testing ===
Another important issue is the uncertainty of prenatal genetic testing. Uncertainty on genetic testing results from several reasons: the genetic test is associated with a disease but the prognosis and/or probability is unknown, the genetic test provides information different than the familiar disease they tested for, found genetic variants have unknown significance, and finally, results may not be associated with found fetal abnormalities. Richardson and Ormond thoroughly addressed the issue of uncertainty of genetic testing and explained its implication for bioethics. First, the principle of beneficence is assumed in prenatal testing by decreasing the risk of miscarriage, however, uncertain information derived from genetic testing may harm the parents by provoking anxiety and leading to the termination of a fetus that is probably healthy. Second, the principle of autonomy is undermined given a lack of comprehension resulting from new technologies and changing knowledge in the field of genetics. And third, the principle of justice raised issues regarding equal access to emerging prenatal tests.
=== Availability of treatments ===
If a genetic disease is detected, there is often no treatment that can help the fetus until it is born. However, in the US, there are prenatal surgeries for spina bifida fetus. Early diagnosis gives the parents time to research and discuss post-natal treatment and care, or in some cases, abortion. Genetic counselors are usually called upon to help families make informed decisions regarding results of prenatal diagnosis.
=== Patient education ===
Researchers have studied how disclosing amniocentesis or chorionic villous sampling (CVS) results on a fixed date versus a variable date (i.e. "when available") affects maternal anxiety. Systematic review of the relevant articles found no conclusive evidence to support issuing amniocentesis results as soon as they become available (in comparison to issuing results on a pre-defined fixed date). The researchers concluded that further studies evaluating the effect of different strategies for disclosing CVS results on maternal anxiety are needed.
=== Concerns from disability rights activists and scholars ===
Since its introduction in 2011 to 2025, there has been a global expansion of non-invasive prenatal testing (NIPT). Initially, only women at-high risk for chromosomal abnormalities underwent NIPT, however in recent years it has become routine during pregnancy. NIPT is especially accurate at detecting trisomy 21, also known as Down's Syndrome, which is the most common form of chromosomal disorder in live births. In England, Whales, and Scotland abortion due to disability is legal under the Abortion Act of 1967. In the US, it is estimated that NIPT has potentially led to a 30% decrease of people living with Down's Syndrome. Disability rights activists and scholars have suggested a more critical view of prenatal testing not as a test itself but rather for its implications for people with disabilities. They argue that access to prenatal testing could result in pressure to abort fetuses that might be born with disabilities, and that these pressures rely on eugenics interests and ableist stereotypes. This selective abortion relies on the ideas that people with disabilities cannot live desirable lives, that they will not be able to flourish and that they are burdens to their families. Activists argue that inevitably societal perceptions about disabilities will influence the decision to terminate a pregnancy. For this reason, Marsha Saxton suggests that families should question whether or not they are relying on real, factual information about people with disabilities or on stereotypes if they decide to abort a fetus with a disability.
=== Societal pressures ===
Amniocentesis has become the standard of care for prenatal care visits for women who are "at risk" or over a certain age. The wide use of amniocentesis has been defined as consumeristic. and some argue that this can be in conflict with the right to privacy, Most obstetricians (depending on the country) offer patients the AFP triple test, HIV test, and ultrasounds routinely. However, almost all women meet with a genetic counselor before deciding whether to have prenatal diagnosis. It is the role of the genetic counselor to accurately inform women of the risks and benefits of prenatal diagnosis. Genetic counselors are trained to be non-directive and to support the patient's decision. Some doctors do advise women to have certain prenatal tests and the patient's partner may also influence the woman's decision.
== Legal ==
In August 2023, the Iranian government banned import and manufacture of tests kits required for first screening trimester tests, it will plague the population according to society of medicine in genetic انجمن ژنتیک پزشکی ایران. Iranian state welfare organization had a genetics condition program since 1997.
== See also ==
Amniocentesis
Amniotic stem cell bank
Amniotic stem cells
Chorionic villi
Genetic counseling
Newborn screening
== Notes and references ==
== External links ==
Our Bodies Ourselves chapter on Prenatal Testing and Disability Rights
Prenatal Tests and Why Are They Important? – March Of Dimes | Wikipedia/Prenatal_diagnosis |
A wastebasket diagnosis or trashcan diagnosis is a vague diagnosis given to a patient or to medical records department for essentially non-medical reasons. It may be given when the patient has an obvious but unidentifiable medical problem, when a doctor wants to reassure an anxious patient about the doctor's belief in the existence of reported symptoms, when a patient pressures a doctor for a label, or when a doctor wants to facilitate bureaucratic approval of treatment. It differs from a diagnosis of exclusion in that a wastebasket diagnosis is a diagnostic label of doubtful value, whereas a diagnosis of exclusion is characterized by the diagnosis being arrived at indirectly (through the process of excluding all other plausible causes). Unlike a vague wastebasket diagnosis, the diagnostic label arrived at through a process of exclusion may be precise, accurate, and helpful.
The term may also be used pejoratively to describe disputed medical conditions. In this sense, the term implies that the condition has not been properly classified. It can carry a connotation that the prognosis of individuals with the condition are more heterogeneous than would be associated with a more precisely defined clinical entry. As diagnostic tools improve, it is possible for these kinds of wastebasket diagnoses to be properly defined and reclassified as clinical diagnoses.
Wastebasket diagnoses are often made by medical specialists, and referred back to primary care physicians for long term management.
== Examples ==
Common wastebasket diagnoses include:
Chronic fatigue syndrome (when applied to fatigue of unknown origin)
Fibromyalgia (when applied to pain of unknown origin)
Subclinical hypothyroidism
Seronegative rheumatoid arthritis
Irritable bowel syndrome
Chronic pain syndromes
Interstitial cystitis ("bladder pain syndrome")
Costochondritis (when applied to chest pain of an unknown source)
Gastroesophageal reflux (when applied to chest pain of an unknown source)
Shin splints, which is a label given to multiple separate conditions
Reactive hypoglycemia has been used as a trashcan diagnosis for people who complain about normal physiological reactions to being hungry. In these cases, the labels are offered when nothing more serious can be identified. Bronchitis may be used as a trashcan diagnosis to label sick children.
A diagnosis like fibromyalgia is not invariably a wastebasket diagnosis; many "trashcan" labels can be applied specifically and appropriately, and they are considered wastebasket diagnoses only when they are applied to pain or other common symptoms whose origin or cause cannot be determined.
Different specialists provide different wastebasket labels to the same sets of symptoms. For example, in response to a person with chronic pain but no detected medical pathology, a rheumatologist might label the symptoms fibromyalgia, a specialist in physical medicine and rehabilitation might diagnose regional pain, and an orthopedic surgeon will call it chronic pain syndrome. Other specialties similarly focus on their specialty, producing the wastebasket labels from their own fields.
Some diagnoses are being used as trashcan diagnoses in response to unintentional incentives. For example, government-run schools in the United States get additional funding for providing services to students with autism spectrum disorders, so some children with atypical behavior patterns are labeled as having ASD so the school can more easily obtain funding for special education services.
== History ==
Fake diagnoses are not a modern invention. Medicine around the world has a long history of using and abusing the concept of trashcan diagnoses, from "rectifying the humors" to marthambles to neurasthenia to garbled Latin-sounding names which were made up to impress the patient's family.
== Management ==
The medical community is often split on the best approach to managing a wastebasket diagnosis. The biggest challenge for a physician is maintaining their interest and desire to see the patient through their illness. Antidepressants and cognitive therapies are commonly employed, speaking to the possible emotional basis that underpins these diagnoses or the physician's effort to psychopathologize the patient whose disorder the physician can not identify.
== See also ==
Diagnosis of exclusion, the diagnosis given to a patient when all other plausible options have been ruled out
Bright's disease
== References == | Wikipedia/Wastebasket_diagnosis |
In epidemiology, a clinical case definition, a clinical definition, or simply a case definition lists the clinical criteria by which public health professionals determine whether a person's illness is included as a case in an outbreak investigation—that is, whether a person is considered directly affected by an outbreak. Absent an outbreak, case definitions are used in the surveillance of public health in order to categorize those conditions present in a population (e.g., incidence and prevalence).
== How are they used ==
A case definition defines a case by placing limits on time, person, place, and shared definition with data collection of the phenomenon being studied. Time criteria may include all cases of a disease identified from, for example, January 1, 2008 to March 1, 2008. Person criteria may include age, gender, ethnicity, and clinical characteristics such as symptoms (e.g. cough and fever) and the results of clinical tests (e.g. pneumonia on chest X-ray). Place criteria will usually specify a geographical entity such as a town, state, or country, but may be as small as an institution, a school class, or a restaurant meal session. Shared definition of the phenomenon impacts the study methods and ensures terminology is used in a consistent manner.
Case definitions are often used to label individuals as suspect, probable, or confirmed cases. For example, in the investigation of an outbreak of pneumococcal pneumonia in a nursing home the case definition may be specified as:
Suspect Case: All residents of Nursing Home A with onset of cough and fever between January 1, 2008 and February 1, 2008.
Probable Case: Meet the suspect case definition plus have pneumonia on chest X-ray.
Confirmed Case: Meet the probable case definition plus have pneumococcal infection confirmed by blood culture or other isolation of pneumococci from normally sterile site.
By creating a case definition, public health professionals are better equipped to study an outbreak and determine possible causes.
As investigations proceed, a case definition may be expanded or narrowed, a characteristic of the dynamic nature of outbreak investigations. At any given time, the case definition is supposed to be the gold standard to diagnose a given disease. A sensitive case definition, often applied early in an outbreak, will capture all cases, but will include many non-cases. A specific case definition, usually applied after the outbreak is considered more well understood, will exclude most non-cases, but will also exclude some actual cases.
== Diagnostic criteria ==
The term diagnostic criteria designates a case definition with a specific combination of signs, symptoms, and test results that the clinician uses to attempt to determine the correct diagnosis.
Some examples of diagnostic criteria are:
Amsterdam criteria for hereditary nonpolyposis colorectal cancer
McDonald criteria for multiple sclerosis
ACR criteria for systemic lupus erythematosus
== Clinical definitions ==
When diagnostic criteria are universally accepted they can be considered a "clinical definition" because they define the limits of the affected population, determining which patients are inside and outside of the set.
A clinical definition should be regarded as a statistical analysis tool, and not a substitute for a pathological definition when this is required. Posthumous diagnosis allows to establish the sensitivity and specificity of the clinical definitions.
== See also ==
Public Health
Epidemiology
Outbreak
Sensitivity and specificity
Diagnostic criteria
== References == | Wikipedia/Clinical_case_definition |
The Merck Manual of Diagnosis and Therapy, referred to as The Merck Manual,
is the world's best-selling medical textbook, and the oldest continuously published English language medical textbook. First published in 1899, the current print edition of the book, the 20th Edition, was published in 2018. In 2014, Merck decided to move The Merck Manual to digital-only, online publication, available in both professional and consumer versions; this decision was reversed in 2017, with the publication of the 20th edition the following year. The Merck Manual of Diagnosis and Therapy is one of several medical textbooks, collectively known as The Merck Manuals, which are published by Merck Publishing, a subsidiary of the pharmaceutical company Merck Co., Inc. in the United States and Canada, and MSD (as The MSD Manuals) in other countries in the world. Merck also formerly published The Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals.
== History and editions ==
The first edition of The Merck Manual was published in 1899 by Merck & Co., Inc. for physicians and pharmacists and was titled Merck's Manual of the Materia Medica. The 192 page book which sold for US $1.00, was divided into three sections, Part I ("Materia Medica") was an alphabetical listing of all known compounds thought to be of therapeutic value with uses and doses; Part II ("Therapeutic Indications") was an alphabetical compendium of symptoms, signs, and diseases with a list of all known treatments; and Part III ("Classification of Medicaments (sic) According to their Physiologic Actions") was a listing of therapeutic agents according to their method of action or drug classification. Many of the terms used are now considered archaic, such as abasia, astasia, errhines and rubefacients - sternutatories, and many of the agents listed are now not considered to be standard therapeutic agents but were considered useful at the time, including poisonous compounds such as mercury, lead, strychnine and arsenic. There were 108 remedies listed for indigestion (dyspepsia), including alcohol, arsenic, cocaine, gold chloride, mercury, morphine, nux vomica, opium, silver nitrate, strychnine, and "Turkish baths (for malaise after dining out)".: 118 Bismuth, calcium, magnesium salts were also on the list, which are ingredients found in many modern gastrointestinal treatments available today. Arsenic was recommended for over 100 illnesses including anemia, diarrhea, hydrophobia, elephantiasis, and impotence. The formulas include "aletris cordial", a "uterine tonic and restorative", which contained "aletris farinosa or True Unicorn combined with aromatics".: 15 The manufacturer, Rio Chemicals of St. Louis was clear to differentiate the inclusion of true unicorn rather than false unicorn in its preparation.
The earliest versions did contain drugs that are still in use today for the same purposes, for example digitalis for heart failure;,: 90 : 166 salicylates for headache: 166 rheumatism: 225 and fever,: 124 : 227 nitroglycerin for cardiac angina pectoris;,: 88 and bismuth salicylate for diarrhea: 114
Merck also began publishing Merck's Archives of the Materia Medica, a monthly journal consisting of papers related to drugs and uses, which was available for an annual subscription of US $1.00.
The second edition of The Merck Manual was published in 1901, was expanded to 282 pages and included new sections on poisons and antidotes, tables and conversion charts, and a detailed explanation of the metric system.
The 5th edition, published in 1923 was delayed due to paper shortages caused by World War I, and the release of the 6th edition was delayed until 1934 due to the Stock Market Crash. The editor of that edition, Dr. M. R. Dinkelspiel had overseen the growth and reorganization of the Manual to discuss specific diseases, diagnosis and treatment options, and external specialists reviewed each section. The 8th edition of the Manual was delayed by World War II until 1950.
The 13th edition, released in 1977 was the first time the textbook was produced using magnetic tape and IBM punch cards, the previous version having been typed on a manual typewriter. The Centennial (17th) Edition published in 1999 included a separate facsimile version of the 1899 1st edition.: 113
It is reported that both Admiral Richard E. Byrd took the book with him on his expedition to the South Pole in 1929 and Albert Schweitzer had a copy of The Merck Manual with him at his hospital mission in Africa in 1913.
The recommended doses given in Part 1 of 1901 edition of The Manual were for adults when given by mouth. It included the following dose adjustment recommendations:
=== Print editions of The Merck Manual ===
1899
1901
1905
1911
1923
1934
1940
1950
1956
1961 (There were two printings in 1961, June and Nov; a third in Aug 1962 and a fourth in June 1963)
1966
1972
1977
1982
1984
1992 (2 million copies sold)
1999 (Centennial Edition)
2006
2011
2018 (current print edition)
== Content ==
The Merck Manual is organized, like many internal medicine textbooks, into organ systems (see List of Medical Topics below) which discuss each major diseases of that system, covering diagnosis (signs, symptoms, tests), prognosis and treatment. It provides a comprehensive yet concise compendium of medical knowledge into about 3500 pages, by emphasizing practical information of use to a practicing physician. In addition to 24 sections covering medical topics, it includes a pharmacology section listing drugs by generic and brand name, a list of drug interactions and a pill identifier, a News and Commentary section, videos on procedures and examination techniques, quizzes and case histories, clinical calculators, conversion tables and other resources. The text is characterized by the combination of conciseness, completeness, and being up-to-date. It is updated continuously by an independent editorial board and over 300 peer reviewers that contribute to the textbook, which goes through an average of 10 revisions by both internal and external reviewers before publication. The internal editorial staff consists of 4 physician reviews, one executive editor and four non-medical lay editors. The latest version has been translated into 17 languages. In addition to the online version, The Merck Manual Professional Edition is also available as a mobile app in both iOS and Android platforms, produced by Unbound Medicine, Inc.
=== Medical topic sections (online edition) ===
K1. Cardiovascular Disorders
2. Clinical Pharmacology
3. Critical Care Medicine
4. Dental Disorders
5. Dermatological Disorders
6. Ear, Nose, and Throat Disorders
7. Endocrine and Metabolic Disorders
8. Eye Disorders
9. Gastrointestinal Disorders
10. Genitourinary Disorders
11. Geriatrics
12. Gynecology and Obstetrics
13. Hematology and Oncology
14. Hepatic and Biliary Disorders
15. Immunology; Allergic Disorders
16. Infectious Diseases
17. Injuries; Poisoning
18. Musculoskeletal and Connective Tissue Disorders
19. Neurologic Disorders
20. Nutritional Disorders
21. Pediatrics
22. Psychiatric Disorders
23. Pulmonary Disorders
24. Special Subjects
== Awards and recognition ==
The Merck Manual was listed in the 2003 Brandon Hill "Selected List of Books and Journals for the Small Medical Library" as a recommended medical textbook for diagnosis, geriatrics, and patient education.
The Merck Manuals were awarded five 2015 eHealthcare Leadership Awards including a Gold Award for Best Healthcare Content for Professionals, and a Distinction Award: Best Overall Healthcare Site, Consumer at the nineteenth annual Healthcare Internet Conference held in November 2015 in Orlando, Florida.
Merck Publishing offers resources for "The Merck Manual Award" provided annually to outstanding medical students. The qualifications for the award are determined by each medical school. Medical schools that give this award include University of North Carolina School of Medicine, University of Central Florida School of Medicine and the University of Illinois School of Medicine.
== Other Merck manuals ==
=== The Merck Manual of Geriatrics ===
First published in 1990, sections of The Merck Manual were made into a separate volume dealing with diseases and management of illnesses in the elderly. It has gone through three print editions, the last version published in 2000. Since the transition of The Merck Manual in 2015 to a web only based version, the Manual of Geriatrics is accessible through the Professional and Consumer portals of the online text. A search engine on the Merck Manual site allows searches limited to the contents of The Merck Manual of Geriatrics.
=== The Merck Manual of Patient Symptoms ===
The Merck Manual of Patient Symptoms is a concise, pocket size reference guide intended for medical students and allied health care professionals in training. It covers symptoms, diagnosis and treatment.
== Consumer editions ==
=== The Merck Manual of Medical Information – Home Edition ===
The Merck Manual of Medical Information – Home Edition was published in 1997 and was a re-edited version of the Professional version using less technical language intended for patients, caregivers and people interested in medical topics without training in health fields. This edition sold over 2 million copies. The Second Home Edition was released in 2003, and the third edition was published in 2009 as The Merck Manual Home Health Handbook, and sold over 4 million copies. Since 2015 the Consumer version content is available only via the online Merck Manual website. A condensed consumer-oriented version was published at The Merck Manual Go-To Home Guide for Symptoms in 2013.
=== The Merck Manual of Women's and Men's Health ===
In 2014, The Second Home Edition was extracted from the Professional version of The Manual and published as The Merck Manual of Women's and Men's Health
=== The Merck Manual of Health & Aging ===
A consumer version of The Merck Manual of Geriatrics was released in print in 2004 as The Merck Manual of Health & Aging, which included information on aging and the care of older people in non-technical language for the public. The content was incorporated into the Consumer version of the online Merck Manual in 2015.
== Veterinary medicine ==
=== The Merck Veterinary Manual ===
The Merck Veterinary Manual has been published since 1955 for professional veterinarians and other professionals in the veterinary field. It is the most widely used veterinary medicine textbook. It is still published in a print version and the 11th edition is scheduled for release on July 12, 2016. The Merck Veterinary Manual has been translated into seven languages, including Croatian, French, Italian, Japanese, Portuguese, Romanian and Spanish. It is also available as a mobile app in both iOS and Android platforms, as well as an online version.
=== Merck/Merial Manual for Pet Health (Home Edition) ===
A consumer version written in non-technical language as a joint publication between Merck and Merial released as the Merck/Merial Manual for Pet Health (Home Edition) was first published in 2007. ISBN 978-0911910995. A consumer oriented version of the Merck Veterinary Manual is available online as the Pet Health Edition.
== Notes ==
== See also ==
The Merck Index
== References ==
== External links ==
Merck Manuals full text online:
Professional edition
Home edition
Merck Manual Mobile Apps | Wikipedia/Merck_Manual_of_Diagnosis_and_Therapy |
Self-diagnosis is the process of diagnosing, or identifying, medical conditions in oneself. It may be assisted by medical dictionaries, books, resources on the Internet, past personal experiences, or recognizing symptoms or medical signs of a condition that a family member previously had or currently has.
Depending on the nature of an individual's condition and the accuracy of the information they access, self-diagnoses can vary greatly in their safety. Due to self-diagnoses' varied accuracy, public attitudes toward self-diagnosis include denials of its legitimacy and applause of its ability to promote healthcare access and allow for individuals to find solidarity and support. Furthermore, external influences such as marketing, social media trends, societal stigma around disease, and to which demographic population one belongs greatly affect the use of self-diagnosis.
== Appropriate use ==
Self-diagnosis is prone to error and may be potentially dangerous if inappropriate decisions are made, which can stem from broad or inaccurately applied symptoms as well as confirmation bias. Because of the risks, self-diagnosis is officially discouraged by physicians and patient care organizations. Physicians are also discouraged from engaging in self-diagnosis due to potential lack of objectivity. An inaccurate self-diagnosis—a misdiagnosis—can result in improper health care, including using the wrong treatment or not seeking care for a serious condition that was under-diagnosed. Further concerns include undermining physician authority, lacking an unbiased view of oneself, overestimating one's symptoms, or adopting a state of denial about these symptoms.
However, self-diagnosis may be appropriate under certain circumstances. The use of over-the-counter (non-prescription) medications is often involved in self-diagnosis for conditions that are unlikely to be serious and have a low risk of harm by incorrect medication. Some conditions are more likely to be self-diagnosed, especially simple conditions such as head lice and skin abrasions or familiar conditions such as menstrual cramps, headache or the common cold. During the COVID-19 pandemic, self-diagnosis through the use of self-testing kits became commonplace and endorsed by governments, the Centers for Disease Control and Prevention (CDC) providing guidelines by which the American public should go about self-testing.
Complex conditions, including conditions like ADHD in adults and autism spectrum disorder (ASD), are more difficult to self-diagnose accurately. Such self-diagnoses are complicated by multiple factors, such as direct-to-consumer marketing of medications, which is widely criticized for promoting inappropriate self-diagnosis. Additionally, especially among younger generations, access to social media and the Internet has increased the ease with which individuals can access symptom lists and self-diagnose themselves with these complex conditions, potentially inaccurately.
== Influencing factors ==
=== Marketing ===
==== Direct-to-consumer advertising ====
Pharmaceutical and medical companies consider self-diagnosis in their marketing strategies as a means of connecting with their consumer base. Pharmaceutical companies have put a considerable amount of funding into marketing campaigns, which a 2007 study linked to an increase in seemingly healthy patients seeking out more diagnostic screenings. Specific marketing campaigns, termed disease awareness campaigns, disseminate information about a certain condition to consumers, rather than specific patients already diagnosed, and promote specific drugs developed by a pharmaceutical company as a remedy for said condition.
Often, these campaigns are proliferated through the creation of unbranded websites with checklists of ambiguous and broad symptoms that are stated to be representative of a specific disease, which has caused the American Medical Association (AMA) to warn doctors of this form of direct-to-consumer advertising. The AMA's concern was that the symptom checklists state that a widely applicable set of symptoms are indicative of a specific condition, improperly educating consumers about the disease and convincing them to adopt that diagnosis for a condition they may not have. Ebling assesses that naming the disease gives it an increased authenticity that merits a medical solution, which the websites present to be a specific, branded drug, all without appearing to be obviously sponsored. Medical professionals have taken concern with this promotion of a medical solution, accusing it to be a means of profiting off of consumers who are attempting to treat a condition they may not have. Doctors further criticize these campaigns for being misleading because they also often use language that celebrates the agency a patient is assuming over themselves by gaining this knowledge and seeking out a solution.
These ambiguous symptom checklists have been mirrored by advertisements by medical brands on TikTok that present their content as traditional influencer posts, then asking users if they exhibit any symptoms that could be applied to various conditions, such as “Are you nervous?” From this point, like the websites, these advertisements encourage users to empower themselves to address a specific condition they might have by using the company's services, which may include consultations or specific medications.
However, there is no consensus among studies as to whether exposure to direct-to-consumer advertising leads to a higher rate of requesting brand-name drugs.
==== Premenstrual dysphoric disorder (PMDD) ====
The pharmaceutical industry has also played a role in promoting drugs that treat premenstrual dysphoric disorder (PMDD). Sarafem, a differently-branded version of Prozac, which is used to treat depression, was created during the time when Prozac's patent was soon to expire. United States patent law required Eli Lilly and Company, Prozac's developer, to present a new use for the drug to extend their patent. Ebling states that Eli Lilly sought out doctors who would support the designation of PMDD as its own disease, resulting in FDA recognition of the condition and approval of Sarafem to serve as a treatment for it. The company succeeded in avoiding the competition that would have been generated by the production of a generic version of Prozac.
Since then, PMDD has become more commonly recognized, now having its own category in the DSM-V. However, it is still not consistently recognized among healthcare professionals due to some doctors still considering it a contested condition.
==== Self-diagnosis kits ====
Self-diagnosis itself is becoming a more lucrative industry given the popularity of self-testing kits. While these are most commonly associated with COVID-19, self-testing kits exist for a wide range of conditions, such as prostate cancer, Alzheimers, and menopause. Though healthcare professionals warn of their potential to be unreliable, these kits appeal to the public due to their easy use, convenience, and inexpensiveness. Despite the fact that doctors warn that they cannot necessarily conclusively diagnose a condition nor encapsulate a disease's full complexity, the industry creating these tests is growing in profitability.
==== Smartphone applications ====
Developers of medical diagnosis applications can also be fueled by commercial interests. A number of applications receive monetary returns for acting as referrals to health insurance companies, doctor's offices, and pharmacies. These forms of monetary compensation are often not mentioned in the app's contents or general overview.
=== The role of stigma ===
==== Public stigma ====
Though self-diagnosis may work to counter the stigma associated with disease, it faces its own share of public disapproval. Those who publish posts encouraging self-diagnosis do not always have verified medical credentials even though they often present their posts as providing expert advice. As a result, self-diagnoses are not always accepted by the public because they can be seen as misleading (see later section on Use of Social Media and Webpages).
Medical experts are concerned that self-diagnosis can overemphasize and enforce stereotypical perceptions of a disorder, positing that social media posting can ignore the medical complexity of physical and mental health disorders.
==== Support ====
Self-diagnosis can provide a reprieve from societal stigma surrounding mental illness. An individual who diagnoses themselves with a condition is able to seek out online communities of others with the same condition, providing them with a sense of recognition and belonging. On TikTok, those who deem themselves to exhibit traits of conditions such as obsessive-compulsive disorder, dissociative identity disorder, and ASD have found communities of support. Similarly, specific online communities exist for autistic people, which autistic adults report as assisting with combatting feelings of not fitting in prior to being able to identify with the disorder. Communities for health problems not necessarily recognized by the medical establishment also exist online with the same purpose of providing support and understanding.
Relatedly, self-diagnosis can foster a sense of self-understanding that promotes self-acceptance in the face of harsh social norms. This has been particularly influential for autistic people. Autistic people may display different behaviors than non-autistic individuals, prompting autistic people to feel “othered.” Without an explanation as to why they may feel different than others, they have a higher likelihood of feeling confused and having low self-esteem, studies linking delayed diagnosis in autistic individuals with higher rates of anxiety, depression, and suicidal tendencies. However, advocates for self-diagnosis posit that with an explanation, autistic people can understand why they may feel different, alleviating this burden. This understanding can also promote a greater comprehension of their strengths, weaknesses, and symptoms, allowing them to better navigate everyday life.
Additionally, social media users argue that the prevalence of self-diagnosis has promoted an open discussion surrounding mental health, working to remove the stigmas from various diseases and conditions. Online discussion of self-diagnosis has also been espoused as a tool to provide the benefits of a diagnosis to those who face financial or geographic boundaries to receiving a professional diagnosis.
=== Prevalence of the internet ===
The Internet and other connected resources have become popular places to start the self-diagnosis process. The availability of medical information online allows patients to have greater access to medical knowledge.
==== Smartphone applications ====
There are a multitude of medical and health apps available on both the Apple App Store and Google Play Store that can be used for self-diagnosing purposes. Approximately 20% of smartphone users have a health-related application downloaded onto their device.
Experts have criticized the creators of such medical apps as promoting a false sense of credibility in order to increase the number of downloads. For example, these apps will often use widely recognized medical symbols such as the red cross or a stethoscope on their thumbnails and diagnostic pages, as well as emphasize terms such as "algorithm", "sensors", and "computer" in the diagnosis process to convey a sense of scientific objectivity. Lupton and Jutel, in their analysis of 35 self-diagnosis apps, argue that these techniques portray self-diagnosis apps as having an augmented authority in determining diagnoses.
In relation to the amount of power that health-related smartphone apps have in determining a diagnosis, researchers have emphasized the importance of using such apps judiciously. In order to maintain a balance between patient agency and professional medical authority, many self-diagnosis applications remind users of the incomplete medical certainty of the diagnosis provided and to encourage them to obtain secondary professional medical advice from a doctor or specialist. Additionally, the sources of application diagnosis information can often be difficult to determine or verify. There have been cases where certain health-related applications made claims to receiving significant contributions of content from prestigious educational institutions to increase downloads, but little information was provided as to the extent and verifiability of such contributions.
==== Use of chatbots ====
A recent technology that has started to take hold in the realm of self-diagnosis is the utilization of chatbot-based symptom checker (CSC) applications. CSCs were designed to combat the problem of extended wait times to see a doctor and the unavailability of punctual medical advice. Patients have also utilized chatbots to determine severity of their potential diagnosis before going through the process of seeing a doctor and incurring the financial strain that can come with it. Chatbots utilize artificial intelligence (AI) in order to assist patients in their medical concerns during all hours of the day. The operational mechanism of CSCs is a text-to-text system, where the chatbot asks a series of health-related questions in order to determine a diagnosis. The effectiveness of chatbots in the process of self-diagnosis is still highly debated among researchers.
Studies have found that users have varying opinions on the required input for chatbot websites and applications. In some cases, chatbots offer limited space to input multiple symptoms and locations of symptoms for diagnosis determination. Interfaces have presented users with a "pre-structured symptom selection list" which has forced users to be more general with their responses than they would prefer. Other users have felt that questions asked by self-diagnosing chatbots require too much detail, leaving them confused or overwhelmed.
People are also using AI chatbots for self-diagnosis.
==== Social media ====
Social media has started to take on a particularly important role in the process of self-diagnosis, especially the diagnosis of mental health disorders. Social media users seeking answers often self-diagnose after resonating with a particular trait of a disorder that has been mentioned in a social media post. Self-diagnosis through social media is generally more prevalent in individuals who have obsessive–compulsive disorder (OCD), anxiety, depression, or other complex trauma.
Increased access to the ability to self-diagnose via the Internet can have benefits for patient-doctor communication. By assessing a patient's self-diagnosis, a medical professional can see with which specific traits of a disease the patient identified and can work with them to create a potentially more effective diagnosis and treatment.
Self-diagnosis through social media may have some drawbacks associated with it. Some social media postings can simplify a diagnosis, leading to a spread of misinformation about the emphasized disease. Some online self-diagnosis tests state that common, broad symptoms, like anxiety and mood swings, are definite indicators of specific disorders, causing social media users to report such posts for inaccuracy. People who publish health-related posts on the self-diagnosis of health issues may not have verified medical credentials even though they have posed their post as providing expert advice. Journalist and author Doreen Dodgen-Magee considers self-diagnosis tests to work due to confirmation bias, which was witnessed when there was a statistical increase in the number of teenage girls approaching their doctors with a concern they had Tourette syndrome after multiple videos naming broad symptoms as signs of Tourettes went viral on TikTok.
== Impact on varying demographics ==
=== Ethnic and socio-economic backgrounds ===
==== Vulnerable demographics ====
Ani and Bazargan from the Department of Family Medicine and Research Centers in Minority Institutions found that accessibility, affordability, continuity of medical care, and financial strains are the primary factors that determine whether patients choose to use self-diagnose or formal diagnoses. By utilizing the Behavioral Model for Vulnerable Populations, the study sampled over 1,394 African American and Latino households. Apart from their minority ethnic status, the households also had the following intersectional identities: 89% were female, 50% were single-parent households, 60% had less than a high school education, 73% were unemployed, and 33% were non-English speakers. Throughout the research process, 43% of the participants reported that a physician had never diagnosed at least one of their illnesses. The study's results note the significant influence of socio-economic backgrounds on using self-diagnosis as a more efficient and accessible medical solution. The study, however, also raised a concern regarding self-diagnosis in minority communities. Results show that the possibility of seeking self-diagnosis was far more likely when there were noticeable symptoms than when the symptoms were non-noticeable. If regular health checks were not offered to these demographics, they most likely would not realize their health conditions until they become irreversible. Commenting on this unrepairable outcome, Pete Wharmby, author of two books about autism, expressed frustration for non-white autistic people: "Autism is often undiagnosed, especially in demographics that are not young white males. This means self-diagnosis is often a requirement to get an official diagnosis. Some cannot get this dx, but still, deserve to be heard."
==== COVID-19 pandemic ====
COVID-19 also contributed to the increase in self-diagnosis among minority populations. Samantha Artiga from the Kaiser Family Foundation reports that when statistics were corrected to account for differences in age by race and ethnicity, it became clear that Black, Hispanic, AIAN, and NHOPI persons had the highest rates of COVID-19 cases and deaths in compared to white people. These demographics had a correlated surge in self-diagnosed COVID-19 cases. The Conversation highlights how using internet resources to evaluate COVID-19 symptoms and self-triage was promoted during the pandemic, exhibiting how online health information gained new significance.
==== The benefits and costs for vulnerable demographics ====
This trend of turning to self-diagnosis among minorities can be potentially dangerous, given the unfiltered and unauthorized information online. A report from Psychreg criticizes self-diagnosis for its potentially hazardous nature, reporting that 61% of the advice on social media (specifically, TikTok) is incorrect. The Camber Mental Health Organization also notes the potential danger of online self-diagnosis, indicating that influencers without proper license offer public advice that can further jeopardize the vulnerable demographics.
Other studies present non-dangerous aspects of self-diagnosis for these populations. A new study published by the Department of Public Health and Primary Care at Leiden University Medical Centre explains that patients use the internet to find reliable medical information about minor ailments and thus prevent symptoms from worsening if immediate health care cannot be provided. After surveying 1,372 participants, the study finds that most patients utilize this symptom-based approach. Suppose the patients expect the potential diagnosis to be more lethal. In that case, they tend to conduct further research on the internet to verify their suspicions about their condition.
=== Age ===
Younger generations are more likely to perform self-diagnosis. Kwakernaak explains their findings of a positive correlation between self-diagnosing accuracy and the age variable. There was an inverse relationship between age and accuracy; the younger the patient was, the more likely they would find high-quality websites for information. Kunst from Statista conducts a survey that presents the frequency data of each age group using apps for self-diagnosis. The group aged 18–19 years old were almost two times more likely to use the Internet regularly or occasionally compared to all the other age groups. The data showed that 10% of those in that age group used self-diagnosis regularly compared to 4% of respondents older than 61. The study posits that this frequent usage may explain why the younger population had more experience searching for high-quality websites and receiving accurate diagnoses. However, Kunst notes that this conclusion may be biased as the survey was conducted online and thereby only targeted respondents who had frequent access to the Internet.
== See also ==
Cure
Cyberchondria
Home remedy
Related mental disorders:
Delusional parasitosis
Hypochondria
Medical students' disease
Morgellons
Therapy
== References == | Wikipedia/Self-diagnosis |
A medical algorithm is any computation, formula, statistical survey, nomogram, or look-up table, useful in healthcare. Medical algorithms include decision tree approaches to healthcare treatment (e.g., if symptoms A, B, and C are evident, then use treatment X) and also less clear-cut tools aimed at reducing or defining uncertainty. A medical prescription is also a type of medical algorithm.
== Scope ==
Medical algorithms are part of a broader field which is usually fit under the aims of medical informatics and medical decision-making. Medical decisions occur in several areas of medical activity including medical test selection, diagnosis, therapy and prognosis, and automatic control of medical equipment.
In relation to logic-based and artificial neural network-based clinical decision support systems, which are also computer applications used in the medical decision-making field, algorithms are less complex in architecture, data structure and user interface. Medical algorithms are not necessarily implemented using digital computers. In fact, many of them can be represented on paper, in the form of diagrams, nomographs, etc.
== Examples ==
A wealth of medical information exists in the form of published medical algorithms. These algorithms range from simple calculations to complex outcome predictions. Most clinicians use only a small subset routinely.
Examples of medical algorithms are:
Calculators, e.g. an on-line or stand-alone calculator for body mass index (BMI) when stature and body weight are given;
Flowcharts and drakon-charts, e.g. a binary decision tree for deciding what is the etiology of chest pain
Look-up tables, e.g. for looking up food energy and nutritional contents of foodstuffs
Nomograms, e.g. a moving circular slide to calculate body surface area or drug dosages.
A common class of algorithms are embedded in guidelines on the choice of treatments produced by many national, state, financial and local healthcare organisations and provided as knowledge resources for day to day use and for induction of new physicians. A field which has gained particular attention is the choice of medications for psychiatric conditions. In the United Kingdom, guidelines or algorithms for this have been produced by most of the circa 500 primary care trusts, substantially all of the circa 100 secondary care psychiatric units and many of the circa 10 000 general practices. In the US, there is a national (federal) initiative to provide them for all states, and by 2005 six states were adapting the approach of the Texas Medication Algorithm Project or otherwise working on their production.
A grammar—the Arden syntax—exists for describing algorithms in terms of medical logic modules. An approach such as this should allow exchange of MLMs between doctors and establishments, and enrichment of the common stock of tools.
== Purpose ==
The intended purpose of medical algorithms is to improve and standardize decisions made in the delivery of medical care. Medical algorithms assist in standardizing selection and application of treatment regimens, with algorithm automation intended to reduce potential introduction of errors. Some attempt to predict the outcome, for example critical care scoring systems.
Computerized health diagnostics algorithms can provide timely clinical decision support, improve adherence to evidence-based guidelines, and be a resource for education and research.
Medical algorithms based on best practice can assist everyone involved in delivery of standardized treatment via a wide range of clinical care providers. Many are presented as protocols and it is a key task in training to ensure people step outside the protocol when necessary. In our present state of knowledge, generating hints and producing guidelines may be less satisfying to the authors, but more appropriate.
== Cautions ==
In common with most science and medicine, algorithms whose contents are not wholly available for scrutiny and open to improvement should be regarded with suspicion.
Computations obtained from medical algorithms should be compared with, and tempered by, clinical knowledge and physician judgment.
== See also ==
Artificial intelligence in healthcare
Medical guideline
Odds algorithm
== Further reading ==
Johnson, Kathy A.; Svirbely, John R.; Sriram, M.G.; Smith, Jack W.; Kantor, Gareth; Rodriguez, Jorge Raul (November 2002). "Automated Medical Algorithms: Issues for Medical Errors". Journal of the American Medical Informatics Association. 9 (6 Suppl 1): s56 – s57. doi:10.1197/jamia.M1228. PMC 419420. | Wikipedia/Medical_algorithm |
A clinical decision support system (CDSS) is a health information technology that provides clinicians, staff, patients, and other individuals with knowledge and person-specific information to help health and health care. CDSS encompasses a variety of tools to enhance decision-making in the clinical workflow. These tools include computerized alerts and reminders to care providers and patients, clinical guidelines, condition-specific order sets, focused patient data reports and summaries, documentation templates, diagnostic support, and contextually relevant reference information, among other tools. CDSSs constitute a major topic in artificial intelligence in medicine.
== Characteristics ==
A clinical decision support system is an active knowledge system that uses variables of patient data to produce advice regarding health care. This implies that a CDSS is simply a decision support system focused on using knowledge management.
=== Purpose ===
The main purpose of modern CDSS is to assist clinicians at the point of care. This means that clinicians interact with a CDSS to help to analyze and reach a diagnosis based on patient data for different diseases.
In the early days, CDSSs were conceived to make decisions for the clinician literally. The clinician would input the information and wait for the CDSS to output the "right" choice, and the clinician would simply act on that output. However, the modern methodology of using CDSSs to assist means that the clinician interacts with the CDSS, utilizing both their knowledge and the CDSS's, better to analyse the patient's data than either human or CDSS could make on their own. Typically, a CDSS makes suggestions for the clinician to review, and the clinician is expected to pick out useful information from the presented results and discount erroneous CDSS suggestions.
The two main types of CDSS are knowledge-based and non-knowledge-based:
An example of how a clinician might use a clinical decision support system is a diagnosis decision support system (DDSS). DDSS requests some of the patients' data and, in response, proposes a set of appropriate diagnoses. The physician then takes the output of the DDSS and determines which diagnoses might be relevant and which are not, and, if necessary, orders further tests to narrow down the diagnosis.
Another example of a CDSS would be a case-based reasoning (CBR) system. A CBR system might use previous case data to help determine the appropriate amount of beams and the optimal beam angles for use in radiotherapy for brain cancer patients; medical physicists and oncologists would then review the recommended treatment plan to determine its viability.
Another important classification of a CDSS is based on the timing of its use. Physicians use these systems at the point of care to help them as they are dealing with a patient, with the timing of use being either pre-diagnosis, during diagnosis, or post-diagnosis. Pre-diagnosis CDSS systems help the physician prepare the diagnoses. CDSSs help review and filter the physician's preliminary diagnostic choices to improve outcomes. Post-diagnosis CDSS systems are used to mine data to derive connections between patients and their past medical history and clinical research to predict future events. As of 2012, it has been claimed that decision support will begin to replace clinicians in common tasks in the future.
Another approach, used by the National Health Service in England, is to use a DDSS to triage medical conditions out of hours by suggesting a suitable next step to the patient (e.g. call an ambulance, or see a general practitioner on the next working day). The suggestion, which may be disregarded by either the patient or the phone operative if common sense or caution suggests otherwise, is based on the known information and an implicit conclusion about what the worst-case diagnosis is likely to be; it is not always revealed to the patient because it might well be incorrect and is not based on a medically-trained person's opinion - it is only used for initial triage purposes.
=== Knowledge-based ===
Most CDSSs consist of three parts: the knowledge base, an inference engine, and a mechanism to communicate. The knowledge base contains the rules and associations of compiled data which most often take the form of IF-THEN rules. If this was a system for determining drug interactions, then a rule might be that IF drug X is taken AND drug Y is taken THEN alert the user. Using another interface, an advanced user could edit the knowledge base to keep it up to date with new drugs. The inference engine combines the rules from the knowledge base with the patient's data. The communication mechanism allows the system to show the results to the user as well as have input into the system.
An expression language such as GELLO or CQL (Clinical Quality Language) is needed for expressing knowledge artefacts in a computable manner. For example: if a patient has diabetes mellitus, and if the last haemoglobin A1c test result was less than 7%, recommend re-testing if it has been over six months, but if the last test result was greater than or equal to 7%, then recommend re-testing if it has been over three months.
The current focus of the HL7 CDS WG is to build on the Clinical Quality Language (CQL). The U.S. Centers for Medicare & Medicaid Services (CMS) has announced that it plans to use CQL for the specification of Electronic Clinical Quality Measures (eCQMs).
=== Non-knowledge-based ===
CDSSs which do not use a knowledge base use a form of artificial intelligence called machine learning, which allow computers to learn from past experiences and/or find patterns in clinical data. This eliminates the need for writing rules and expert input. However, since systems based on machine learning cannot explain the reasons for their conclusions, most clinicians do not use them directly for diagnoses, reliability and accountability reasons. Nevertheless, they can be useful as post-diagnostic systems, for suggesting patterns for clinicians to look into in more depth.
As of 2012, three types of non-knowledge-based systems are support-vector machines, artificial neural networks and genetic algorithms.
Artificial neural networks use nodes and weighted connections between them to analyse the patterns found in patient data to derive associations between symptoms and a diagnosis.
Genetic algorithms are based on simplified evolutionary processes using directed selection to achieve optimal CDSS results. The selection algorithms evaluate components of random sets of solutions to a problem. The solutions that come out on top are then recombined and mutated and run through the process again. This happens over and over until the proper solution is discovered. They are functionally similar to neural networks in that they are also "black boxes" that attempt to derive knowledge from patient data.
Non-knowledge-based networks often focus on a narrow list of symptoms, such as symptoms for a single disease, as opposed to the knowledge-based approach, which covers the diagnosis of many diseases.
An example of a non-knowledge-based CDSS is a web server developed using a support vector machine for the prediction of gestational diabetes in Ireland.
== Regulations ==
=== History, United States ===
The IOM had published a report in 1999, To Err is Human, which focused on the patient safety crisis in the United States, pointing to the incredibly high number of deaths. This statistic attracted great attention to the quality of patient care. The Institute of Medicine (IOM) promoted the usage of health information technology, including clinical decision support systems, to advance the quality of patient care.
With the enactment of the American Recovery and Reinvestment Act of 2009 (ARRA), there was a push for widespread adoption of health information technology through the Health Information Technology for Economic and Clinical Health Act (HITECH). Through these initiatives, more hospitals and clinics were integrating electronic medical records (EMRs) and computerized physician order entry (CPOE) within their health information processing and storage.
Despite the absence of laws, the CDSS vendors would almost certainly be viewed as having a legal duty of care to both the patients who may adversely be affected due to CDSS usage and the clinicians who may use the technology for patient care. However, duties of care legal regulations are not explicitly defined yet.
With the enactment of the HITECH Act included in the ARRA, encouraging the adoption of health IT, more detailed case laws for CDSS and EMRs were still being defined by the Office of National Coordinator for Health Information Technology (ONC) and approved by Department of Health and Human Services (HHS). A definition of "Meaningful use" has yet to be published.
== Effectiveness ==
The evidence of the effectiveness of CDSS is mixed. There are certain diseases which benefit more from CDSS than other disease entities. A 2018 systematic review identified six medical conditions in which CDSS improved patient outcomes in hospital settings, including blood glucose management, blood transfusion management, physiologic deterioration prevention, pressure ulcer prevention, acute kidney injury prevention, and venous thromboembolism prophylaxis.
A 2014 systematic review did not find a benefit in terms of risk of death when the CDSS was combined with the electronic health record. There may be some benefits, however, in terms of other outcomes.
A 2005 systematic review had concluded that CDSSs improved practitioner performance in 64% of the studies and patient outcomes in 13% of the studies. CDSSs features associated with improved practitioner performance included automatic electronic prompts rather than requiring user activation of the system.
A 2005 systematic review found "Decision support systems significantly improved clinical practice in 68% of trials."' The CDSS features associated with success included integration into the clinical workflow rather than as a separate log-in or screen, electronic rather than paper-based templates, providing decision support at the time and location of care rather than prior, and providing care recommendations.
However, later systematic reviews were less optimistic about the effects of CDS, with one from 2011 stating "There is a large gap between the postulated and empirically demonstrated benefits of [CDSS and other] eHealth technologies ... their cost-effectiveness has yet to be demonstrated".
A five-year evaluation of the effectiveness of a CDSS in implementing rational treatment of bacterial infections for antimicrobial stewardship was published in 2014; according to the authors, it was the first long-term study of a CDSS.
== Challenges to adoption ==
=== Clinical challenges ===
Much effort has been put forth by many medical institutions and software companies to produce viable CDSSs to support all aspects of clinical tasks. However, with the complexity of clinical workflows and the demands on staff time high, care must be taken by the institution deploying the support system to ensure that the system becomes an integral part of the clinical workflow. Some CDSSs have met with varying amounts of success, while others have suffered from common problems preventing or reducing successful adoption and acceptance.
Two sectors of the healthcare domain in which CDSSs have had a large impact are the pharmacy and billing sectors. Commonly used pharmacy and prescription-ordering systems now perform batch-based checking orders for negative drug interactions and report warnings to the ordering professional. Another sector of success for CDSS is in billing and claims filing. Since many hospitals rely on Medicare reimbursements to stay in operation, systems have been created to help examine both a proposed treatment plan and the current rules of Medicare to suggest a plan that attempts to address both the care of the patient and the financial needs of the institution.
Other CDSSs that are aimed at diagnostic tasks have found success, but are often very limited in deployment and scope. The Leeds Abdominal Pain System went operational in 1971 for the University of Leeds hospital. It was reported to have produced a correct diagnosis in 91.8% of cases, compared to the clinicians' success rate of 79.6%.
Despite the wide range of efforts by institutions to produce and use these systems, widespread adoption and acceptance have still not yet been achieved for most offerings. One large roadblock to acceptance has historically been workflow integration. A tendency to focus only on the functional decision-making core of the CDSS existed, causing a deficiency in planning how the clinician will use the product in situ. CDSSs were stand-alone applications, requiring the clinician to cease working on their current system, switch to the CDSS, input the necessary data (even if it had already been inputted into another system), and examine the results produced. The additional steps break the flow from the clinician's perspective and cost precious time.
=== Technical challenges and barriers to implementation ===
Clinical decision support systems face steep technical challenges in a number of areas. Biological systems are profoundly complicated, and a clinical decision may utilise an enormous range of potentially relevant data. For example, an electronic evidence-based medicine system may potentially consider a patient's symptoms, medical history, family history and genetics, as well as historical and geographical trends of disease occurrence, and published clinical data on therapeutic effectiveness when recommending a patient's course of treatment.
Clinically, a large deterrent to CDSS acceptance is workflow integration.
While it has been shown that clinicians require explanations of Machine Learning-Based CDSS, in order to able to understand and trust their suggestions, there is an overall distinct lack of application of explainable Artificial Intelligence in the context of CDSS, thus adding another barrier to the adoption of these systems.
Another source of contention with many medical support systems is that they produce a massive number of alerts. When systems produce a high volume of warnings (especially those that do not require escalation), besides the annoyance, clinicians may pay less attention to warnings, causing potentially critical alerts to be missed. This phenomenon is called alert fatigue.
=== Maintenance ===
One of the core challenges facing CDSS is difficulty in incorporating the extensive quantity of clinical research being published on an ongoing basis. In a given year, tens of thousands of clinical trials are published. Currently, each one of these studies must be manually read, evaluated for scientific legitimacy, and incorporated into the CDSS in an accurate way. In 2004, it was stated that the process of gathering clinical data and medical knowledge and putting them into a form that computers can manipulate to assist in clinical decision-support is "still in its infancy".
Nevertheless, it is more feasible for a business to do this centrally, even if incompletely, than for each doctor to try to keep up with all the research being published.
In addition to being laborious, integration of new data can sometimes be difficult to quantify or incorporate into the existing decision support schema, particularly in instances where different clinical papers may appear conflicting. Properly resolving these sorts of discrepancies is often the subject of clinical papers itself (see meta-analysis), which often take months to complete.
=== Evaluation ===
In order for a CDSS to offer value, it must demonstrably improve clinical workflow or outcome. Evaluation of CDSS quantifies its value to improve a system's quality and measure its effectiveness. Because different CDSSs serve different purposes, no generic metric applies to all such systems; however, attributes such as consistency (with and with experts) often apply across a wide spectrum of systems.
The evaluation benchmark for a CDSS depends on the system's goal: for example, a diagnostic decision support system may be rated based upon the consistency and accuracy of its classification of disease (as compared to physicians or other decision support systems). An evidence-based medicine system might be rated based upon a high incidence of patient improvement or higher financial reimbursement for care providers.
== Combining with electronic health records ==
Implementing EHRs was an inevitable challenge. This challenge is because it is a relatively uncharted area, and there are many issues and complications during the implementation phase of an EHR. This can be seen in the numerous studies that have been undertaken. However, challenges in implementing electronic health records (EHRs) have received some attention. Still, less is known about transitioning from legacy EHRs to newer systems.
EHRs are a way to capture and utilise real-time data to provide high-quality patient care, ensuring efficiency and effective use of time and resources. Incorporating EHR and CDSS together into the process of medicine has the potential to change the way medicine has been taught and practiced. It has been said that "the highest level of EHR is a CDSS".
Since "clinical decision support systems (CDSS) are computer systems designed to impact clinician decision making about individual patients at the point in time that these decisions are made", it is clear that it would be beneficial to have a fully integrated CDSS and EHR.
Even though the benefits can be seen, fully implementing a CDSS integrated with an EHR has historically required significant planning by the healthcare facility/organisation for the CDSS to be successful and effective.
The success and effectiveness can be measured by the increased patient care being delivered and reduced adverse events occurring. In addition, there would be a saving of time and resources and benefits in terms of autonomy and financial benefits to the healthcare facility/organisation.
=== Benefits ===
A successful CDSS/EHR integration will allow the provision of best practice, high-quality care to the patient, which is the ultimate goal of healthcare. Three areas that can be addressed with the implementation of CDSS and Electronic Health Records (EHRs), are:
Medication prescription errors
Adverse drug events
Other medical errors
CDSSs will be most beneficial in the future when healthcare facilities are "100% electronic" in terms of real-time patient information, thus simplifying the number of modifications that have to occur to ensure that all the systems are up to date with each other.
The measurable benefits of clinical decision support systems on physician performance and patient outcomes remain the subject of ongoing research.
=== Barriers ===
Implementing electronic health records (EHR) in healthcare settings incurs challenges; none more important than maintaining efficiency and safety during rollout, but in order for the implementation process to be effective, an understanding of the EHR users' perspectives is key to the success of EHR implementation projects. In addition to this, adoption needs to be actively fostered through a bottom-up, clinical-needs-first approach. The same can be said for CDSS.
As of 2007, the main areas of concern with moving into a fully integrated EHR/CDSS system have been:
Privacy
Confidentiality
User-friendliness
Document accuracy and completeness
Integration
Uniformity
Acceptance
Alert desensitisation
as well as the key aspects of data entry that need to be addressed when implementing a CDSS to avoid potential adverse events from occurring. These aspects include whether:
correct data is being used
all the data has been entered into the system
current best practice is being followed
the data is evidence-based
A service oriented architecture has been proposed as a technical means to address some of these barriers.
=== Status in Australia ===
As of July 2015, the planned transition to EHRs in Australia is facing difficulties. Most healthcare facilities are still running completely paper-based systems; some are in a transition phase of scanned EHRs or moving towards such a transition phase.
Victoria has attempted to implement EHR across the state with its HealthSMART program, but it has cancelled the project due to unexpectedly high costs.
South Australia (SA) however is slightly more successful than Victoria in the implementation of an EHR. This may be because all public healthcare organisations in SA are centrally run.
SA is in the process of implementing "Enterprise patient administration system (EPAS)". This system is the foundation for all public hospitals and health care sites for an EHR within SA, and it was expected that by the end of 2014, all facilities in SA will be connected to it. This would allow for successful integration of CDSS into SA and increase the benefits of the EHR.
By July 2015 it was reported that only 3 out of 75 health care facilities implemented EPAS.
With the largest health system in the country and a federated rather than a centrally administered model, New South Wales is making consistent progress towards statewide implementation of EHRs. The current iteration of the state's technology, eMR2, includes CDSS features such as a sepsis pathway for identifying at-risk patients based upon data input to the electronic record. As of June 2016, 93 of 194 sites in-scope for the initial roll-out had implemented eMR2.
=== Status in Finland ===
The EBMEDS Clinical Decision Support service provided by Duodecim Medical Publications Ltd is used by more than 60% of Finnish public health care doctors.
=== Status in India ===
There have been many recent initiatives in India to promote digital health. New Platforms are emerging in India like Eka.care, Clinisio, Raxa etc, providing EHR integrated clinical decision support.
== Research ==
=== Prescription errors ===
A study in the UK tested the Salford Medication Safety Dashboard (SMASH), a web-based CDSS application to help GPs and pharmacists find people in their electronic health records who might face safety hazards due to prescription errors. The dashboard was successfully used in identifying and helping patients with already registered unsafe prescriptions and later it helped monitoring new cases as they appeared.
== See also ==
Gello Expression Language
International Health Terminology Standards Development Organisation
Medical algorithm
Medical informatics
Personal Health Information Protection Act (a law in force in Ontario)
Treatment decision support (decision support tools for patients)
Artificial intelligence in healthcare
== References ==
== External links ==
Duodecim EBMEDS Clinical Decision Support
Decision support chapter from Coiera's Guide to Health Informatics
OpenClinical Archived 2 February 2020 at the Wayback Machine maintains an extensive archive of Artificial Intelligence systems in routine clinical use.
Robert Trowbridge/ Scott Weingarten. Chapter 53. Clinical Decision Support Systems
Stanford CDSS
Clinical Decision Support Systems: Enhancing Healthcare Through Technology
In today's rapidly advancing healthcare landscape, clinical decision support systems (CDSS) play a pivotal role in improving patient care, enhancing clinical outcomes, and supporting healthcare professionals in making informed decisions. This article explores the concept, benefits, challenges, and future prospects of CDSS.
What is a Clinical Decision Support System (CDSS)?
A Clinical Decision Support System (CDSS) is a computerized tool designed to assist healthcare providers in making clinical decisions by integrating medical knowledge with patient data. These systems utilize algorithms, databases, and patient information to provide tailored recommendations, alerts, and reminders to healthcare professionals at the point of care.
Components of a CDSS:
1. **Knowledge Base**: Contains medical guidelines, protocols, best practices, and clinical rules.
2. **Patient Data Interface**: Integrates with electronic health records (EHR) systems to access patient demographics, medical history, test results, and current medications.
3. **Inference Engine**: Analyzes patient data and applies clinical rules to generate suggestions or alerts based on predefined algorithms.
4. **User Interface**: Presents recommendations, alerts, and relevant information to healthcare providers in a user-friendly format.
Benefits of Clinical Decision Support Systems:
1. **Improved Clinical Decision Making**: CDSS provides evidence-based recommendations, reducing errors and variability in clinical practice.
2. **Enhanced Patient Safety**: Alerts for drug interactions, allergies, and potential adverse events help prevent medical errors and improve patient outcomes.
3. **Efficiency**: Streamlines workflow by providing quick access to relevant information, reducing the time spent on manual data retrieval and analysis.
4. **Cost-Effectiveness**: Helps in optimizing resource utilization, reducing unnecessary tests, treatments, and hospitalizations.
5. **Continuing Education**: Acts as a learning tool by keeping healthcare providers updated with the latest medical research and guidelines.
Challenges in Implementing CDSS:
1. **Integration Complexity**: Integrating CDSS with existing EHR systems and workflows can be challenging and time-consuming.
2. **Data Quality and Interoperability**: Dependence on accurate and complete data is crucial for the effectiveness of CDSS.
3. **User Acceptance**: Resistance to change and unfamiliarity with new technology among healthcare providers.
4. **Alert Fatigue**: Overwhelming healthcare providers with excessive alerts and reminders, leading to desensitization.
5. **Legal and Ethical Issues**: Concerns regarding liability, privacy, and confidentiality of patient data.
Future Trends and Innovations:
1. **Artificial Intelligence and Machine Learning**: Advanced algorithms for predictive analytics, personalized medicine, and real-time decision-making.
2. **Mobile and Cloud-based Solutions**: Remote access and seamless integration across different healthcare settings.
3. **Natural Language Processing**: Enhancing CDSS capabilities to interpret unstructured data such as clinical notes and imaging reports.
4. **Patient-Centered CDSS**: Involving patients in decision-making processes and personalized health management.
Conclusion:
Clinical Decision Support Systems represent a transformative technology in healthcare, offering substantial benefits in clinical practice, patient safety, and healthcare efficiency. While challenges remain in implementation and adoption, ongoing advancements in technology and healthcare delivery are poised to further enhance the capabilities and impact of CDSS in improving overall healthcare outcomes.
In conclusion, CDSS are pivotal tools in the evolving landscape of healthcare technology, enabling healthcare professionals to leverage data-driven insights and medical knowledge effectively at the point of care, ultimately leading to better patient outcomes and enhanced healthcare delivery. | Wikipedia/Clinical_decision_support_system |
A nursing diagnosis may be part of the nursing process and is a clinical judgment about individual, family, or community experiences/responses to actual or potential health problems/life processes. Nursing diagnoses foster the nurse's independent practice (e.g., patient comfort or relief) compared to dependent interventions driven by physician's orders (e.g., medication administration). Nursing diagnoses are developed based on data obtained during the nursing assessment. A problem-based nursing diagnosis presents a problem response present at time of assessment. Risk diagnoses represent vulnerabilities to potential problems, and health promotion diagnoses identify areas which can be enhanced to improve health. Whereas a medical diagnosis identifies a disorder, a nursing diagnosis identifies the unique ways in which individuals respond to health or life processes or crises. The nursing diagnostic process is unique among others. A nursing diagnosis integrates patient involvement, when possible, throughout the process. NANDA International (NANDA-I) is a body of professionals that develops, researches and refines an official taxonomy of nursing diagnosis.
All nurses must be familiar with the steps of the nursing process in order to gain the most efficiency from their positions. In order to correctly diagnose, the nurse must make quick and accurate inferences from patient data during assessment, based on knowledge of the nursing discipline and concepts of concern to nurses.
== NANDA International ==
NANDA International, Inc., formerly known as the North American Nursing Diagnosis Association, is the primary organization for defining, researching, revising, distributing and integrating standardized nursing diagnoses worldwide. NANDA-I has worked in this area for more than 45 years to ensure that diagnoses are developed through a peer-reviewed process requiring standardised levels of evidence, definitions, defining characteristics, related factors or risk factors that enable nurses to identify potential diagnoses in the course of a nursing assessment. NANDA-I believes that it is critical that nurses are required to utilise standardised languages that provide not just terms (diagnoses) but the embedded knowledge from clinical practice and research that provides diagnostic criteria (definitions, defining characteristics) and the related or etiologic factors upon which nurses intervene. NANDA-I terms are developed and refined for actual (current) health responses and for risk situations, as well as providing diagnoses to support health promotion. Diagnoses are applicable to individuals, families, groups and communities. The taxonomy is published in multiple countries and has been translated into 18 languages; it is in use worldwide. As research in the field of nursing continues to grow, NANDA-I continually develops and adds new diagnostic labels.
Nursing diagnoses are a critical part of ensuring that the knowledge and contribution of nursing practice to patient outcomes are found within the electronic health record and can be linked to nurse-sensitive patient outcomes.
== Global ==
The ICNP (International Classification for Nursing Practice) published by the International Council of Nurses has been accepted by the World Health Organization family of classifications. ICNP is a nursing language which can be used by nurses to diagnose.
== Evolution of Nursing Diagnosis ==
Nursing diagnoses have become more structured as nursing education has improved. Diagnoses became more organized as critical thinking and problem-solving skills became more important in nursing. Standardized nursing diagnoses allow nurses to communicate clearly and provide better care.
== Development and Standardization of Nursing Diagnoses ==
Experts constantly update nursing diagnoses to make them better. One way they do this is through the Delphi method, where groups of nursing experts discuss and refine diagnoses over several rounds until they reach an agreement.
The Delphi method helps ensure that nursing diagnoses are clear, useful, and based on research. This method allows experts to improve nursing diagnoses so that nurses can apply them correctly in different healthcare settings. This process keeps nursing diagnoses up to date and relevant for patient care. It also helps promote consistency in how nurses assess and describe patient needs, which is important for communication and care planning.
== Structure ==
The NANDA-I system of nursing diagnosis provides for four categories and each has 3 parts: diagnostic label or the human response, related factors or the cause of the response, and defining characteristics found in the selected patient are the signs/symptoms present that are supporting the diagnosis.
Problem-focused diagnosis
A clinical judgment about human experience/responses to health conditions/life processes that exist in an individual, family, or community. An example of an actual nursing diagnosis is: Sleep deprivation.
Risk diagnosis
Describes human responses to health conditions/life processes that may develop in a vulnerable individual/family/community. It is supported by risk factors that contribute to increased vulnerability. An example of a risk diagnosis is: Risk for shock.
Health promotion diagnosis
A clinical judgment about a person's, family's or community's motivation and desire to increase wellbeing and actualise human health potential as expressed in the readiness to enhance specific health behaviours, and can be used in any health state. An example of a health promotion diagnosis is: Readiness for enhanced nutrition.
Syndrome diagnosis
A clinical judgment describing a specific cluster of nursing diagnoses that occur together, and are best addressed together and through similar interventions. An example of a syndrome diagnosis is: Relocation stress syndrome.
== Process ==
The diagnostic process requires a nurse to use critical thinking. In addition to knowing the nursing diagnoses and their definitions, the nurse becomes aware of defining characteristics and behaviors of the diagnoses, related factors to the diagnoses, and the interventions suited for treating the diagnoses.
Assessment
The first step of the nursing process is assessment. During this phase, the nurse gathers information about a patient's psychological, physiological, sociological, and spiritual status. This data can be collected in a variety of ways. Generally, nurses will conduct a patient interview. Physical examinations, referencing a patient's health history, obtaining a patient's family history, and general observation can also be used to gather assessment data. Patient interaction is generally the heaviest during this evaluative stage.
Diagnosis
The diagnosing phase involves a nurse making an educated judgement about a potential or actual health problem with a patient. Multiple diagnoses are sometimes made for a single patient. These assessments not only include a description of the problem or illness (e.g. sleep deprivation) but also whether or not a patient is at risk of developing further problems. These diagnoses are also used to determine a patient's readiness for health improvement and whether or not they may have developed a syndrome. The diagnoses phase is a critical step as it is used to determine the course of treatment.
Planning
Once a patient and nurse agree of the diagnoses, a plan of action can be developed. If multiple diagnoses need to be addressed, the head nurse will prioritise each assessment and devote attention to severe symptoms and high risk patients. Each problem is assigned a clear, measurable goal for the expected beneficial outcome. For this phase, nurses generally refer to the evidence-based Nursing Outcome Classification, which is a set of standardised terms and measurements for tracking patient wellness. The Nursing Interventions Classification may also be used as a resource for planning.
Implementation
The implementing phase is where the nurse follows through on the decided plan of action. This plan is specific to each patient and focuses on achievable outcomes. Actions involved in a nursing care plan include monitoring the patient for signs of change or improvement, directly caring for the patient or performing necessary medical tasks, educating and instructing the patient about further health management, and referring or contacting the patient for a follow-up. Implementation can take place over the course of hours, days, weeks, or even months.
Evaluation
Once all nursing intervention actions have taken place, the nurse completes an evaluation to determine if the goals for patient wellness have been met. The possible patient outcomes are generally described under three terms: patient's condition improved, patient's condition stabilised, and patient's condition deteriorated. In the event where the condition of the patient has shown no improvement, or if the wellness goals were not met, the nursing process begins again from the first step.
== The Role of Nursing Assessment in Diagnosis ==
A nursing assessment is the first step in making a nursing diagnosis. The way a nurse collects and organizes patient information affects how accurate the diagnosis will be.
Studies show that some nursing assessment tools have weaknesses, which can lead to less accurate diagnoses. Better assessment methods improve patient care by giving nurses a clearer picture of a patient’s health. When nurses have the right tools, they can make better diagnoses and choose the best care for their patients.
== Communication and Cultural Considerations in Nursing Diagnosis ==
Good communication is important when making nursing diagnoses. Nurses care for patients from different backgrounds, and cultural differences can affect how patients describe their symptoms.
Nurses need intercultural communication skills to understand their patients better. When nurses respect and consider cultural differences, they can make more accurate diagnoses and provide care that fits each patient’s needs.
Cultural competence means understanding different health beliefs, values, and ways of communicating. For example, some patients may describe pain differently or may have different views on illness and recovery. If there is a misunderstanding, a patient might not get the right diagnosis or treatment. Nurses should be aware of these differences to provide the best care.
== Challenges in Learning Nursing Diagnosis ==
Learning how to use nursing diagnoses can be difficult for nursing students. Many students struggle with clinical reasoning, which is the ability to think through patient problems and choose the right diagnosis.
Stress and mental health challenges can also affect how well students learn. It may be hard to tell the difference between similar diagnoses or apply them in real-life situations. To help students learn better, nursing schools use case studies, simulations, and hands-on training. These tools help students practice and feel more confident when working with patients.
== Impact of Nursing Diagnosis on Patient Care ==
Nursing diagnoses help improve patient care by:
Identifying patients’ needs more clearly
Helping nurses and other healthcare workers communicate better
Improving patient safety by finding risks early
Supporting evidence-based nursing, so care is based on research
Studies show that accurate nursing diagnoses lead to better health outcomes. If nurses have good assessment tools, strong communication skills, and the right training, they can make better diagnoses and improve patient care.
== Examples ==
The following are nursing diagnoses arising from the nursing literature with varying degrees of authentication by ICNP or NANDA-I standards.
Anxiety
Constipation
Pain
Decreased Activity Tolerance
Impaired Gas Exchange
Excessive Fluid Volume
Caregiver Role Strain
Ineffective Coping
Readiness for Enhanced Health Maintenance
Readiness for enhanced spiritual well-being
Liver cirrhosis
== See also ==
Clinical Care Classification System
Clinical formulation
Nursing
Nursing process
Nursing care plan
Nursing Interventions Classification (NIC)
Nursing Outcomes Classification (NOC)
== References ==
== External links ==
Müller-Staub, M; Needham, I; Odenbreit, M; Lavin, M. A.; Van Achterberg, T (2007). "Improved quality of nursing documentation: Results of a nursing diagnoses, interventions, and outcomes implementation study". International Journal of Nursing Terminologies and Classifications. 18 (1): 5–17. doi:10.1111/j.1744-618X.2007.00043.x. PMID 17430533. | Wikipedia/Nursing_diagnosis |
Valvular heart disease is any cardiovascular disease process involving one or more of the four valves of the heart (the aortic and mitral valves on the left side of heart and the pulmonic and tricuspid valves on the right side of heart). These conditions occur largely as a consequence of aging, but may also be the result of congenital (inborn) abnormalities or specific disease or physiologic processes including rheumatic heart disease and pregnancy.
Anatomically, the valves are part of the dense connective tissue of the heart known as the cardiac skeleton and are responsible for the regulation of blood flow through the heart and great vessels. Valve failure or dysfunction can result in diminished heart functionality, though the particular consequences are dependent on the type and severity of valvular disease. Treatment of damaged valves may involve medication alone, but often involves surgical valve repair or valve replacement.
== Classification ==
Stenosis and insufficiency/regurgitation represent the dominant functional and anatomic consequences associated with valvular heart disease. Irrespective of disease process, alterations to the valve occur that produce one or a combination of these conditions. Insufficiency and regurgitation are synonymous terms that describe an inability of the valve to prevent backflow of blood as leaflets of the valve fail to join (coapt) correctly. Stenosis is characterized by a narrowing of the valvular orifice that prevents adequate outflow of blood. Stenosis can also result in insufficiency if thickening of the annulus or leaflets results in inappropriate leaf closure.
=== Aortic and mitral valve disorders ===
Aortic and mitral valve disorders are left heart diseases that are more prevalent than diseases of the pulmonary or tricuspid valve in the right heart due to the higher pressures in the left heart.
Stenosis of the aortic valve is characterized by a thickening of the valvular annulus or leaflets that limits the ability of blood to be ejected from the left ventricle into the aorta. Stenosis is typically the result of valvular calcification but may be the result of a congenitally malformed bicuspid aortic valve. This defect is characterized by the presence of only two valve leaflets. It may occur in isolation or in concert with other cardiac anomalies.
Aortic insufficiency, or regurgitation, is characterized by an inability of the valve leaflets to appropriately close at the end systole, thus allowing blood to flow inappropriately backward into the left ventricle. Causes of aortic insufficiency in the majority of cases are unknown, or idiopathic. It may be the result of connective tissue or immune disorders, such as Marfan syndrome or systemic lupus erythematosus, respectively. Processes that lead to aortic insufficiency usually involve dilation of the valve annulus, thus displacing the valve leaflets, which are anchored in the annulus.
Mitral stenosis is caused largely by rheumatic heart disease, though is rarely the result of calcification. In some cases, vegetations form on the mitral leaflets as a result of endocarditis, an inflammation of the heart tissue. Mitral stenosis is uncommon and not as age-dependent as other types of valvular disease.
Mitral insufficiency can be caused by dilation of the left heart, often a consequence of heart failure. In these cases, the left ventricle of the heart becomes enlarged and causes displacement of the attached papillary muscles, which control the mitral.
=== Pulmonary and tricuspid valve disorders ===
Pulmonary and tricuspid valve diseases are right heart diseases. Pulmonary valve diseases are the least common heart valve disease in adults.
Pulmonary valve stenosis is often the result of congenital malformations and is observed in isolation or as part of a larger pathologic process, as in Tetralogy of Fallot, Noonan syndrome, and congenital rubella syndrome. Unless the degree of stenosis is severe, individuals with pulmonary stenosis usually have excellent outcomes and better treatment options. Often patients do not require intervention until later in adulthood as a consequence of calcification that occurs with aging.
Pulmonary valve insufficiency occurs commonly in healthy individuals to a very mild extent and does not require intervention. More appreciable insufficiency is typically the result of damage to the valve due to cardiac catheterization, intra-aortic balloon pump insertion, or other surgical manipulations. Additionally, insufficiency may be the result of carcinoid syndrome, inflammatory processes such a rheumatoid disease or endocarditis, or congenital malformations. It may also be secondary to severe pulmonary hypertension.
Tricuspid valve stenosis without co-occurrent regurgitation is highly uncommon and typically the result of rheumatic disease. It may also be the result of congenital abnormalities, carcinoid syndrome, obstructive right atrial tumors (typically lipomas or myxomas), or hypereosinophilic syndromes.
Minor tricuspid insufficiency is common in healthy individuals. In more severe cases it is a consequence of dilation of the right ventricle, leading to displacement of the papillary muscles which control the valve's ability to close. Dilation of the right ventricle occurs secondary to ventricular septal defects, right to left shunting of blood, eisenmenger syndrome, hyperthyroidism, and pulmonary stenosis. Tricuspid insufficiency may also be the result of congenital defects of the tricuspid valve, such as Ebstein's anomaly.
== Signs and symptoms ==
=== Aortic stenosis ===
Symptoms of aortic stenosis may include heart failure symptoms, such as dyspnea on exertion (most frequent symptom), orthopnea and paroxysmal nocturnal dyspnea, angina pectoris, and syncope, usually exertional.
Medical signs of aortic stenosis include pulsus parvus et tardus, that is, diminished and delayed carotid pulse, fourth heart sound, decreased A2 sound, sustained apex beat, precordial thrill. Auscultation may reveal a systolic murmur of a harsh crescendo-decrescendo type, heard in 2nd right intercostal space and radiating to the carotid arteries.
=== Aortic regurgitation ===
Patients with aortic regurgitation may experience heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, and angina pectoris. In acute cases patients may experience cyanosis and circulatory shock.
Medical signs of aortic regurgitation include increased pulse pressure by increased systolic and decreased diastolic blood pressure, but these findings may not be significant if acute. The patient may have a diastolic decrescendo murmur best heard at left sternal border, water hammer pulse, Austin Flint murmur, and a displaced apex beat down and to the left. A third heart sound may be present
=== Mitral stenosis ===
Patients with mitral stenosis may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, chest pain, hemoptysis, thromboembolism, or ascites and edema (if right-sided heart failure develops). Symptoms of mitral stenosis increase with exercise and pregnancy
On auscultation of a patient with mitral stenosis, typically the most prominent sign is a loud S1. Another finding is an opening snap followed by a low-pitched diastolic rumble with presystolic accentuation. The opening snap follows closer to the S2 heart tone with worsening stenosis. The murmur is heard best with the bell of the stethoscope lying on the left side and its duration increases with worsening disease. Advanced disease may present with signs of right-sided heart failure such as parasternal heave, jugular venous distension, hepatomegaly, ascites and/or pulmonary hypertension (presenting with a loud P2). Signs increase with exercise and pregnancy.
=== Mitral regurgitation ===
Patients with mitral regurgitation may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, or pulmonary edema.
On auscultation of a patient with mitral stenosis, there may be a holosystolic murmur at the apex, radiating to the back or clavicular area, a third heart sound, and a loud, palpable P2, heard best when lying on the left side. Patients also commonly have atrial fibrillation. Patients may have a laterally displaced apex beat, often with heave In acute cases, the murmur and tachycardia may be only distinctive signs.
=== Tricuspid regurgitation ===
Patients with tricuspid regurgitation may experience symptoms of right-sided heart failure, such as ascites, hepatomegaly, edema and jugular venous distension.
Signs of tricuspid regurgitation include pulsatile liver, prominent V waves and rapid y descents in jugular venous pressure. Auscultatory findings include inspiratory third heart sound at left lower sternal border (LLSB) and a blowing holosystolic murmur at LLSB, intensifying with inspiration, and decreasing with expiration and Valsalva maneuver. Patients may have a parasternal heave along LLSB. Atrial fibrillation is usually present in patients with tricuspid regurgitation
== Causes ==
=== Calcific disease ===
Calcification of the leaflets of the aortic valve is a common with increasing age, but the mechanism is likely to be more related to increased lipoprotein deposits and inflammation than the "wear and tear" of advance age. Aortic stenosis due to calcification of tricuspid aortic valve with age comprises >50% of the disease. Aortic stenosis due to calcification of a bicuspid aortic valve comprises about 30–40% of the disease. Hypertension, diabetes mellitus, hyperlipoproteinemia and uremia may speed up the process of valvular calcification.
=== Dysplasia ===
Heart valve dysplasia is an error in the development of any of the heart valves, and a common cause of congenital heart defects in humans as well as animals; tetralogy of Fallot is a congenital heart defect with four abnormalities, one of which is stenosis of the pulmonary valve. Ebstein's anomaly is an abnormality of the tricuspid valve, and its presence can lead to tricuspid valve regurgitation. A bicuspid aortic valve is an aortic valve with only 2 cusps as opposed to the normal 3. It is present in about 0.5% to 2% of the general population and causes increased calcification due to higher turbulent flow through the valve.
=== Connective tissue disorders ===
Marfan's Syndrome is a connective tissue disorder that can lead to chronic aortic or mitral regurgitation. Osteogenesis imperfecta is a disorder in formation of type I collagen and can also lead to chronic aortic regurgitation.
=== Inflammatory disorders ===
Inflammation of the heart valves due to any cause is called valvular endocarditis; this is usually due to bacterial infection but may also be due to cancer (marantic endocarditis), certain autoimmune conditions (Libman-Sacks endocarditis, seen in systemic lupus erythematosus) and hypereosinophilic syndrome (Loeffler endocarditis). Endocarditis of the valves can lead to regurgitation through that valve, which is seen in the tricuspid, mitral, and aortic valves. Certain medications have been associated with valvular heart disease, most prominently ergotamine derivatives pergolide and cabergoline.
Valvular heart disease resulting from rheumatic fever is referred to as rheumatic heart disease. Acute rheumatic fever, which frequently manifests with carditis and valvulitis, is a late sequela of Group A beta-hemolytic streptococcus infection in the throat, often lagging the initial infection by weeks to months. Cardiac involvement is dependent on the cross-reaction of antibodies directed against M proteins produced by bacteria with human proteins present in the myocardium or endocardium (although acute rheumatic fever may present as pancarditis with additional involvement of the pericardium). This results in generalized inflammation in the heart, producing acute erosions and vegetations with fibrin deposition in the mitral valve that may be followed by chronic changes over years to decades, including shortening of the chordae tendinae and thickening or fusion of the mitral leaflets, leading to a severely compromised "buttonhole" or "fish mouth" valve.
In 70% of cases rheumatic heart disease involves only the mitral valve, while 25% of cases involve both the aortic and mitral valves. Involvement of other heart valves without damage to the mitral is exceedingly rare. Mitral stenosis is almost always caused by rheumatic heart disease. Less than 10% of aortic stenosis is caused by rheumatic heart disease. Rheumatic fever can also cause chronic mitral and aortic regurgitation.
While developed countries once had a significant burden of rheumatic fever and rheumatic heart disease, medical advances and improved social conditions have dramatically reduced their incidence. Many developing countries, as well as indigenous populations within developed countries, still carry a significant burden of rheumatic fever and rheumatic heart disease and there has been a resurgence in efforts to eradicate the diseases in these populations. Among persons who have experienced rheumatic fever, long-term intramuscular antibiotic therapy is used as secondary prophylaxis against additional streptococcal infections, which can contribute to progression of rheumatic heart disease. In people with severe valvular disease, however, short-term risks of cardiovascular compromise after intramuscular injections may outweigh the benefits, and oral therapy may be considered instead of IM injections in this subset of patients.
Diseases of the aortic root can cause chronic aortic regurgitation. These diseases include syphilitic aortitis, Behçet's disease, and reactive arthritis.
=== Heart disease ===
Tricuspid regurgitation is usually secondary to right ventricular dilation which may be due to left ventricular failure (the most common cause), right ventricular infarction, inferior myocardial infarction, or cor pulmonale Other causes of tricuspid regurgitation include carcinoid syndrome and myxomatous degeneration.
== Diagnosis ==
=== Aortic stenosis ===
Patients with aortic stenosis can have chest X-ray findings showing dilation of the ascending aorta, but they may also have a completely normal chest X-ray. Direct visualization of calcifications on chest X-ray is uncommon. Other findings include dilation of the left ventricle. ECG typically shows left ventricular hypertrophy in patients with severe stenosis, but it may also show signs of left heart strain. Echocardiography is the diagnostic gold standard, which shows left ventricular hypertrophy, leaflet calcification, and abnormal leaflet closure.
=== Aortic regurgitation ===
Chest X-ray is not as sensitive as other tests, but it may show aortic root dilation (especially in causes involving the aortic root) and apex displacement. An ECG may show left ventricular hypertrophy and signs of left heart strain. Left axis deviation can be a sign of advanced disease. An echocardiogram can be helpful in determining the root cause of the disease, as it will clearly show aortic root dilation or dissection if it exists. Typically the pump function of the heart during systole is normal, but an echocardiogram will show flow reversal during diastole. This disease is classified using regurgitant fraction (RF), or the amount of volume that flows back through the valve divided by the total forward flow through the valve during systole. Severe disease has an RF of >50%, while progressive aortic regurgitation has an RF of 30–49%.
=== Mitral stenosis ===
Chest x-ray in mitral stenosis will typically show an enlarged left atrium, and may show dilation of the pulmonary veins. ECG can show left atrial enlargement, due to increased pressures in the left atrium. Echocardiography is helpful in determining the severity of the disease by estimating the pulmonary artery systolic pressure. This test can also show leaflet calcification and the pressure gradient over the mitral valve. Severe mitral stenosis is defined as a mitral valve area <1.5 cm2. Progressive mitral stenosis has a normal valve area but will have increased flow velocity across the mitral valve.
=== Mitral regurgitation ===
Chest x-ray in mitral regurgitation can show an enlarged left atrium, as well as pulmonary venous congestion. It may also show valvular calcifications specifically in combined mitral regurgitation and stenosis due to rheumatic heart disease. ECG typically shows left atrial enlargement, but can also show right atrial enlargement if the disease is severe enough to cause pulmonary hypertension. Echocardiography is useful in visualizing the regurgitant flow and calculating the RF. It can also be used to determine the degree of calcification, and the function and closure of the valve leaflets. Severe disease has an RF of >50%, while progressive mitral regurgitation has an RF of <50%.
== Treatment ==
Some of the most common treatments of valvular heart disease are avoiding smoking and excessive alcohol consumption, antibiotics, antithrombotic medications such as aspirin, anticoagulants, balloon dilation, and water pills.
In some cases, surgery may be necessary.
=== Aortic stenosis ===
Treatment of aortic stenosis is not necessary in asymptomatic patients, unless the stenosis is classified as severe based on valve hemodynamics. Both asymptomatic severe and symptomatic aortic stenosis are treated with aortic valve replacement (AVR) surgery. AVR surgery can be performed using mechanical or tissue valves depending on age and other relevant factors. Trans-catheter Aortic Valve Implantation (TAVI) is an alternative to AVR and is recommended in high risk patients who may not be suitable for surgical AVR. Any angina is treated with short-acting nitrovasodilators, beta-blockers and/or calcium blockers, although nitrates can drastically decrease blood pressure in patients with severe aortic stenosis and are therefore contraindicated. Any hypertension is treated aggressively, but caution must be taken in administering beta-blockers. Any heart failure is treated with digoxin, diuretics, nitrovasodilators and, if not contraindicated, cautious inpatient administration of ACE inhibitors. Moderate stenosis is monitored with echocardiography every 1–2 years, possibly with supplementary cardiac stress test. Severe stenosis should be monitored with echocardiography every 3–6 months. In patients with non-severe asymptomatic aortic valve stenosis, increased age- and sex adjusted N-terminal pro-brain natriuretic peptide (NT-proBNP) levels alone and combined with a 50% or greater increase from baseline had been found associated with increased event rates of aortic valve stenosis related events (cardiovascular death, hospitalization with heart failure due to progression of aortic valve stenosis, or aortic valve replacement surgery). In patients with non-severe asymptomatic aortic valve stenosis and no overt coronary artery disease, the increased troponin T (above 14 pg/mL) was found associated with an increased 5-year event rate of ischemic cardiac events (myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery).
=== Aortic regurgitation ===
Aortic regurgitation is treated with aortic valve replacement, which is recommended in patients with symptomatic severe aortic regurgitation. Aortic valve replacement is also recommended in patients that are asymptomatic but have chronic severe aortic regurgitation and left ventricular ejection fraction of less than 50%. Hypertension is treated in patients with chronic aortic regurgitation, with the anti-hypersensives of choice being calcium channel blockers, ACE inhibitors, or ARBs. Also, endocarditis prophylaxis is indicated before dental, gastrointestinal or genitourinary procedures. Mild to moderate aortic regurgitation should be followed with echocardiography and a cardiac stress test once every 1–2 years. In severe moderate/severe cases, patients should be followed with echocardiography and cardiac stress test and/or isotope perfusion imaging every 3–6 months.
=== Mitral stenosis ===
For patients with symptomatic severe mitral stenosis, percutaneous balloon mitral valvuloplasty (PBMV) is recommended. If this procedure fails, then it may be necessary to undergo mitral valve surgery, which may involve valve replacement, repair, or commisurotomy. Anticoagulation is recommended for patients that have mitral stenosis in the setting of atrial fibrillation or a previous embolic event. No therapy is required for asymptomatic patients. Diuretics may be used to treat pulmonary congestion or edema.
=== Mitral regurgitation ===
Surgery is recommended for chronic severe mitral regurgitation in symptomatic patients with left ventricular ejection fraction (LVEF) of greater than 30%, and asymptomatic patients with LVEF of 30-60% or left ventricular end diastolic volume (LVEDV) > 40%. Surgical repair of the leaflets is preferred to mitral valve replacement as long as the repair is feasible. Mitral regurgitation may be treated medically with vasodilators, diuretics, digoxin, antiarrhythmics, and chronic anticoagulation. Mild to moderate mitral regurgitation should be followed with echocardiography and cardiac stress test every 1–3 years. Severe mitral regurgitation should be followed with echocardiography every 3–6 months.
== Epidemiology ==
In the United States, about 2.5% of the population has moderate to severe valvular heart disease. The prevalence of these diseases increase with age, and 75 year-olds in the United States have a prevalence of about 13%. In industrially underdeveloped regions, rheumatic disease is the most common cause of valve diseases, and it can cause up to 65% of the valve disorders seen in these regions.
=== Aortic stenosis ===
Aortic stenosis is typically the result of aging, occurring in 12.4% of the population over 75 years of age, and represents the most common cause of outflow obstruction in the left ventricle. Bicuspid aortic valves are found in up to 1% of the population, making it one of the most common cardiac abnormalities.
=== Aortic regurgitation ===
The prevalence of aortic regurgitation also increases with age. Moderate to severe disease has a prevalence of 13% in patients between the ages of 55 and 86. This valve disease is primarily caused by aortic root dilation, but infective endocarditis has been an increased risk factor. It has been found to be the cause of aortic regurgitation in up to 25% of surgical cases.
=== Mitral stenosis ===
Mitral stenosis is caused almost exclusively by rheumatic heart disease, and has a prevalence of about 0.1% in the United States. Mitral stenosis is the most common valvular heart disease in pregnancy.
=== Mitral regurgitation ===
Mitral regurgitation is significantly associated with normal aging, rising in prevalence with age. It is estimated to be present in over 9% of people over 75.
== Special populations ==
=== Pregnancy ===
The evaluation of individuals with valvular heart disease who are or wish to become pregnant is a difficult issue. Issues that have to be addressed include the risks during pregnancy to the mother and the developing fetus by the presence of maternal valvular heart disease as a pre-existing disease in pregnancy.
Normal physiological changes during pregnancy require, on average, a 50% increase in circulating blood volume that is accompanied by an increase in cardiac output that usually peaks between the midportion of the second and third trimesters. The increased cardiac output is due to an increase in the stroke volume, and a small increase in heart rate, averaging 10 to 20 beats per minute. Additionally uterine circulation and endogenous hormones cause systemic vascular resistance to decrease and a disproportionately lowering of diastolic blood pressure causes a wide pulse pressure. Inferior vena caval
obstruction from a gravid uterus in the supine position can result in an abrupt decrease in cardiac preload, which leads to hypotension with weakness and lightheadedness. During labor and delivery cardiac output increases more in part due to the associated anxiety and pain, as well as due to uterine contractions which will cause an increase in systolic and diastolic blood pressure.
Valvular heart lesions associated with high maternal and fetal risk during pregnancy include:
Severe aortic stenosis with or without symptoms
Aortic regurgitation with NYHA functional class III-IV symptoms
Mitral stenosis with NYHA functional class II-IV symptoms
Mitral regurgitation with NYHA functional class III-IV symptoms
Aortic and/or mitral valve disease resulting in severe pulmonary hypertension (pulmonary pressure greater than 75% of systemic pressures)
Aortic and/or mitral valve disease with severe LV dysfunction (EF less than 0.40)
Mechanical prosthetic valve requiring anticoagulation
Marfan syndrome with or without aortic regurgitation
In individuals who require an artificial heart valve, consideration must be made for deterioration of the valve over time (for bioprosthetic valves) versus the risks of blood clotting in pregnancy with mechanical valves with the resultant need of drugs in pregnancy in the form of anticoagulation.
== References == | Wikipedia/Valvular_heart_disease |
The 1990 Clinic of Zaragoza radiotherapy accident was a radiological accident that occurred from 10 to 20 December 1990, at University Clinic Hospital Lozano Blesa of Zaragoza, in Aragon, Spain.
In the accident, at least 27 patients were injured, and 11 of them died due to the overexposure, according to the International Atomic Energy Agency (IAEA). All of the injured were cancer patients receiving external beam radiotherapy.
== Chronology ==
On 7 December 1990, a technician performed maintenance on an electron accelerator at the Clinic of Zaragoza. On 10 December, it returned to service after the repairs.
Affected patients immediately suffered burns on the skin of the irradiated area, as well as inflammation of the internal organs and bone marrow. The first overexposed patient died on 16 February 1991, two months after irradiation. Fatalities increased until, on 25 December 1991, the last of a total of 25 patients died. The IAEA established that 11 of the deaths were due to the faulty maintenance.
On 19 December 1990, the Nuclear Safety Council (CSN) was scheduled to make its annual review of the device but, due to bureaucratic reasons, this review was delayed. The CSN found the electron accelerator power was too high. The unit was deactivated on 20 December 1990 and restarted on 8 March 1991.
== The accident ==
The radiotherapy unit was repaired without following the correct instructions. The unit, in service 14 years at the time of the failure, had a breakdown in the electron beam accelerator control system ("deviator"). Repairs incorrectly increased output power, so patients that should have received therapy at 7 MeV were instead treated at 40 MeV.
== See also ==
Therac-25
Ionizing radiation
List of civilian radiation accidents
Radioactive scrap metal
List of orphan source incidents
1962 Mexico City radiation accident
Goiânia accident, a similar accident in Brazil in 1987
Nuclear and radiation accidents and incidents
Ciudad Juárez cobalt-60 contamination incident
Samut Prakan radiation accident
== References == | Wikipedia/1990_Clinic_of_Zaragoza_radiotherapy_accident |
In dosimetry, linear energy transfer (LET) is the amount of energy that an ionizing particle transfers to the material traversed per unit distance. It describes the action of radiation into matter.
It is identical to the retarding force acting on a charged ionizing particle travelling through the matter. By definition, LET is a positive quantity. LET depends on the nature of the radiation as well as on the material traversed.
A high LET will slow down the radiation more quickly, generally making shielding more effective and preventing deep penetration. On the other hand, the higher concentration of deposited energy can cause more severe damage to any microscopic structures near the particle track. If a microscopic defect can cause larger-scale failure, as is the case in biological cells and microelectronics, the LET helps explain why radiation damage is sometimes disproportionate to the absorbed dose. Dosimetry attempts to factor in this effect with radiation weighting factors.
Linear energy transfer is closely related to stopping power, since both equal the retarding force. The unrestricted linear energy transfer is identical to linear electronic stopping power, as discussed below. But the stopping power and LET concepts are different in the respect that total stopping power has the nuclear stopping power component, and this component does not cause electronic excitations. Hence nuclear stopping power is not contained in LET.
The appropriate SI unit for LET is the newton, but it is most typically expressed in units of kiloelectronvolts per micrometre (keV/μm) or megaelectronvolts per centimetre (MeV/cm). While medical physicists and radiobiologists usually speak of linear energy transfer, most non-medical physicists talk about stopping power.
== Restricted and unrestricted LET ==
The secondary electrons produced during the process of ionization by the primary charged particle are conventionally called delta rays, if their energy is large enough so that they themselves can ionize. Many studies focus upon the energy transferred in the vicinity of the primary particle track and therefore exclude interactions that produce delta rays with energies larger than a certain value Δ. This energy limit is meant to exclude secondary electrons that carry energy far from the primary particle track, since a larger energy implies a larger range. This approximation neglects the directional distribution of secondary radiation and the non-linear path of delta rays, but simplifies analytic evaluation.
In mathematical terms, Restricted linear energy transfer is defined by
L
Δ
=
d
E
Δ
d
x
,
{\displaystyle L_{\Delta }={\frac {{\text{d}}E_{\Delta }}{{\text{d}}x}},}
where
d
E
Δ
{\displaystyle {\text{d}}E_{\Delta }}
is the energy loss of the charged particle due to electronic collisions while traversing a distance
d
x
{\displaystyle {{\text{d}}x}}
, excluding all secondary electrons with kinetic energies larger than Δ. If Δ tends toward infinity, then there are no electrons with larger energy, and the linear energy transfer becomes the unrestricted linear energy transfer which is identical to the linear electronic stopping power. Here, the use of the term "infinity" is not to be taken literally; it simply means that no energy transfers, however large, are excluded.
== Application to radiation types ==
During his investigations of radioactivity, Ernest Rutherford coined the terms alpha rays, beta rays and gamma rays for the three types of emissions that occur during radioactive decay.
=== Alpha particles and other positive ions ===
Linear energy transfer is best defined for monoenergetic ions, i.e. protons, alpha particles, and the heavier nuclei called HZE ions found in cosmic rays or produced by particle accelerators. These particles cause frequent direct ionizations within a narrow diameter around a relatively straight track, thus approximating continuous deceleration. As they slow down, the changing particle cross section modifies their LET, generally increasing it to a Bragg peak just before achieving thermal equilibrium with the absorber, i.e., before the end of range. At equilibrium, the incident particle essentially comes to rest or is absorbed, at which point LET is undefined.
Since the LET varies over the particle track, an average value is often used to represent the spread. Averages weighted by track length or weighted by absorbed dose are present in the literature, with the latter being more common in dosimetry. These averages are not widely separated for heavy particles with high LET, but the difference becomes more important in the other type of radiations discussed below.
Often overlooked for alpha particles is the recoil-nucleus of the alpha emitter, which has significant ionization energy of roughly 5% of the alpha particle, but because of its high electric charge and large mass, has an ultra-short range of only a few Angstroms. This can skew results significantly if one is examining the Relative Biological Effectiveness of the alpha particle in the cytoplasm, while ignoring the recoil nucleus contribution, which alpha-parent being one of numerous heavy metals, is typically adhered to chromatic material such as chromosomes.
=== Beta particles ===
Electrons produced in nuclear decay are called beta particles. Because of their low mass relative to atoms, they are strongly scattered by nuclei (Coulomb or Rutherford scattering), much more so than heavier particles. Beta particle tracks are therefore crooked. In addition to producing secondary electrons (delta rays) while ionizing atoms, they also produce bremsstrahlung photons. A maximum range of beta radiation can be defined experimentally which is smaller than the range that would be measured along the particle path.
=== Gamma rays ===
Gamma rays are photons, whose absorption cannot be described by LET. When a gamma quantum passes through matter, it may be absorbed in a single process (photoelectric effect, Compton effect or pair production), or it continues unchanged on its path. (Only in the case of the Compton effect, another gamma quantum of lower energy proceeds). Gamma ray absorption therefore obeys an exponential law (see Gamma rays); the absorption is described by the absorption coefficient or by the half-value thickness.
LET has therefore no meaning when applied to photons. However, many authors speak of "gamma LET" anyway, where they are actually referring to the LET of the secondary electrons, i.e., mainly Compton electrons, produced by the gamma radiation. The secondary electrons will ionize far more atoms than the primary photon. This gamma LET has little relation to the attenuation rate of the beam, but it may have some correlation to the microscopic defects produced in the absorber. Even a monoenergetic gamma beam will produce a spectrum of electrons, and each secondary electron will have a variable LET as it slows down, as discussed above. The "gamma LET" is therefore an average.
The transfer of energy from an uncharged primary particle to charged secondary particles can also be described by using the mass energy-transfer coefficient.
== Biological effects ==
Many studies have attempted to relate linear energy transfer to the relative biological effectiveness (RBE) of radiation, with inconsistent results. The relationship varies widely depending on the nature of the biological material, and the choice of endpoint to define effectiveness. Even when these are held constant, different radiation spectra that shared the same LET have significantly different RBE.
Despite these variations, some overall trends are commonly seen. The RBE is generally independent of LET for any LET less than 10 keV/μm, so a low LET is normally chosen as the reference condition where RBE is set to unity. Above 10 keV/μm, some systems show a decline in RBE with increasing LET, while others show an initial increase to a peak before declining. Mammalian cells usually experience a peak RBE for LET's around 100 keV/μm. These are very rough numbers; for example, one set of experiments found a peak at 30 keV/μm.
The International Commission on Radiation Protection (ICRP) proposed a simplified model of RBE-LET relationships for use in dosimetry. They defined a quality factor of radiation as a function of dose-averaged unrestricted LET in water, and intended it as a highly uncertain, but generally conservative, approximation of RBE. Different iterations of their model are shown in the graph to the right. The 1966 model was integrated into their 1977 recommendations for radiation protection in ICRP 26. This model was largely replaced in the 1991 recommendations of ICRP 60 by radiation weighting factors that were tied to the particle type and independent of LET. ICRP 60 revised the quality factor function and reserved it for use with unusual radiation types that did not have radiation weighting factors assigned to them.
== Application fields ==
When used to describe the dosimetry of ionizing radiation in the biological or biomedical setting, the LET (like linear stopping power) is usually expressed in units of keV/μm.
In space applications, electronic devices can be disturbed by the passage of energetic electrons, protons or heavier ions that may alter the state of a circuit, producing "single event effects". The effect of the radiation is described by the LET (which is here taken as synonymous with stopping power), typically expressed in units of MeV·cm2/mg of material, the units used for mass stopping power (the material in question is usually Si for MOS devices). The units of measurement arise from a combination of the energy lost by the particle to the material per unit path length (MeV/cm) divided by the density of the material (mg/cm3).
"Soft errors" of electronic devices due to cosmic rays on earth are, however, mostly due to neutrons which do not directly interact with the material and whose passage can therefore not be described by LET. Rather, one measures their effect in terms of neutrons per cm2 per hour, see Soft error.
== References == | Wikipedia/Linear_energy_transfer |
In vascular diseases, endothelial dysfunction is a systemic pathological state of the endothelium. The main cause of endothelial dysfunction is impaired bioavailability of nitric oxide.
In addition to acting as a semipermeable membrane, the endothelium is responsible for maintaining vascular tone and regulating oxidative stress by releasing mediators, such as nitric oxide, prostacyclin and endothelin, and by controlling local angiotensin-II activity.
Dysfunctional endothelium is characterized by vasoconstriction, increased vascular permeability, thrombosis, and inflammation. This pathological state is often associated with elevated levels of biomarkers such as prothrombin time, D-dimer, von Willebrand factor, fibrin degradation products, C-reactive protein (CRP), ferritin, Interleukin 6 (IL-6), and plasma creatinine. The result of this endothelial dysregulation is a cascade of adverse effects, including vasoconstriction, vascular leakage, thrombosis, hyperinflammation, and a disrupted antiviral immune response. These changes contribute to the progression of vascular diseases.
In a healthy state, the endothelium exhibits vasodilation, tightly controlled vascular permeability, and anti-thrombotic and anti-inflammatory properties. This balance ensures the smooth functioning of the vascular system.
== Research ==
=== Atherosclerosis ===
Endothelial dysfunction may be involved in the development of atherosclerosis and may predate vascular pathology. Endothelial dysfunction may also lead to increased adherence of monocytes and macrophages, as well as promoting infiltration of low-density lipoprotein (LDL) in the vessel wall. Oxidized LDL is a hallmark feature of atherosclerosis, by promoting the formation of foam cells, monocyte chemotaxis, and platelet activation, leading to atheromatous plaque instability and ultimately to rupture. Dyslipidemia and hypertension are well known to contribute to endothelial dysfunction, and lowering blood pressure and LDL has been shown to improve endothelial function, particularly when lowered with ACE inhibitors, calcium channel blockers, and statins. Steadily laminar flow with high shear stress in blood vessels protects against atherosclerosis, whereas disturbed flow promotes atherosclerosis.
=== Nitric oxide ===
Nitric oxide (NO) suppresses platelet aggregation, inflammation, oxidative stress, vascular smooth muscle cell migration and proliferation, and leukocyte adhesion. A feature of endothelial dysfunction is the inability of arteries and arterioles to dilate fully in response to an appropriate stimulus, such as exogenous nitroglycerine, that stimulates release of vasodilators from the endothelium like NO. Endothelial dysfunction is commonly associated with decreased NO bioavailability, which is due to impaired NO production by the endothelium or inactivation of NO by reactive oxygen species. As a co-factor for nitric oxide synthase, tetrahydrobiopterin (BH4) supplementation has shown beneficial results for the treatment of endothelial dysfunction in animal experiments and clinical trials, although the tendency of BH4 to become oxidized to BH2 remains a problem.
=== Testing and diagnosis ===
In the coronary circulation, angiography of coronary artery responses to vasoactive agents may be used to test for endothelial function, and venous occlusion plethysmography and ultrasonography are used to assess endothelial function of peripheral vessels in humans.
A non-invasive method to measure endothelial dysfunction is % Flow-Mediated Dilation (FMD) as measured by Brachial Artery Ultrasound Imaging (BAUI). Current measurements of endothelial function via FMD vary due to technical and physiological factors. Furthermore, a negative correlation between percent flow mediated dilation and baseline artery size is recognised as a fundamental scaling problem, leading to biased estimates of endothelial function.
von Willebrand factor is a marker of endothelial dysfunction, and is consistently elevated in atrial fibrillation.
A non-invasive, FDA-approved device for measuring endothelial function that works by measuring Reactive Hyperemia Index (RHI) is Itamar Medical's EndoPAT. It has shown an 80% sensitivity and 86% specificity to diagnose coronary artery disease when compared against the gold standard, acetylcholine angiogram. This results suggests that this peripheral test reflects the physiology of the coronary endothelium.
Since NO maintains low tone and high compliance of the small arteries at rest, a reduction of age-dependent small artery compliance is a marker for endothelial dysfunction that is associated with both functional and structural changes in the microcirculation. Small artery compliance or stiffness can be assessed simply and at rest and can be distinguished from large artery stiffness by use of pulsewave analysis.
=== Endothelial dysfunction and stents ===
Stent implantation has been correlated with impaired endothelial function in several studies. Sirolimus eluting stents were previously used because they showed low rates of in-stent restenosis, but further investigation showed that they often impair endothelial function in humans and worsen conditions. One drug used to inhibit restenosis is iopromide-paclitaxel.
=== COVID-19 complication in the lungs ===
COVID-19 can present with an acute lung injury manifestation that arises from endothelial dysfunction.
=== Risk reduction ===
Treatment of hypertension and hypercholesterolemia may improve endothelial function in people taking statins (HMGCoA-reductase inhibitor), and renin angiotensin system inhibitors, such as ACE inhibitors and angiotensin II receptor antagonists. Calcium channel blockers and selective beta 1 antagonists may also improve endothelial dysfunction. Life style modifications such as smoking cessation have also been shown to improve endothelial function and lower the risk of major cardiovascular events.
== See also ==
Atherosclerosis
Endothelial activation
Nitric oxide
endothelial nitric oxide synthase
Prostacyclin
Endothelium-derived relaxing factor
Endothelin
Integrin network
Endothelial shear stress
== References == | Wikipedia/Endothelial_dysfunction |
Particle therapy is a form of external beam radiotherapy using beams of energetic neutrons, protons, or other heavier positive ions for cancer treatment. The most common type of particle therapy as of August 2021 is proton therapy.
In contrast to X-rays (photon beams) used in older radiotherapy, particle beams exhibit a Bragg peak in energy loss through the body, delivering their maximum radiation dose at or near the tumor and minimizing damage to surrounding normal tissues.
Particle therapy is also referred to more technically as hadron therapy, excluding photon and electron therapy. Neutron capture therapy, which depends on a secondary nuclear reaction, is also not considered here. Muon therapy, a rare type of particle therapy not within the categories above, has also been studied theoretically; however, muons are still most commonly used for imaging, rather than therapy.
== Method ==
Particle therapy works by aiming energetic ionizing particles at the target tumor. These particles damage the DNA of tissue cells, ultimately causing their death. Because of their reduced ability to repair DNA, cancerous cells are particularly vulnerable to such damage.
The figure shows how beams of electrons, X-rays or protons of different energies (expressed in MeV) penetrate human tissue. Electrons have a short range and are therefore only of interest close to the skin (see electron therapy). Bremsstrahlung X-rays penetrate more deeply, but the dose absorbed by the tissue then shows the typical exponential decay with increasing thickness. For protons and heavier ions, on the other hand, the dose increases while the particle penetrates the tissue and loses energy continuously. Hence the dose increases with increasing thickness up to the Bragg peak that occurs near the end of the particle's range. Beyond the Bragg peak, the dose drops to zero (for protons) or almost zero (for heavier ions).
The advantage of this energy deposition profile is that less energy is deposited into the healthy tissue surrounding the target tissue. This enables higher dose prescription to the tumor, theoretically leading to a higher local control rate, as well as achieving a low toxicity rate.
The ions are first accelerated by means of a cyclotron or synchrotron. The final energy of the emerging particle beam defines the depth of penetration, and hence, the location of the maximum energy deposition. Since it is easy to deflect the beam by means of electro-magnets in a transverse direction, it is possible to employ a raster scan method, i.e., to scan the target area quickly, as the electron beam scans a TV tube. If, in addition, the beam energy and hence the depth of penetration is varied, an entire target volume can be covered in three dimensions, providing an irradiation exactly following the shape of the tumor. This is one of the great advantages compared to conventional X-ray therapy.
At the end of 2008, 28 treatment facilities were in operation worldwide and over 70,000 patients had been treated by means of pions, protons and heavier ions. Most of this therapy has been conducted using protons.
At the end of 2013, 105,000 patients had been treated with proton beams, and approximately 13,000 patients had received carbon-ion therapy.
As of April 1, 2015, for proton beam therapy, there are 49 facilities in the world, including 14 in the US with another 29 facilities under construction. For Carbon-ion therapy, there are eight centers operating and four under construction. Carbon-ion therapy centers exist in Japan, Germany, Italy, and China. Two US federal agencies are hoping to stimulate the establishment of at least one US heavy-ion therapy center.
== Proton therapy ==
Proton therapy is a type of particle therapy that uses a beam of protons to irradiate diseased tissue, most often to treat cancer. The chief advantage of proton therapy over other types of external beam radiotherapy (e.g., radiation therapy, or photon therapy) is that the dose of protons is deposited over a narrow range of depth, which results in minimal entry, exit, or scattered radiation dose to healthy nearby tissues. High dose rates are key in cancer treatment advancements. PSI demonstrated that for cyclotron-based proton therapy facility using momentum cooling, it is possible to achieve remarkable dose rates of 952 Gy/s and 2105 Gy/s at the Bragg peak (in water) for 70 MeV and 230 MeV beams, respectively. When combined with field-specific ridge filters, Bragg peak-based FLASH proton therapy becomes feasible.
== Fast-neutron therapy ==
Fast neutron therapy utilizes high energy neutrons typically between 50 and 70 MeV to treat cancer. Most fast neutron therapy beams are produced by reactors, cyclotrons (d+Be) and linear accelerators. Neutron therapy is currently available in Germany, Russia, South Africa and the United States. In the United States, the only treatment center still operational is in Seattle, Washington. The Seattle center use a cyclotron which produces a proton beam impinging upon a beryllium target.
== Carbon ion radiotherapy ==
Carbon ion therapy (C-ion RT) was pioneered at the National Institute of Radiological Sciences (NIRS) in Chiba, Japan, which began treating patients with carbon ion beams in 1994. This facility was the first to utilize carbon ions clinically, marking a significant advancement in particle therapy for cancer treatment. The therapeutic advantages of carbon ions were recognized earlier, but NIRS was instrumental in establishing its clinical application.
C-ion RT uses particles more massive than protons or neutrons. Carbon ion radiotherapy has increasingly garnered scientific attention as technological delivery options have improved and clinical studies have demonstrated its treatment advantages for many cancers such as prostate, head and neck, lung, and liver cancers, bone and soft tissue sarcomas, locally recurrent rectal cancer, and pancreatic cancer, including locally advanced disease. It also has clear advantages to treat otherwise intractable hypoxic and radio-resistant cancers while opening the door for substantially hypo-fractionated treatment of normal and radio-sensitive disease.
By mid 2017, more than 15,000 patients have been treated worldwide in over 8 operational centers. Japan has been a conspicuous leader in this field. There are five heavy-ion radiotherapy facilities in operation and plans exist to construct several more facilities in the near future. In Germany this type of treatment is available at the Heidelberg Ion-Beam Therapy Center (HIT) and at the Marburg Ion-Beam Therapy Center (MIT). In Italy the National Centre of Oncological Hadrontherapy (CNAO) provides this treatment. Austria will open a CIRT center in 2017, with centers in South Korea, Taiwan, and China soon to open. No CIRT facility now operates in the United States but several are in various states of development.
== Biological advantages of heavy-ion radiotherapy ==
From a radiation biology standpoint, there is considerable rationale to support use of heavy-ion beams in treating cancer patients. All proton and other heavy ion beam therapies exhibit a defined Bragg peak in the body so they deliver their maximum lethal dosage at or near the tumor. This minimizes harmful radiation to the surrounding normal tissues. However, carbon-ions are heavier than protons and so provide a higher relative biological effectiveness (RBE), which increases with depth to reach the maximum at the end of the beam's range. Thus the RBE of a carbon ion beam increases as the ions advance deeper into the tumor-lying region. CIRT provides the highest linear energy transfer (LET) of any currently available form of clinical radiation. This high energy delivery to the tumor results in many double-strand DNA breaks which are very difficult for the tumor to repair. Conventional radiation produces principally single strand DNA breaks which can allow many of the tumor cells to survive. The higher outright cell mortality produced by CIRT may also provide a clearer antigen signature to stimulate the patient's immune system.
== Particle therapy of moving targets ==
The precision of particle therapy of tumors situated in thorax and abdominal region is strongly affected by the target motion. The mitigation of its negative influence requires advanced techniques of tumor position monitoring (e.g., fluoroscopic imaging of implanted radio-opaque fiducial markers or electromagnetic detection of inserted transponders) and irradiation (gating, rescanning, gated rescanning and tumor tracking).
== References ==
== External links ==
Touro University announces first combined particle therapy center in U.S.
PTCOG annual conference | Wikipedia/Particle_therapy |
Cancer treatments are a wide range of treatments available for the many different types of cancer, with each cancer type needing its own specific treatment. Treatments can include surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy including small-molecule drugs or monoclonal antibodies, and PARP inhibitors such as olaparib. Other therapies include hyperthermia, immunotherapy, photodynamic therapy, and stem-cell therapy. Most commonly cancer treatment involves a series of separate therapies such as chemotherapy before surgery. Angiogenesis inhibitors are sometimes used to enhance the effects of immunotherapies.
The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient. Biomarker testing can help to determine the type of cancer, and indicate the best therapy. A number of experimental cancer treatments are continuously under development. In 2023 it was estimated that one in five people will be diagnosed with cancer at some point in their lifetime.
The primary goal of cancer treatment is to either cure the cancer by its complete removal, or to considerably prolong the life of the individual. Palliative care is involved when the prognosis is poor and the cancer termed as terminal. There are many types of cancer, and many of these can be successfully treated if detected early enough.
== Types of treatments ==
The treatment of cancer has undergone evolutionary changes as understanding of the underlying biological processes has increased. Tumor removal surgeries have been documented in ancient Egypt, hormone therapy and radiation therapy were developed in the late 19th century. Chemotherapy, immunotherapy and newer targeted therapies are products of the 20th century. As new information about the biology of good cancer emerges, treatments will be developed and modified to increase effectiveness, precision, survivability, and quality of life.
=== Surgery ===
Malignant tumours can be cured if entirely removed by surgery. But if the cancer has already spread (metastasized) to other sites, complete surgical excision is usually impossible. In the Halstedian model of cancer progression, tumors grow locally, then spread to the lymph nodes, then to the rest of the body. This has given rise to the popularity of local-only treatments such as surgery for small cancers. Even small localized tumors are increasingly recognized as possessing metastatic potential.
Examples of surgical procedures for cancer include mastectomy, and lumpectomy for breast cancer, prostatectomy for prostate cancer, and lung cancer surgery for non-small cell lung cancer. The goal of the surgery can be either the removal of only the tumor, the entire organ, or part of the organ. A single cancer cell is invisible to the naked eye but can regrow into a new tumor, a process called recurrence. For this reason, the pathologist will examine the surgical specimen to determine if a margin of healthy tissue is present, thus decreasing the chance that microscopic cancer cells are left in the patient.
In addition to removal of the primary tumor, surgery is often necessary for staging, e.g. determining the extent of the disease and whether it has metastasized to regional lymph nodes. Staging is a major determinant of prognosis and of the need for adjuvant therapy. Occasionally, surgery is necessary to control symptoms, such as spinal cord compression or bowel obstruction. This is referred to as palliative treatment.
Surgery may be performed before or after other forms of treatment. Treatment before surgery is often described as neoadjuvant. In breast cancer, the survival rate of patients who receive neoadjuvant chemotherapy are no different from those who are treated following surgery. Giving chemotherapy earlier allows oncologists to evaluate the effectiveness of the therapy, and may make removal of the tumor easier. However, the survival advantages of neoadjuvant treatment in lung cancer are less clear.
=== Radiation therapy ===
Radiation therapy (radiotherapy) is the use of ionizing radiation to kill cancer cells and shrink tumors by damaging their DNA causing cellular death. Radiation therapy can either damage DNA directly or create charged particles (free radicals) within the cells that can in turn damage the DNA. Radiation therapy can be administered externally via external beam radiotherapy or internally via brachytherapy. The effects of radiation therapy are localised and confined to the region being treated. Although radiation damages both cancer cells and normal cells, most normal cells can recover from the effects of radiation and function properly. The goal of radiation therapy is to damage as many cancer cells as possible, while limiting harm to nearby healthy tissue. Hence, it is given in many fractions, allowing healthy tissue to recover between fractions.
Radiation therapy may be used to treat almost every type of solid tumor, and may also be used to treat leukemia and lymphoma. Radiation dose to each site depends on a number of factors, including the radio sensitivity of each cancer type and whether there are tissues and organs nearby that may be damaged by radiation. Thus, as with every form of treatment, radiation therapy is not without its side effects.
Radiation therapy can lead to dry mouth from exposure of salivary glands to radiation, resulting in decreased saliva secretion. Post therapy, the salivary glands will resume functioning but rarely in the same fashion. Dry mouth caused by radiation can be a permanent problem.
=== Chemotherapy ===
Chemotherapy is the treatment of cancer with drugs ("anticancer drugs") that can destroy cancer cells. Chemotherapy can be given in a variety of ways such as injections into the muscles, skin, artery, or vein, or it could even be taken by mouth in the form of a pill. In current usage, the term "chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy (see below). Chemotherapy drugs interfere with cell division in various possible ways, e.g. with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can. Hence, chemotherapy has the potential to harm healthy tissue, especially those tissues that have a high replacement rate (e.g. intestinal lining). These cells usually repair themselves after chemotherapy.
Because some drugs work better together than alone, two or more drugs are often given at the same time. This is called "combination chemotherapy"; most chemotherapy regimens are given in a combination.
Since chemotherapy affects the whole body, it can have a wide range of side effects. Patients often find that they start losing their hair since the drugs that are combatting the cancer cells also attack the cells in the hair roots. This powerful treatment can also lead to fatigue, loss of appetite, and vomiting depending on the person.
The treatment of some leukaemias and lymphomas requires the use of high-dose chemotherapy, and total body irradiation (TBI). This treatment ablates the bone marrow, and hence the body's ability to recover and repopulate the blood. For this reason, bone marrow, or peripheral blood stem cell harvesting is carried out before the ablative part of the therapy, to enable "rescue" after the treatment has been given. This is known as autologous stem cell transplantation.
=== Targeted therapies ===
Targeted therapy, which first became available in the late 1990s, has had a significant impact in the treatment of some types of cancer, and is currently a very active research area. This constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule drugs are targeted therapy drugs that are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors imatinib (Gleevec/Glivec) and gefitinib (Iressa).
Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (Herceptin) used in breast cancer, and the anti-CD20 antibody rituximab, used in a variety of B-cell malignancies.
Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g. RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. Especially oligo- or multimers of these binding motifs are of great interest, since this can lead to enhanced tumor specificity and avidity.
Photodynamic therapy (PDT) is a ternary treatment for cancer involving a photosensitizer, tissue oxygen, and light (often using lasers). PDT can be used as treatment for basal cell carcinoma (BCC) or lung cancer; PDT can also be useful in removing traces of malignant tissue after surgical removal of large tumors. In February 2019, medical scientists announced that iridium attached to albumin, creating a photosensitized molecule, can penetrate cancer cells and, after being irradiated with light, destroy the cancer cells.
High-energy therapeutic ultrasound could increase higher-density anti-cancer drug load and nanomedicines to target tumor sites by 20x fold higher than traditional target cancer therapy.
Targeted therapies under pre-clinical development as potential cancer treatments include morpholino splice switching oligonucleotides, which induce ERG exon skipping in prostate cancer models, multitargeted kinase inhibitors that inhibit the PI3K with other pathways including MEK and PIM, and inhibitors of NF-κB in models of chemotherapy resistance.
A systematic review published in Cochrane database found that targeted therapies significantly improve progression-free survival by 35 to 40% in metastatic or relapsed cancer. While the research points to promising clinical outcomes, there is still limited evidence on the long-term effects of targeted therapies in terms of overall survival, quality of life, and severe adverse events.
=== Immunotherapy ===
Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients. Cancer vaccines to generate specific immune responses are the subject of intensive research for a number of tumors, notably malignant melanoma and renal cell carcinoma. Sipuleucel-T is a vaccine-like strategy for prostate cancer in which dendritic cells from the patient are loaded with prostatic acid phosphatase peptides to induce a specific immune response against prostate-derived cells. It gained FDA approval in 2010.
Allogeneic hematopoietic stem cell transplantation (usually from the bone marrow) from a genetically non-identical donor can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a phenomenon known as graft-versus-tumor effect. For this reason, allogeneic HSCT leads to a higher cure rate than autologous transplantation for several cancer types, although the side effects are also more severe.
The cell based immunotherapy in which the patients own natural killer cells (NKs) and cytotoxic T cells are used has been in practice in Japan since 1990. NK cells and TCs primarily kill the cancer cells when they are developed. This treatment is given together with the other modes of treatment such as surgery, radiotherapy or chemotherapy and termed autologous immune enhancement therapy (AIET).
Immune checkpoint therapy focuses on two immune checkpoint proteins, cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Under normal conditions, the immune system utilizes checkpoint proteins as negative feedback mechanisms to return to homeostasis once pathogens have been cleared from the body. In a tumor microenvironment, cancer cells can commandeer this physiological regulatory system to "put a brake" on the anti-cancer immune response and evade immune surveillance. 2018 Nobel Prize in medicine is awarded to Dr. James Allison of University of Texas MD Anderson Cancer Center in U.S. and Dr. Tasuku Honjo Kyoto University in Japan for their contributions in advance of PD-1 and CTLA-4 immune checkpoint therapy.
=== Hormonal therapy ===
The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial. Although the side effects from hormone therapy vary depending on the type, patients can experience symptoms such as hot flashes, nausea, and fatigue.
=== Angiogenesis inhibitors ===
Angiogenesis inhibitors prevent the extensive growth of blood vessels (angiogenesis) that tumors need to survive and grow. Continued growth allows the invasion of cells into neighbouring tissues, and metastasis into distal tissues. There are many approved angiogenesis inhibitors including bevacizumab, axitinib, and cabozantinib.
Flavonoids have been shown to downregulate the angiogenic stimulation of VEGF and Hypoxia-inducible factor (HIF) but none have reached clinical trials.
=== Exercise prescription ===
Exercise prescription is becoming a mainstream adjunct treatment for cancer, based on studies which show that exercise (compared to no exercise) is associated with reduced recurrence rates, improved mortality outcomes, reduction of side effects from traditional cancer treatments. Although it is uncertain whether improved outcomes with exercise are correlated or causative, the benefit-risk ratio of including exercise as part of cancer treatment is large, as exercise has further benefits (e.g. cardiovascular, mental health) without major risks, although there is a small risk of overuse injury if added too aggressively. Exercise physiologists and exercise medicine specialists can assist oncologists and primary care practitioners with exercise prescription in cancer patients.
=== Synthetic lethality ===
Synthetic lethality arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. The deficiencies can arise through mutations, epigenetic alterations or inhibitors of one or both of the genes.
Cancer cells are frequently deficient in a DNA repair gene. (Also see DNA repair deficiency in cancer.) This DNA repair defect either may be due to mutation or, often, epigenetic silencing (see epigenetic silencing of DNA repair). If this DNA repair defect is in one of seven DNA repair pathways (see DNA repair pathways), and a compensating DNA repair pathway is inhibited, then the tumor cells may be killed by synthetic lethality. Non-tumorous cells, with the initial pathway intact, can survive.
==== Ovarian cancer ====
Mutations in DNA repair genes BRCA1 or BRCA2 (active in homologous recombinational repair) are synthetically lethal with inhibition of DNA repair gene PARP1 (active in the base excision repair and in the microhomology-mediated end joining pathways of DNA repair).
Ovarian cancers have a mutational defect in BRCA1 in about 18% of patients (13% germline mutations and 5% somatic mutations) (see BRCA1). Olaparib, a PARP inhibitor, was approved in 2014 by the US FDA for use in BRCA-associated ovarian cancer that had previously been treated with chemotherapy. The FDA, in 2016, also approved the PARP inhibitor rucaparib to treat women with advanced ovarian cancer who have already been treated with at least two chemotherapies and have a BRCA1 or BRCA2 gene mutation.
==== Colon cancer ====
In colon cancer, epigenetic defects in the WRN gene appear to be synthetically lethal with inactivation of TOP1. In particular, irinotecan inactivation of TOP1 was synthetically lethal with deficient expression of the DNA repair WRN gene in patients with colon cancer. In a 2006 study, 45 patients had colonic tumors with hypermethylated WRN gene promoters (silenced WRN expression), and 43 patients had tumors with unmethylated WRN gene promoters, so that WRN protein expression was high. Irinotecan was more strongly beneficial for patients with hypermethylated WRN promoters (39.4 months survival) than for those with unmethylated WRN promoters (20.7 months survival). The WRN gene promoter is hypermethylated in about 38% of colorectal cancers.
There are five different stages of colon cancer, and these five stages all have treatment:
Stage 0, is where the patient is required to undergo surgery to remove the polyp (American Cancer Society).
Stage 1, depending on the location of the cancer in the colon and lymph nodes, the patient undergoes surgery just like Stage 0.
Stage 2 patients undergoes removing nearby lymph nodes, but depending on what the doctor says, the patent might have to undergo chemotherapy after surgery (if the cancer is at higher risk of coming back).
Stage 3, is where the cancer has spread all throughout the lymph nodes but not yet to other organs or body parts. When getting to this stage, Surgery is conducted on the colon and lymph nodes, then the doctor orders Chemotherapy (FOLFOX or CapeOx) to treat the colon cancer in the location needed (American Cancer Society). The last a patient can get is Stage 4.
Stage 4 patients only undergo surgery if it is for the prevention of the cancer, along with pain relief. If the pain continues with these two options, the doctor might recommended radiation therapy. The main treatment strategy is chemotherapy due to how aggressive the cancer becomes in this stage, not only to the colon but to the lymph nodes.
== Symptom control and palliative care ==
Although the control of the symptoms of cancer is not typically thought of as a treatment directed at the cancer, it is an important determinant of the quality of life of cancer patients, and plays an important role in the decision whether the patient is able to undergo other treatments. In general, doctors have the therapeutic skills to reduce pain including, chemotherapy-induced nausea and vomiting, diarrhea, hemorrhage and other common problems in cancer patients. The multidisciplinary specialty of palliative care has increased specifically in response to the symptom control needs for these groups of patients.
Pain medication, such as morphine, oxycodone, and antiemetics are drugs to suppress nausea and vomiting. These are very commonly used in patients with cancer-related symptoms. Improved antiemetics such as ondansetron and analogues, as well as aprepitant have made aggressive treatments much more feasible in cancer patients.
Cancer pain can be associated with continuing tissue damage due to the disease process, or the treatment (i.e. surgery, radiation, chemotherapy). There is always a role for environmental factors and affective disturbances in the genesis of pain behaviors, However these are not usually the predominant etiologic factors in patients with cancer pain. Some patients with severe pain associated with cancer are nearing the end of their lives, but in all cases, palliative therapies should be used to control the pain. Issues such as the social stigma of using opioids and health care consumption can be concerns and may need to be addressed for the person to feel comfortable taking the medications required to control his or her symptoms. The typical strategy for cancer pain management is to get the patient as comfortable as possible using the least amount of medications possible, even if that means using opioids, surgery, and physical measures.
Historically, doctors were reluctant to prescribe narcotics to terminal cancer patients due to addiction and respiratory function suppression. The palliative care movement, a more recent offshoot of the hospice movement, has engendered more widespread support for preemptive pain treatment for cancer patients. The World Health Organization also noted uncontrolled cancer pain as a worldwide problem and established a "ladder" as a guideline for how practitioners should treat pain in patients who have cancer
Cancer-related fatigue is a very common symptom of cancer, and there are a number of approaches put forward for helping with this.
=== Mental struggles/pain ===
Cancer patients undergo many obstacles and one of these includes mental strain. It is very common for cancer patients to become stressed, overwhelmed, uncertain, and even depressed. The use of chemo is a very harsh treatment causing the cells of the body to die. Physical effects like this do not only inflict pain but also cause patients to become mentally exhausted and want to give up. For a lot of reasons including these, hospitals offer many types of therapy and mental healing. Some of these include yoga, meditation, communication therapy, and spiritual ideas. All of these are meant to calm and relax the mind, or to give hope for the patients that may feel drained.
=== Insomnia ===
A common disorder experienced by people that have survived cancer treatments is insomnia. Almost 60% of cancer survivors experience insomnia, and if it is not treated properly it can have long term effects on physiological and physical health. Insomnia is defined as dissatisfaction with sleep duration or quality and difficulties initiating or maintaining sleep. Insomnia can heavily reduce one's quality of life. Cognitive behavioral therapy has been seen to reduce insomnia and depression for cancer survivors.
=== Muscle strength ===
Decreased muscle strength is a common side effect to many different cancer treatments. Because of this, exercise is very important especially in the first year after treatment. It has been shown that yoga, water exercise, and pilates can improve the emotional well-being and quality of life of breast cancer survivors.
=== Fatigue ===
Fatigue is an unrelenting feeling of physical and mental tiredness that cannot be traced back to activity levels. It is a very common experience in cancer survivors, with most patients reporting some level of fatigue before, during, and after treatment. The cause of the fatigue can be due to the cancer itself, but frequently it is medical interventions to treat the cancer – like chemotherapy, radiation, surgery, and hormone therapy – that cause the feelings of extreme tiredness. The exact processes behind cancer-related fatigue are unknown. However, evidence suggests that biological processes like inflammation and stress hormone disruption may play a role. In addition, pre-existing risk factors like a genetic predisposition, sleeping troubles, a pre-existing mood disorder, adverse childhood experiences, and low levels of physical activity are associated with increased levels of cancer-related fatigue.
Treatment options for cancer-related fatigue can be pharmacological or non-pharmacological. Medications like erythropoietin, stimulants, and antidepressants can be prescribed, but their efficacy is modest. Thus, non-pharmacological interventions are the preferred treatment for cancer-related fatigue. Aerobic exercise and psychosocial interventions like cognitive behavioral therapy and mindfulness show promise in reducing feelings of fatigue in cancer patients.
=== Hospice care ===
Hospice care provides palliative care at home, or in a dedicated hospice institution, for a person with an advanced illness termed as terminal. Untreated cancer will prove terminal, and sometimes a choice is made to forgo treatment and its unpleasant side effects, and opt instead for hospice care. Hospice care aims to provide support for the person's medical, emotional, social, practical, psychological, and spiritual needs.
Advance care planning (ACP) can help a person to decide for themself their future care wishes as they approach end of life. ACP helps adults at any stage of health to decide, and record in writing, their wishes for medical treatment preferences, and future wants, preferably as previously discussed with relatives or carers.
== Research ==
Clinical trials, also called research studies, test new treatments in people with cancer. The goal of this research is to find better ways to treat cancer and help cancer patients. Clinical trials test many types of treatment such as new drugs, new approaches to surgery or radiation therapy, new combinations of treatments, or new methods such as gene therapy.
A clinical trial is one of the final stages of a long and careful cancer research process. The search for new treatments begins in the laboratory, where scientists first develop and test new ideas. If an approach seems promising, the next step may be testing a treatment in animals to see how it affects cancer in a living being and whether it has harmful effects. Of course, treatments that work well in the lab or in animals do not always work well in people. Studies are done with cancer patients to find out whether promising treatments are safe and effective.
Patients who take part may be helped personally by the treatment they receive. They get up-to-date care from cancer experts, and they receive either a new treatment being tested or the best available standard treatment for their cancer. At the same time, new treatments also may have unknown risks, but if a new treatment proves effective or more effective than standard treatment, study patients who receive it may be among the first to benefit. There is no guarantee that a new treatment being tested or a standard treatment will produce good results. In children with cancer, a survey of trials found that those enrolled in trials were on average not more likely to do better or worse than those on standard treatment; this confirms that success or failure of an experimental treatment cannot be predicted.
=== Exosome research ===
Exosomes are lipid-covered microvesicles shed by solid tumors into bodily fluids, such as blood and urine. Current research is being done attempting to use exosomes as a detection and monitoring method for a variety of cancers. The hope is to be able to detect cancer with a high sensitivity and specificity via detection of specific exosomes in the blood or urine. The same process can also be used to more accurately monitor a patient's treatment progress. Enzyme linked lectin specific assay or ELLSA Archived 13 July 2011 at the Wayback Machine has been proven to directly detect melanoma derived exosomes from fluid samples. Previously, exosomes had been measured by total protein content in purified samples and by indirect immunomodulatory effects. ELLSA directly measures exosome particles in complex solutions, and has already been found capable of detecting exosomes from other sources, including ovarian cancer and tuberculosis-infected macrophages.
Exosomes, secreted by tumors, are also believed to be responsible for triggering programmed cell death (apoptosis) of immune cells; interrupting T-cell signaling required to mount an immune response; inhibiting the production of anti-cancer cytokines, and has implications in the spread of metastasis and allowing for angiogenesis. Studies are currently being done with "Lectin affinity plasmapheresis" (LAP), LAP is a blood filtration method which selectively targets the tumor based exosomes and removes them from the bloodstream. It is believed that decreasing the tumor-secreted exosomes in a patient's bloodstream will slow down progression of the cancer while at the same time increasing the patients own immune response.
== Complementary and alternative ==
Complementary and alternative medicine (CAM) treatments are the diverse group of medical and health care systems, practices, and products that are not part of conventional medicine and have not been shown to be effective. "Complementary medicine" refers to methods and substances used along with conventional medicine, while "alternative medicine" refers to compounds used instead of conventional medicine. CAM use is common among people with cancer; a 2000 study found that 69% of cancer patients had used at least one CAM therapy as part of their cancer treatment. Most complementary and alternative medicines for cancer have not been rigorously studied or tested. Some alternative treatments which have been investigated and shown to be ineffective continue to be marketed and promoted.
== Special circumstances ==
=== In pregnancy ===
The incidence of pregnancy-associated cancer has risen due to the increasing age of pregnant mothers. Cancers may also be detected incidentally during maternal screening.
Cancer treatment needs to be selected to do least harm to both the woman and her embryo/fetus. In some cases a therapeutic abortion may be recommended.
Radiation therapy is out of the question, and chemotherapy always poses the risk of miscarriage and congenital malformations. Little is known about the effects of medications on the child.
Even if a drug has been tested as not crossing the placenta to reach the child, some cancer forms can harm the placenta and make the drug pass over it anyway. Some forms of skin cancer may even metastasize to the child's body.
Diagnosis is also made more difficult, since computed tomography is infeasible because of its high radiation dose. Still, magnetic resonance imaging works normally. However, contrast media cannot be used, since they cross the placenta.
As a consequence of the difficulties to properly diagnose and treat cancer during pregnancy, the alternative methods are either to perform a Cesarean section when the child is viable in order to begin a more aggressive cancer treatment, or, if the cancer is malignant enough that the mother is unlikely to be able to wait that long, to perform an abortion in order to treat the cancer.
=== In utero ===
Fetal tumors are sometimes diagnosed while still in utero. Teratoma is the most common type of fetal tumor, and usually is benign. In some cases these are surgically treated while the fetus is still in the uterus.
== Society and culture ==
=== Racial and social disparities ===
Cancer is a significant issue that is affecting the world. Specifically in the U.S., 1,735,350 new cases of cancer, and 609,640 deaths were expected by the end of 2018. Adequate treatment can prevent many cancer deaths but there are racial and social disparities in treatments which has a significant factor in high death rates. Minorities are more likely to receive inadequate treatment while white patients are more likely to receive efficient treatments in a timely manner. Having satisfactory treatment in a timely manner can increase the patient's likelihood of survival. It has been shown that chances of survival are significantly greater for white patients than for African American patients.
The annual average mortality of patients with colorectal cancer between 1992 and 2000 was 27 and 18.5 per 100,000 white patients and 35.4 and 25.3 per 100,000 black patients. In a journal that analyzed multiple studies testing racial disparities when treating colorectal cancer found contradicting findings. The US Veterans Administration and an adjuvant trial found that there was no evidence to support racial differences in treating colorectal cancer. However, two studies suggested that African American patients received less satisfactory and poorer quality treatment compared to white patients. One of these studies specifically was provided by the Center for Intramural Research. They found that black patients were 41% less likely to receive colorectal treatment and were more likely to be hospitalized in a teaching hospital with less certified physicians compared to white patients. Furthermore, black patients were more likely to be diagnosed with oncologic sequelae, which is a severity of the illness in result of poorly treated cancer. Lastly, for every 1,000 patients in the hospital, there were 137.4 black patient deaths and 95.6 white patient deaths.
An article in a breast cancer journal analyzed the disparities of breast cancer treatments in the Appalachian Mountains. African American women were found to be three times more likely to die compared to Asians and two times more likely to die compared to white women. According to the study, African American women are at a survival disadvantage compared to other races. Black women are also more likely to receive less successful treatment than white women by not receiving surgery or therapy. Furthermore, the US National Cancer Institute panel identified breast cancer treatments, given to black women, as inappropriate and not adequate compared to the treatment given to white women.
From these studies, researchers have noted that there are definite disparities in the treatment of cancer, specifically who has access to the best treatment and can receive it in a timely manner. This eventually leads to disparities between who dies from cancer and who is more likely to survive.
The cause of these disparities is generally that African Americans have less medical care coverage, insurance and access cancer centers than other races. For an example, black patients with breast cancer and colorectal cancer were shown to be more likely to have Medicaid or no insurance compared to other races. The location of the health care facility also plays a role in why African Americans receive less treatment in comparison to other races. However, some studies say that African Americans do not trust doctors and do not always seek the help they need and that this explains why fewer African Americans receive treatment. Others suggest that African Americans seek more treatment than whites and that it is simply a lack of the resources available to them. In this case, analyzing these studies will identify the treatment disparities and look to prevent them by discovering potential causes of these disparities.
=== Public perception ===
Despite recognition of improvements in outcomes, visceral fear of the disease is ubiquitous, and people may have to struggle to control it.
Among lung cancer patients, stigma, shame, social isolation, and discrimination are common. Such patients are sometimes told that they deserve cancer because of their smoking. Those patients also may have feelings of guilt for having cancer. Stigma in cervical cancer was predominantly driven by fear of social judgment and rejection, self-blame, and shame, with notable negative influences from gender and social norms, as both human papillomavirus infection and cervical cancer were stigmatized due to the perception that they arise from reckless behavior such as having multiple sexual partners or neglecting screening. Resilience may be a potent protective mechanism against stigmatization. Resilience in context of cancer treatment is patient's physiological and psychological capacity to effectively adapt, recover, and maintain optimal functioning in the face of the medical challenges. It encompasses the ability to cope with and overcome adversity, maintain emotional well-being, and promote overall health and healing.
== See also ==
== References ==
== Bibliography ==
"Understanding What Cancer Is: Ancient Times to Present". www.cancer.org.
Chahine S, Urquhart R (October 2019). "A cross-sectional population-based survey looking at the impact of cancer survivorship care plans on meeting the needs of cancer survivors in the posttreatment stage". Supportive Care in Cancer. 27 (10): 3785–3792. doi:10.1007/s00520-019-04685-5. PMID 30721368. S2CID 59604164.
Colby DA, Shifren K (1 January 2013). "Optimism, mental health, and quality of life: A study among breast cancer patients". Psychology, Health & Medicine. 18 (1): 10–20. doi:10.1080/13548506.2012.686619. PMID 22690751. S2CID 205772143.
"How Does Radiation Therapy Work?" American Cancer Society. N.p., n.d. Web. 21 March 2017.
Piazza MF, Galletta M, Portoghese I, Pilia I, Ionta MT, Contu P, Mereu A, Campagna M (August 2017). "Meeting psychosocial and health information needs to ensure quality of cancer care in outpatients". European Journal of Oncology Nursing. 29: 98–105. doi:10.1016/j.ejon.2017.06.001. PMID 28720273.
Northouse LL (1 September 2012). "Helping Patients and Their Family Caregivers Cope With Cancer". Oncology Nursing Forum. 39 (5): 500–506. doi:10.1188/12.ONF.500-506. PMID 22940514. S2CID 21512508.
"Radiation Therapy for Brain Cancer | CTCA." CancerCenter.com. N.p., 1 January 0001. Web. 21 March 2017.
"Radiation Therapy for Cancer." National Cancer Institute. N.p., n.d. Web. 21 March 2017. | Wikipedia/Treatment_of_cancer |
Stereotactic radiation therapy (SRT), also called stereotactic external-beam radiation therapy and stereotaxic radiation therapy, is a type of external radiation therapy that uses special equipment to position the patient and precisely deliver radiation to a tumor. The total dose of radiation is divided into several smaller doses given over several days. Stereotactic radiation therapy is used to treat brain tumors and other brain disorders. It is also being studied in the treatment of other types of cancer, such as lung cancer.
What differentiates Stereotactic from conventional radiotherapy is the precision with which it is delivered. There are multiple systems available, some of which use specially designed frames which physically attach to the patient's skull while newer more advanced techniques use thermoplastic masks and highly accurate imaging systems to locate the patient. The result is the delivery of high doses of radiation with sub-millimetre accuracy.
Stereotactic External-Beam radiation Therapy, sometimes called SBRT is now being used to treat Small Cell Lung Cancer, and Sarcomas that have metastasized to the lungs. The high doses used in thoracic SBRT can sometimes cause adverse effects ranging from mild rib fatigue and transient esophagitis, to fatal events such as pneumonitis or hemorrhage. Stereotactic ablative radiotherapy, administers very high doses of radiation, using several beams of various intensities aimed at different angles to precisely target the tumor(s)in the lungs. The images taken from CAT scans and MRIs are used to design a four-dimensional, customized treatment plan that determines each beam's intensity and positioning. The goal is to deliver the highest possible dose of radiation to kill the cancer while minimizing exposure to healthy organs. Since sarcomas often metastasize to the lungs, this treatment is an effective tool in fighting the progression of the disease.
== References ==
== External links ==
Stereotactic radiation therapy entry in the public domain NCI Dictionary of Cancer Terms
This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute. | Wikipedia/Stereotactic_radiation_therapy |
Radionuclide therapy (RNT, also known as unsealed source radiotherapy or molecular radiotherapy) uses radioactive substances called radiopharmaceuticals to treat medical conditions, particularly cancer. These are introduced into the body by various means (injection or ingestion are the two most commonplace) and localise to specific locations, organs or tissues depending on their properties and administration routes. This includes anything from a simple compound such as sodium iodide that locates to the thyroid via trapping the iodide ion, to complex biopharmaceuticals such as recombinant antibodies which are attached to radionuclides and seek out specific antigens on cell surfaces.
This is a type of targeted therapy which uses the physical, chemical and biological properties of the radiopharmaceutical to target areas of the body for radiation treatment. The related diagnostic modality of nuclear medicine employs the same principles but uses different types or quantities of radiopharmaceuticals in order to image or analyse functional systems within the patient.
RNT contrasts with sealed-source therapy (brachytherapy) where the radionuclide remains in a capsule or metal wire during treatment and needs to be physically placed precisely at the treatment position.
When the radionuclides are ligands (such as with Lutathera and Pluvicto), the technique is also known as radioligand therapy.
== Clinical use ==
=== Thyroid conditions ===
Iodine-131 (131I) is the most common RNT worldwide and uses the simple compound sodium iodide with a radioactive isotope of iodine. The patient (human or animal) may ingest an oral solid or liquid amount or receive an intravenous injection of a solution of the compound. The iodide ion is selectively taken up by the thyroid gland. Both benign conditions like thyrotoxicosis and certain malignant conditions like papillary thyroid cancer can be treated with the radiation emitted by radioiodine. Iodine-131 produces beta and gamma radiation. The beta radiation released damages both normal thyroid tissue and any thyroid cancer that behaves like normal thyroid in taking up iodine, so providing the therapeutic effect, whilst most of the gamma radiation escapes the patient's body.
Most of the iodine not taken up by thyroid tissue is excreted through the kidneys into the urine. After radioiodine treatment the urine will be radioactive or 'hot', and the patients themselves will also emit gamma radiation. Depending on the amount of radioactivity administered, it can take several days for the radioactivity to reduce to the point where the patient does not pose a radiation hazard to bystanders. Patients are often treated as inpatients and there are international guidelines, as well as legislation in many countries, which govern the point at which they may return home.
=== Bone metastasis ===
Radium-223 chloride, strontium-89 chloride and samarium-153 EDTMP are used to treat secondary cancer in the bones. Radium and strontium mimic calcium in the body. Samarium is bound to tetraphosphate EDTMP, phosphates are taken up by osteoblastic (bone forming) repairs that occur adjacent to some metastatic lesions.
=== Bone marrow conditions ===
Beta emitting phosphorus-32 (32P), as sodium phosphate, is used to treat overactive bone marrow, in which it is otherwise naturally metabolised.
=== Joint inflammation ===
==== Yttrium-90 colloid ====
An yttrium-90 (90Y) colloidal suspension is used for radiosynovectomy in the knee joint.
=== Liver tumours ===
==== Yttrium-90 spheres ====
90Y in the form of a resin or glass spheres can be used to treat primary and metastatic liver cancers.
=== Neuroendocrine tumours ===
==== Iodine-131 mIBG ====
131I-mIBG (metaiodobenzylguanidine) is used for the treatment of phaeochromocytoma and neuroblastoma.
==== Lutetium-177 ====
177Lu is bound with a DOTA chelator to target neuroendocrine tumours.
== Experimental antibody based methods ==
At the Institute for Transuranium Elements (ITU) work is being done on alpha-immunotherapy, this is an experimental method where antibodies bearing alpha isotopes are used. Bismuth-213 is one of the isotopes which has been used. This is made by the alpha decay of actinium-225. The generation of one short-lived isotope from longer lived isotope is a useful method of providing a portable supply of a short-lived isotope. This is similar to the generation of technetium-99m by a technetium generator. The actinium-225 is made by the irradiation of radium-226 with a cyclotron.
== References == | Wikipedia/Radionuclide_therapy |
Auger therapy is a form of radiation therapy for the treatment of cancer which relies on low-energy electrons (emitted by the Auger effect) to damage cancer cells, rather than the high-energy radiation used in traditional radiation therapy. Similar to other forms of radiation therapy, Auger therapy relies on radiation-induced damage to cancer cells (particularly DNA damage) to arrest cell division, stop tumor growth and metastasis and kill cancerous cells. It differs from other types of radiation therapy in that electrons emitted via the Auger effect (Auger electrons) are released with low kinetic energy. In contrast to traditional α- and β-particle emitters, Auger electron emitters exhibit low cellular toxicity during transit in blood or bone marrow.
Due to their low kinetic energy, emitted Auger electrons travel over a very short range: much less than the size of a single cell, on the order of less than a few-hundred nanometers. This very short-range delivery of energy permits highly targeted therapies, since the radiation-emitting nuclide will be in close proximity to the delivery site (e.g., a DNA strand) to cause cytotoxicity. However, this is a technical challenge; Auger therapeutics must enter their cell-nuclear targets to be most effective. Auger therapeutics are radiolabelled biomolecules, capable of entering cells of interest and binding to specific sub-cellular components. These typically carry a radioactive atom capable of emitting Auger electrons. The Auger electron emission from the atom is stimulated by radioactive decay, or by external pst (primary system therapy, such as X-ray) excitation.
== Auger dose ==
The electron energy in a vacuum may be accurately measured with an electron detector in a Faraday cage, where the bias placed on the cage will accurately define the particle energy reaching the detector. The range of low-energy electrons in tissue or water, particularly electrons at the nanometer scale, cannot be easily measured; it must be inferred, since low-energy electrons scatter at large angles and travel in a zigzag path whose termination distance must be considered statistically and from differential measurements of higher-energy electrons at a much higher range. A 20 eV electron in water, for example, could have a range of 20 nm for 103 Gy or 5 nm for 104.7 Gy. For a group of 9–12 Auger electrons with energies at 12–18 eV in water (including the effect of water ionization at approximately 10 eV), an estimate of 106 Gy is probably sufficiently accurate. The illustration shows the simulated dose calculation in water for an electron using a Monte Carlo random walk which gives up to 0.1 MGy. For a moderately-heavy atom to yield a dozen or more Auger electrons from its inner-shell ionization, the Auger dose becomes 106 Gy per event.
== Candidates for molecular modification with in situ dose ==
With a large, localized dose in situ for molecular modification, the most obvious target molecule is the DNA duplex (where the complementary strands are separated by several nanometers). However, DNA duplex atoms are light elements (with only a few electrons each). Even if they could be induced by a photon beam to deliver Auger electrons, at under 1 keV they would be too soft to penetrate tissue sufficiently for therapy. Mid-range or heavy atoms (from bromine to platinum, for example) which could be induced by sufficiently hard X-ray photons to generate enough electrons to provide low-energy charges in an Auger cascade, will be considered for therapy.
=== Bromine electrons disrupting herpes-specific gene expression ===
When a normal cell transforms, replicating uncontrollably, many unusual genes (including viral material such as herpes genes which are not normally expressed) are expressed with viral-specific functions. The molecule proposed to disrupt the herpes gene is BrdC, where Br replaces a methyl (CH3) with nearly the same ionic radius and location (at the 5th position for BrdU, which has an oxygen molecule at the top). Therefore, BrdC could be oxidized and used as BrdU. Before oxidation, BrdC was unusable as dC or dU in mammalian cells (except for the herpes gene, which could incorporate the BrdC). The bromine atom is made from arsenic, with the addition of an alpha particle in a particle accelerator to form 77Br. It has a half-life of 57 hours and undergoes electron capture: the K-electron is captured by a proton in an unstable nucleus, creating a K hole in Br, and leading to its Auger cascade and disrupting the herpes gene without killing the cell.
This experiment was performed during the 1970s at Memorial Sloan Kettering Cancer Center by Lawrance Helson and C. G. Wang, using 10 neuroblastoma cell cultures, Two cultures were successful in terminating the cell replication with 77Br in vitro, and the experiments were followed by a group of nude mice with implanted tumors.
The in vivo mouse experiments were complicated when the mouse livers cleaved off the sugar component of BrdC rendering the mammalian and herpes genes to incorporate the 77Br-containing base, making no distinction between them. However, the Auger dose with 77BrdC disrupted the herpes-specific gene in several transformed cell cultures.
=== DNA-targeted dose using cisplatin ===
The group of metal-based anticancer drugs originated with cisplatin, one of the leading agents in clinical use. Cisplatin acts by binding to DNA, forming one or two intrastrand cross-links of the G-G adduct at 70% and the A-G adduct at ~20% of the major grooves of the double helix. The planar cis compound (on the same side) is composed of a square molecule with two chloride atoms on one side and two ammonia groups on the other side, centered around the heavy platinum (Pt) which could initiate the Auger dose in situ. Entering a cell with a low NaCl concentration, the aqua-chloride group would detach from the compound (allowing the missing chloride to link the G-G or A-G bases and bend the DNA helixes 45 degrees, damaging them). Although platinum-based antineoplastics are used in as much as 70 percent of all chemotherapy, they are not particularly effective against certain cancers (such as breast and prostate tumors).
The aqua-Cl rationale, detaching the chloride atom from the cisplatin when it enters a cell and binding them to G-G or A-G adducts in the major grooves of the DNA helixes, could be applied to other metals—such as ruthenium (Ru)-chemically similar to platinum. Ruthenium is used to coat the anode target of a mammography X-ray tube, enabling operation at any voltage (22–28 kVp) depending on the compressed thickness of the breast and delivering a high-contrast image. Although ruthenium is lighter than platinum, it can be induced to provide an Auger dose in situ to the DNA adducts and deliver localized chemotherapy.
== Monochromatic X-rays to induce inner-shell ionization ==
=== X-ray tube with transmission target for line emissions ===
Monochromatic X-rays may be channeled from synchrotron radiation, obtained from filtered Coolidge X-ray tubes or from the preferred transmission X-ray tubes. To induce inner-shell ionization with resonant scattering from a moderately-heavy atom with dozens of electrons, the X-ray photon energy must be 30 keV or higher to penetrate tissue in therapeutic applications. Although synchrotron radiation is extremely bright and monochromatic without thermal scattering, its brightness falls off at the fourth power of photon energy. At 15–20 kV or higher an X-ray tube with a molybdenum target, for example, could deliver as much X-ray fluence as a typical synchrotron. A Coolidge X-ray tube brightens by 1.7 kVp and synchrotron brightness decreases by 4 kV, implying that it is not useful for Auger therapy.
== References == | Wikipedia/Auger_therapy |
Brachytherapy is a type of radiotherapy, or radiation treatment, offered to certain cancer patients. There are two types of brachytherapy – high dose-rate (HDR) and low dose-rate (LDR). LDR brachytherapy is the one most commonly used to treat prostate cancer. It may be referred to as 'seed implantation' or it may be called 'pinhole surgery'.
In LDR brachytherapy, tiny radioactive particles the size of a grain of rice (Figure 1) are implanted directly into, or very close to, the tumour. These particles are known as 'seeds', and they can be inserted linked together as strands, or individually. The seeds deliver high doses of radiation to the tumour without affecting the normal healthy tissues around it. The procedure is less damaging than conventional radiation therapy, where the radioactive beam is delivered from outside the body and must pass through other tissues before reaching the tumour.
In addition to seeds, a newer polymer-encapsulated LDR source is available. The source features 103Pd along the full length of the device which is contained using low-Z polymers. The polymer construction and linear radioactive distribution of this source creates a very homogenous dose distribution.
LDR prostate brachytherapy (seed or line source implantation) is a proven treatment for low to high risk localized prostate cancer (when the cancer is contained within the prostate). Under a general anaesthetic, the radioactive seeds are injected through fine needles directly into the prostate, so that the radiotherapy can destroy the cancer cells. The seeds are permanently implanted. They remain in place but gradually become inactive as the radioactivity decays naturally and safely over time. Unlike traditional surgery, LDR brachytherapy requires no incisions and is normally carried out as an outpatient (day case) procedure. Sometimes a single overnight stay in hospital is required. Patients usually recover quickly from LDR brachytherapy. Most men can return to work or normal daily activities within a few days. LDR brachytherapy has fewer side-effects with less risk of incontinence or impotence than other treatment options. It is a popular alternative to major surgery (conventional radical prostatectomy or laparoscopic (keyhole surgery) radical prostatectomy).
Isotopes used include iodine 125 (half-life 59.4 days) palladium 103 (half-life 17 days) and cesium-131 (half life 9.7 days).
== Procedure ==
When LDR prostate brachytherapy (seed or polymer source implantation) is carried out, an ultrasound probe is inserted into the rectum (back passage), and images from this probe are used to assess the size and shape of the prostate gland. This is done so that the doctor can identify how to best deliver the right radiation dose for each patient. Then the seeds are inserted in the exact locations identified at the beginning of the procedure. This usually takes 1–2 hours. No surgical incision is required; instead, the radioactive seeds are inserted into the prostate gland using needles which pass through the skin between the scrotum and the rectum (the perineum) and an ultrasound probe is used to accurately guide them to their final position. The needles are put into the target positions and between 70 and 150 seeds are placed into the prostate. The needles are then removed. {•figure•} shows the grid-like device used to guide the needles into the perineal area; co-ordinates or 'map references' on this grid or template are used to pinpoint the exact positions in the prostate where the seeds are to be placed. Figure 3 shows how the seeds are positioned to target the tumour. The doctor uses ultrasound and X-ray pictures to make sure the seeds are in the right place. A special computer software program is used to make sure the prostate gland is completely covered by just the right dose of radiation (see Figure 4) to ensure that all cancer cells present in the prostate have been completely treated.
Once in place, the seeds or sources slowly begin to release their radiation. While the sources are active, the patient must observe some basic precautions. Travel and contact with adults are fine; however, for the first two months following seed implantation, small children and pregnant women should not be in direct contact with the patient for prolonged periods – for example children should not sit on the patient's knee for any length of time. Sexual intercourse can start again within a few weeks. Very occasionally a seed can be expelled in the semen on ejaculation; if this does happen, it will usually occur in the first few ejaculations, so it is advisable to use a condom for the first two or three occasions of intercourse following LDR brachytherapy.
Patients can usually return to normal activities and work within a few days. They should expect to be seen for follow-up after four to six weeks, and then every three months for a year, six-monthly up to five years, then annually.
== Indications ==
LDR prostate brachytherapy (seed or polymer source implantation) is recommended as a treatment for patients whose cancer is at an early stage (cancer stages T1 to T2), and which has not spread beyond the prostate (localised disease). Doctors use a combination of factors such as cancer stage and grade, PSA level, Gleason score and urine flow (bladder emptying) tests to help them decide if a patient is suitable for LDR brachytherapy. Patients should ask their doctors about the results of these different tests and how they influence the type of treatment they may be offered. LDR brachytherapy in combination with external beam radiotherapy may also be recommended for patients with later-stage cancer and higher PSA level and Gleason score.
== Risks and benefits ==
Since its introduction in the mid-1980s, prostate brachytherapy has become a well-established treatment option for patients with early, localised disease. In the US, over 50,000 eligible prostate cancer patients a year are treated using this method. Brachytherapy is now in widespread use across the world. In the UK, prostate brachytherapy is provided at a majority of cancer centres and thousands of patients have been treated.
=== Clinical benefits ===
LDR prostate brachytherapy on its own has been shown to be highly effective for the treatment of early prostate cancer. The rate of survival with no increase in average PSA levels after LDR brachytherapy is similar to that achieved with external beam radiotherapy and radical prostatectomy. However LDR brachytherapy has a lower risk of some of the complications associated with other treatment options.
=== Side effects ===
LDR prostate brachytherapy (seed or polymer source implantation) is a very effective treatment for low to high risk localized cancer, with patients rapidly returning to normal activities. Although patients may experience urinary problems for the first six months or so after their implant, these usually settle down and lasting problems are rare, only occurring in about 1–2% of patients. The complications include:
urinary incontinence, mainly stress incontinence or urge incontinence, difficulty with urination, and urinary retention. According to a review published in 2002, on the long term, significant obstructive symptoms or persistent urinary retention requiring transurethral resection of the prostate (TURP) occurred in 0–8.7% of patients. Urinary incontinence was found in up to 19% of patients treated by implant who had not had a previous TURP, however, the percentage was a lot higher in those who did (up to 86%). The stress incontinence can be regarded as a result of direct damage to the external urethral sphincter that results from the radiation. Treatment may include lifestyle changes, bladder training, and the use of incontinence pads. Surgical treatment in those who fail initial therapy can include the use of a urethral sling or an artificial urinary sphincter.
bowel problems. Some patients (less than 10%) report an increase in bowel problems (diarrhea or urgency of the bowels), but again this usually settles down without further treatment. Radiation proctitis can be found in 0.5–21.4% of patients who received prostate brachytherapy due to the proximity of the prostate and the large bowel, with significant injury (fistula) occurring in 1–2.4% of patients.
erectile dysfunction (difficulty getting and/or keeping an erection; impotence). The problem ranges from 25 to 50% of men who receive prostate brachytherapy, which is less than that observed in men receiving standard external beam radiation. Within three years, not many men will see significant improvement in potency, and occasionally the numbers may worsen. Treatment options include the use of medications (such as sildenafil and tadalafil, or intracavernous ones), vacuum constriction device, or penile implants.
In a 2006 study looking at patients' quality of life, LDR brachytherapy compared favourably with other treatment options. Table 1 summarises the more common side effects related with each form of treatment and how these may affect patient recovery.
== References ==
== External links ==
Prostate UK (UK) | Wikipedia/Prostate_brachytherapy |
Varian Medical Systems is an American radiation oncology treatments and software maker based in Palo Alto, California. Their medical devices include linear accelerators (LINACs) and software for treating cancer and other medical conditions with radiotherapy, radiosurgery, proton therapy, and brachytherapy. The company supplies software for managing cancer clinics, radiotherapy centers, and medical oncology practices. Varian Medical Systems employs more than 7,100 people at manufacturing sites in North America, Europe, and China and approximately 70 sites globally.
In August 2020, Siemens Healthineers announced plans to acquire Varian for $16.4 billion. The deal was completed in April 2021. After the merger Varian continues to operate independently; it retained its headquarters and employees.
== History ==
Varian was founded in 1948 as Varian Associates by Russell H. Varian, Sigurd F. Varian, William Webster Hansen, and Edward Ginzton to sell the Klystron, the first tube which could generate electromagnetic waves at microwave frequencies, and other electromagnetic equipment.
By 1999, Varian Associates had branched into semiconductor, vacuum tube, and medical device fields. On April 2, 1999, these divisions split to become Varian Semiconductor, Varian, Inc., and Varian Medical Systems.
In August 2020, Siemens Healthineers announced plans to acquire Varian Medical Systems in an all-stock deal valued at $16.4 billion. The deal was approved and completed on 15 April 2021.
=== Acquired companies ===
Before its acquisition by Siemens Healthineers, Varian Medical Systems had acquired other companies, including Pan-Pacific Enterprises, ACCEL Instruments, Bio-Imaging Research, Inc. Sigma Micro Informatique Conseil, Argus Software, Dosetek Oy, Velocity Medical Solutions. and MeVis Medical Solutions AG.
In January 2018, the company announced the acquisition of Sirtex Medical for $1.3 billion.
In 2019, the company acquired CyberHeart, a privately held company with intellectual property (IP) that covers the use of radiation in the heart (cardiac radioablation) and other forms of radiosurgery for cardiovascular disease.
=== Spin-off companies ===
On January 30, 2017, a spin-off of Varex Imaging Corporation (manufacturing of X-ray imaging products) from Varian Medical Systems had been successfully completed.
== Products ==
=== Linear accelerators ===
Varian manufactures a range of megavoltage LINACs with varying levels of features and complexity, for example different numbers of multileaf collimators or the ability to perform radiosurgery.
TrueBeam is a radiotherapy system.
The EDGE radiosurgery suite was launched in 2012. The first cancer centers to use the new system were the Champalimaud Foundation in Lisbon, Portugal, and Henry Ford Health System in Detroit, Michigan.
=== Halcyon ===
In 2017, Varian launched Halcyon. The system features unique dual-layer MLC that enables high modulation with low leakage for every field or arc. Halcyon is advertised to be intuitive, friendly and comfortable for clinical staff and patient alike. This is primarily done by automating several functions typically performed manually by radiographers, such as switching between treatment beams automatically. Additionally, Halcyon also features an automated machine performance check for daily LINAC quality assurance, which can speed up the checking of beam constancy and mechanical performance through the use of a phantom.
However, while Halcyon does boast improved automation and workflow improvements which allow for faster patient treatment, these extra automation tasks can make occasionally make it more difficult for medical physicists to perform detailed Quality Assurance on LINAC performance. Nevertheless, automation in both quality assurance and clinical operation generally make the LINAC easier to operate by checkers and radiation therapists.
=== Proton Therapy ===
Varian manufactures the ProBeam Proton Therapy System, with current and planned installations at several sites globally. These are an all pencil-beam scanning proton therapy system utilizing IMPT (intensity modulated proton therapy), which was developed with PSI of Switzerland. Varian also develops medical software and radiology information system for proton treatment planning system.
=== Ethos Therapy ===
On September 16, 2019, during the 2019 American Society for Radiation Oncology (ASTRO) annual meeting, being held Sept. 15–18 in Chicago, Varian announced Ethos therapy, an artificial intelligence (AI)-driven system designed to increase the capability, flexibility and efficiency of radiotherapy. This new system is designed to deliver an entire adaptive treatment in a typical 15-minute timeslot, from patient setup through treatment delivery.
== Litigation ==
=== Defamation case law ===
In 1999, Varian Medical Systems, Inc. sued a former employee for defamation after they posted numerous messages criticizing the company on the Internet. The lawsuit led to the ruling of Varian v. Delfino by the California Supreme Court on the question whether a trial could proceed while denial of the defendant's anti-SLAPP motion was under appeal. After the state supreme court ruled that a new trial would be necessary because of that technical concern, the case was settled on undisclosed terms.
=== University of Pittsburgh ===
On April 25, 2012, a US federal judge in Pittsburgh awarded attorney fees, costs, and doubled damages totaling $73.6 million to the University of Pittsburgh after the university won a suit on medical patent infringement grounds against Varian.
== References ==
== External links ==
Official website | Wikipedia/Varian_Medical_Systems |
Deoxyribonucleic acid ( ; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of all known organisms and many viruses. DNA and ribonucleic acid (RNA) are nucleic acids. Alongside proteins, lipids and complex carbohydrates (polysaccharides), nucleic acids are one of the four major types of macromolecules that are essential for all known forms of life.
The two DNA strands are known as polynucleotides as they are composed of simpler monomeric units called nucleotides. Each nucleotide is composed of one of four nitrogen-containing nucleobases (cytosine [C], guanine [G], adenine [A] or thymine [T]), a sugar called deoxyribose, and a phosphate group. The nucleotides are joined to one another in a chain by covalent bonds (known as the phosphodiester linkage) between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone. The nitrogenous bases of the two separate polynucleotide strands are bound together, according to base pairing rules (A with T and C with G), with hydrogen bonds to make double-stranded DNA. The complementary nitrogenous bases are divided into two groups, the single-ringed pyrimidines and the double-ringed purines. In DNA, the pyrimidines are thymine and cytosine; the purines are adenine and guanine.
Both strands of double-stranded DNA store the same biological information. This information is replicated when the two strands separate. A large part of DNA (more than 98% for humans) is non-coding, meaning that these sections do not serve as patterns for protein sequences. The two strands of DNA run in opposite directions to each other and are thus antiparallel. Attached to each sugar is one of four types of nucleobases (or bases). It is the sequence of these four nucleobases along the backbone that encodes genetic information. RNA strands are created using DNA strands as a template in a process called transcription, where DNA bases are exchanged for their corresponding bases except in the case of thymine (T), for which RNA substitutes uracil (U). Under the genetic code, these RNA strands specify the sequence of amino acids within proteins in a process called translation.
Within eukaryotic cells, DNA is organized into long structures called chromosomes. Before typical cell division, these chromosomes are duplicated in the process of DNA replication, providing a complete set of chromosomes for each daughter cell. Eukaryotic organisms (animals, plants, fungi and protists) store most of their DNA inside the cell nucleus as nuclear DNA, and some in the mitochondria as mitochondrial DNA or in chloroplasts as chloroplast DNA. In contrast, prokaryotes (bacteria and archaea) store their DNA only in the cytoplasm, in circular chromosomes. Within eukaryotic chromosomes, chromatin proteins, such as histones, compact and organize DNA. These compacting structures guide the interactions between DNA and other proteins, helping control which parts of the DNA are transcribed.
== Properties ==
DNA is a long polymer made from repeating units called nucleotides. The structure of DNA is dynamic along its length, being capable of coiling into tight loops and other shapes. In all species it is composed of two helical chains, bound to each other by hydrogen bonds. Both chains are coiled around the same axis, and have the same pitch of 34 ångströms (3.4 nm). The pair of chains have a radius of 10 Å (1.0 nm). According to another study, when measured in a different solution, the DNA chain measured 22–26 Å (2.2–2.6 nm) wide, and one nucleotide unit measured 3.3 Å (0.33 nm) long. The buoyant density of most DNA is 1.7g/cm3.
DNA does not usually exist as a single strand, but instead as a pair of strands that are held tightly together. These two long strands coil around each other, in the shape of a double helix. The nucleotide contains both a segment of the backbone of the molecule (which holds the chain together) and a nucleobase (which interacts with the other DNA strand in the helix). A nucleobase linked to a sugar is called a nucleoside, and a base linked to a sugar and to one or more phosphate groups is called a nucleotide. A biopolymer comprising multiple linked nucleotides (as in DNA) is called a polynucleotide.
The backbone of the DNA strand is made from alternating phosphate and sugar groups. The sugar in DNA is 2-deoxyribose, which is a pentose (five-carbon) sugar. The sugars are joined by phosphate groups that form phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings. These are known as the 3′-end (three prime end), and 5′-end (five prime end) carbons, the prime symbol being used to distinguish these carbon atoms from those of the base to which the deoxyribose forms a glycosidic bond.
Therefore, any DNA strand normally has one end at which there is a phosphate group attached to the 5′ carbon of a ribose (the 5′ phosphoryl) and another end at which there is a free hydroxyl group attached to the 3′ carbon of a ribose (the 3′ hydroxyl). The orientation of the 3′ and 5′ carbons along the sugar-phosphate backbone confers directionality (sometimes called polarity) to each DNA strand. In a nucleic acid double helix, the direction of the nucleotides in one strand is opposite to their direction in the other strand: the strands are antiparallel. The asymmetric ends of DNA strands are said to have a directionality of five prime end (5′ ), and three prime end (3′), with the 5′ end having a terminal phosphate group and the 3′ end a terminal hydroxyl group. One major difference between DNA and RNA is the sugar, with the 2-deoxyribose in DNA being replaced by the related pentose sugar ribose in RNA.
The DNA double helix is stabilized primarily by two forces: hydrogen bonds between nucleotides and base-stacking interactions among aromatic nucleobases. The four bases found in DNA are adenine (A), cytosine (C), guanine (G) and thymine (T). These four bases are attached to the sugar-phosphate to form the complete nucleotide, as shown for adenosine monophosphate. Adenine pairs with thymine and guanine pairs with cytosine, forming A-T and G-C base pairs.
=== Nucleobase classification ===
The nucleobases are classified into two types: the purines, A and G, which are fused five- and six-membered heterocyclic compounds, and the pyrimidines, the six-membered rings C and T. A fifth pyrimidine nucleobase, uracil (U), usually takes the place of thymine in RNA and differs from thymine by lacking a methyl group on its ring. In addition to RNA and DNA, many artificial nucleic acid analogues have been created to study the properties of nucleic acids, or for use in biotechnology.
=== Non-canonical bases ===
Modified bases occur in DNA. The first of these recognized was 5-methylcytosine, which was found in the genome of Mycobacterium tuberculosis in 1925. The reason for the presence of these noncanonical bases in bacterial viruses (bacteriophages) is to avoid the restriction enzymes present in bacteria. This enzyme system acts at least in part as a molecular immune system protecting bacteria from infection by viruses. Modifications of the bases cytosine and adenine, the more common and modified DNA bases, play vital roles in the epigenetic control of gene expression in plants and animals.
A number of noncanonical bases are known to occur in DNA. Most of these are modifications of the canonical bases plus uracil.
Modified Adenine
N6-carbamoyl-methyladenine
N6-methyadenine
Modified Guanine
7-Deazaguanine
7-Methylguanine
Modified Cytosine
N4-Methylcytosine
5-Carboxylcytosine
5-Formylcytosine
5-Glycosylhydroxymethylcytosine
5-Hydroxycytosine
5-Methylcytosine
Modified Thymidine
α-Glutamythymidine
α-Putrescinylthymine
Uracil and modifications
Base J
Uracil
5-Dihydroxypentauracil
5-Hydroxymethyldeoxyuracil
Others
Deoxyarchaeosine
2,6-Diaminopurine (2-Aminoadenine)
=== Grooves ===
Twin helical strands form the DNA backbone. Another double helix may be found tracing the spaces, or grooves, between the strands. These voids are adjacent to the base pairs and may provide a binding site. As the strands are not symmetrically located with respect to each other, the grooves are unequally sized. The major groove is 22 ångströms (2.2 nm) wide, while the minor groove is 12 Å (1.2 nm) in width. Due to the larger width of the major groove, the edges of the bases are more accessible in the major groove than in the minor groove. As a result, proteins such as transcription factors that can bind to specific sequences in double-stranded DNA usually make contact with the sides of the bases exposed in the major groove. This situation varies in unusual conformations of DNA within the cell (see below), but the major and minor grooves are always named to reflect the differences in width that would be seen if the DNA was twisted back into the ordinary B form.
=== Base pairing ===
In a DNA double helix, each type of nucleobase on one strand bonds with just one type of nucleobase on the other strand. This is called complementary base pairing. Purines form hydrogen bonds to pyrimidines, with adenine bonding only to thymine in two hydrogen bonds, and cytosine bonding only to guanine in three hydrogen bonds. This arrangement of two nucleotides binding together across the double helix (from six-carbon ring to six-carbon ring) is called a Watson-Crick base pair. DNA with high GC-content is more stable than DNA with low GC-content. A Hoogsteen base pair (hydrogen bonding the 6-carbon ring to the 5-carbon ring) is a rare variation of base-pairing. As hydrogen bonds are not covalent, they can be broken and rejoined relatively easily. The two strands of DNA in a double helix can thus be pulled apart like a zipper, either by a mechanical force or high temperature. As a result of this base pair complementarity, all the information in the double-stranded sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication. This reversible and specific interaction between complementary base pairs is critical for all the functions of DNA in organisms.
==== ssDNA vs. dsDNA ====
Most DNA molecules are actually two polymer strands, bound together in a helical fashion by noncovalent bonds; this double-stranded (dsDNA) structure is maintained largely by the intrastrand base stacking interactions, which are strongest for G,C stacks. The two strands can come apart—a process known as melting—to form two single-stranded DNA (ssDNA) molecules. Melting occurs at high temperatures, low salt and high pH (low pH also melts DNA, but since DNA is unstable due to acid depurination, low pH is rarely used).
The stability of the dsDNA form depends not only on the GC-content (% G,C basepairs) but also on sequence (since stacking is sequence specific) and also length (longer molecules are more stable). The stability can be measured in various ways; a common way is the melting temperature (also called Tm value), which is the temperature at which 50% of the double-strand molecules are converted to single-strand molecules; melting temperature is dependent on ionic strength and the concentration of DNA. As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix that determines the strength of the association between the two strands of DNA. Long DNA helices with a high GC-content have more strongly interacting strands, while short helices with high AT content have more weakly interacting strands. In biology, parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow box in some promoters, tend to have a high AT content, making the strands easier to pull apart.
In the laboratory, the strength of this interaction can be measured by finding the melting temperature Tm necessary to break half of the hydrogen bonds. When all the base pairs in a DNA double helix melt, the strands separate and exist in solution as two entirely independent molecules. These single-stranded DNA molecules have no single common shape, but some conformations are more stable than others.
=== Amount ===
In humans, the total female diploid nuclear genome per cell extends for 6.37 Gigabase pairs (Gbp), is 208.23 cm long and weighs 6.51 picograms (pg). Male values are 6.27 Gbp, 205.00 cm, 6.41 pg. Each DNA polymer can contain hundreds of millions of nucleotides, such as in chromosome 1. Chromosome 1 is the largest human chromosome with approximately 220 million base pairs, and would be 85 mm long if straightened.
In eukaryotes, in addition to nuclear DNA, there is also mitochondrial DNA (mtDNA) which encodes certain proteins used by the mitochondria. The mtDNA is usually relatively small in comparison to the nuclear DNA. For example, the human mitochondrial DNA forms closed circular molecules, each of which contains 16,569 DNA base pairs, with each such molecule normally containing a full set of the mitochondrial genes. Each human mitochondrion contains, on average, approximately 5 such mtDNA molecules. Each human cell contains approximately 100 mitochondria, giving a total number of mtDNA molecules per human cell of approximately 500. However, the amount of mitochondria per cell also varies by cell type, and an egg cell can contain 100,000 mitochondria, corresponding to up to 1,500,000 copies of the mitochondrial genome (constituting up to 90% of the DNA of the cell).
=== Sense and antisense ===
A DNA sequence is called a "sense" sequence if it is the same as that of a messenger RNA copy that is translated into protein. The sequence on the opposite strand is called the "antisense" sequence. Both sense and antisense sequences can exist on different parts of the same strand of DNA (i.e. both strands can contain both sense and antisense sequences). In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but the functions of these RNAs are not entirely clear. One proposal is that antisense RNAs are involved in regulating gene expression through RNA-RNA base pairing.
A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction between sense and antisense strands by having overlapping genes. In these cases, some DNA sequences do double duty, encoding one protein when read along one strand, and a second protein when read in the opposite direction along the other strand. In bacteria, this overlap may be involved in the regulation of gene transcription, while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome.
=== Supercoiling ===
DNA can be twisted like a rope in a process called DNA supercoiling. With DNA in its "relaxed" state, a strand usually circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become more tightly or more loosely wound. If the DNA is twisted in the direction of the helix, this is positive supercoiling, and the bases are held more tightly together. If they are twisted in the opposite direction, this is negative supercoiling, and the bases come apart more easily. In nature, most DNA has slight negative supercoiling that is introduced by enzymes called topoisomerases. These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such as transcription and DNA replication.
=== Alternative DNA structures ===
DNA exists in many possible conformations that include A-DNA, B-DNA, and Z-DNA forms, although only B-DNA and Z-DNA have been directly observed in functional organisms. The conformation that DNA adopts depends on the hydration level, DNA sequence, the amount and direction of supercoiling, chemical modifications of the bases, the type and concentration of metal ions, and the presence of polyamines in solution.
The first published reports of A-DNA X-ray diffraction patterns—and also B-DNA—used analyses based on Patterson functions that provided only a limited amount of structural information for oriented fibers of DNA. An alternative analysis was proposed by Wilkins et al. in 1953 for the in vivo B-DNA X-ray diffraction-scattering patterns of highly hydrated DNA fibers in terms of squares of Bessel functions. In the same journal, James Watson and Francis Crick presented their molecular modeling analysis of the DNA X-ray diffraction patterns to suggest that the structure was a double helix.
Although the B-DNA form is most common under the conditions found in cells, it is not a well-defined conformation but a family of related DNA conformations that occur at the high hydration levels present in cells. Their corresponding X-ray diffraction and scattering patterns are characteristic of molecular paracrystals with a significant degree of disorder.
Compared to B-DNA, the A-DNA form is a wider right-handed spiral, with a shallow, wide minor groove and a narrower, deeper major groove. The A form occurs under non-physiological conditions in partly dehydrated samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, and in enzyme-DNA complexes. Segments of DNA where the bases have been chemically modified by methylation may undergo a larger change in conformation and adopt the Z form. Here, the strands turn about the helical axis in a left-handed spiral, the opposite of the more common B form. These unusual structures can be recognized by specific Z-DNA binding proteins and may be involved in the regulation of transcription.
=== Alternative DNA chemistry ===
For many years, exobiologists have proposed the existence of a shadow biosphere, a postulated microbial biosphere of Earth that uses radically different biochemical and molecular processes than currently known life. One of the proposals was the existence of lifeforms that use arsenic instead of phosphorus in DNA. A report in 2010 of the possibility in the bacterium GFAJ-1 was announced, though the research was disputed, and evidence suggests the bacterium actively prevents the incorporation of arsenic into the DNA backbone and other biomolecules.
=== Quadruplex structures ===
At the ends of the linear chromosomes are specialized regions of DNA called telomeres. The main function of these regions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as the enzymes that normally replicate DNA cannot copy the extreme 3′ ends of chromosomes. These specialized chromosome caps also help protect the DNA ends, and stop the DNA repair systems in the cell from treating them as damage to be corrected. In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence.
These guanine-rich sequences may stabilize chromosome ends by forming structures of stacked sets of four-base units, rather than the usual base pairs found in other DNA molecules. Here, four guanine bases, known as a guanine tetrad, form a flat plate. These flat four-base units then stack on top of each other to form a stable G-quadruplex structure. These structures are stabilized by hydrogen bonding between the edges of the bases and chelation of a metal ion in the centre of each four-base unit. Other structures can also be formed, with the central set of four bases coming from either a single strand folded around the bases, or several different parallel strands, each contributing one base to the central structure.
In addition to these stacked structures, telomeres also form large loop structures called telomere loops, or T-loops. Here, the single-stranded DNA curls around in a long circle stabilized by telomere-binding proteins. At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop.
=== Branched DNA ===
In DNA, fraying occurs when non-complementary regions exist at the end of an otherwise complementary double-strand of DNA. However, branched DNA can occur if a third strand of DNA is introduced and contains adjoining regions able to hybridize with the frayed regions of the pre-existing double-strand. Although the simplest example of branched DNA involves only three strands of DNA, complexes involving additional strands and multiple branches are also possible. Branched DNA can be used in nanotechnology to construct geometric shapes, see the section on uses in technology below.
=== Artificial bases ===
Several artificial nucleobases have been synthesized, and successfully incorporated in the eight-base DNA analogue named Hachimoji DNA. Dubbed S, B, P, and Z, these artificial bases are capable of bonding with each other in a predictable way (S–B and P–Z), maintain the double helix structure of DNA, and be transcribed to RNA. Their existence could be seen as an indication that there is nothing special about the four natural nucleobases that evolved on Earth. On the other hand, DNA is tightly related to RNA which does not only act as a transcript of DNA but also performs as molecular machines many tasks in cells. For this purpose it has to fold into a structure. It has been shown that to allow to create all possible structures at least four bases are required for the corresponding RNA, while a higher number is also possible but this would be against the natural principle of least effort.
=== Acidity ===
The phosphate groups of DNA give it similar acidic properties to phosphoric acid and it can be considered as a strong acid. It will be fully ionized at a normal cellular pH, releasing protons which leave behind negative charges on the phosphate groups. These negative charges protect DNA from breakdown by hydrolysis by repelling nucleophiles which could hydrolyze it.
=== Macroscopic appearance ===
Pure DNA extracted from cells forms white, stringy clumps.
== Chemical modifications and altered DNA packaging ==
=== Base modifications and DNA packaging ===
The expression of genes is influenced by how the DNA is packaged in chromosomes, in a structure called chromatin. Base modifications can be involved in packaging, with regions that have low or no gene expression usually containing high levels of methylation of cytosine bases. DNA packaging and its influence on gene expression can also occur by covalent modifications of the histone protein core around which DNA is wrapped in the chromatin structure or else by remodeling carried out by chromatin remodeling complexes (see Chromatin remodeling). There is, further, crosstalk between DNA methylation and histone modification, so they can coordinately affect chromatin and gene expression.
For one example, cytosine methylation produces 5-methylcytosine, which is important for X-inactivation of chromosomes. The average level of methylation varies between organisms—the worm Caenorhabditis elegans lacks cytosine methylation, while vertebrates have higher levels, with up to 1% of their DNA containing 5-methylcytosine. Despite the importance of 5-methylcytosine, it can deaminate to leave a thymine base, so methylated cytosines are particularly prone to mutations. Other base modifications include adenine methylation in bacteria, the presence of 5-hydroxymethylcytosine in the brain, and the glycosylation of uracil to produce the "J-base" in kinetoplastids.
=== Damage ===
DNA can be damaged by many sorts of mutagens, which change the DNA sequence. Mutagens include oxidizing agents, alkylating agents and also high-energy electromagnetic radiation such as ultraviolet light and X-rays. The type of DNA damage produced depends on the type of mutagen. For example, UV light can damage DNA by producing thymine dimers, which are cross-links between pyrimidine bases. On the other hand, oxidants such as free radicals or hydrogen peroxide produce multiple forms of damage, including base modifications, particularly of guanosine, and double-strand breaks. A typical human cell contains about 150,000 bases that have suffered oxidative damage. Of these oxidative lesions, the most dangerous are double-strand breaks, as these are difficult to repair and can produce point mutations, insertions, deletions from the DNA sequence, and chromosomal translocations. These mutations can cause cancer. Because of inherent limits in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer. DNA damages that are naturally occurring, due to normal cellular processes that produce reactive oxygen species, the hydrolytic activities of cellular water, etc., also occur frequently. Although most of these damages are repaired, in any cell some DNA damage may remain despite the action of repair processes. These remaining DNA damages accumulate with age in mammalian postmitotic tissues. This accumulation appears to be an important underlying cause of aging.
Many mutagens fit into the space between two adjacent base pairs, this is called intercalation. Most intercalators are aromatic and planar molecules; examples include ethidium bromide, acridines, daunomycin, and doxorubicin. For an intercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix. This inhibits both transcription and DNA replication, causing toxicity and mutations. As a result, DNA intercalators may be carcinogens, and in the case of thalidomide, a teratogen. Others such as benzo[a]pyrene diol epoxide and aflatoxin form DNA adducts that induce errors in replication. Nevertheless, due to their ability to inhibit DNA transcription and replication, other similar toxins are also used in chemotherapy to inhibit rapidly growing cancer cells.
== Biological functions ==
DNA usually occurs as linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes. The set of chromosomes in a cell makes up its genome; the human genome has approximately 3 billion base pairs of DNA arranged into 46 chromosomes. The information carried by DNA is held in the sequence of pieces of DNA called genes. Transmission of genetic information in genes is achieved via complementary base pairing. For example, in transcription, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNA sequence through the attraction between the DNA and the correct RNA nucleotides. Usually, this RNA copy is then used to make a matching protein sequence in a process called translation, which depends on the same interaction between RNA nucleotides. In an alternative fashion, a cell may copy its genetic information in a process called DNA replication. The details of these functions are covered in other articles; here the focus is on the interactions between DNA and other molecules that mediate the function of the genome.
=== Genes and genomes ===
Genomic DNA is tightly and orderly packed in the process called DNA condensation, to fit the small available volumes of the cell. In eukaryotes, DNA is located in the cell nucleus, with small amounts in mitochondria and chloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the nucleoid. The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, and regulatory sequences such as promoters and enhancers, which control transcription of the open reading frame.
In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about 1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of non-coding repetitive sequences. The reasons for the presence of so much noncoding DNA in eukaryotic genomes and the extraordinary differences in genome size, or C-value, among species, represent a long-standing puzzle known as the "C-value enigma". However, some DNA sequences that do not code protein may still encode functional non-coding RNA molecules, which are involved in the regulation of gene expression.
Some noncoding DNA sequences play structural roles in chromosomes. Telomeres and centromeres typically contain few genes but are important for the function and stability of chromosomes. An abundant form of noncoding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation. These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence.
=== Transcription and translation ===
A gene is a sequence of DNA that contains genetic information and can influence the phenotype of an organism. Within a gene, the sequence of bases along a DNA strand defines a messenger RNA sequence, which then defines one or more protein sequences. The relationship between the nucleotide sequences of genes and the amino-acid sequences of proteins is determined by the rules of translation, known collectively as the genetic code. The genetic code consists of three-letter 'words' called codons formed from a sequence of three nucleotides (e.g. ACT, CAG, TTT).
In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase. This RNA copy is then decoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, which carries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons (43 combinations). These encode the twenty standard amino acids, giving most amino acids more than one possible codon. There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are the TAG, TAA, and TGA codons, (UAG, UAA, and UGA on the mRNA).
=== Replication ===
Cell division is essential for an organism to grow, but, when a cell divides, it must replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent. The double-stranded structure of DNA provides a simple mechanism for DNA replication. Here, the two strands are separated and then each strand's complementary DNA sequence is recreated by an enzyme called DNA polymerase. This enzyme makes the complementary strand by finding the correct base through complementary base pairing and bonding it onto the original strand. As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms are used to copy the antiparallel strands of the double helix. In this way, the base on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA.
=== Extracellular nucleic acids ===
Naked extracellular DNA (eDNA), most of it released by cell death, is nearly ubiquitous in the environment. Its concentration in soil may be as high as 2 μg/L, and its concentration in natural aquatic environments may be as high at 88 μg/L. Various possible functions have been proposed for eDNA: it may be involved in horizontal gene transfer; it may provide nutrients; and it may act as a buffer to recruit or titrate ions or antibiotics. Extracellular DNA acts as a functional extracellular matrix component in the biofilms of several bacterial species. It may act as a recognition factor to regulate the attachment and dispersal of specific cell types in the biofilm; it may contribute to biofilm formation; and it may contribute to the biofilm's physical strength and resistance to biological stress.
Cell-free fetal DNA is found in the blood of the mother, and can be sequenced to determine a great deal of information about the developing fetus.
Under the name of environmental DNA eDNA has seen increased use in the natural sciences as a survey tool for ecology, monitoring the movements and presence of species in water, air, or on land, and assessing an area's biodiversity.
=== Neutrophil extracellular traps ===
Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA, which allow neutrophils, a type of white blood cell, to kill extracellular pathogens while minimizing damage to the host cells.
== Interactions with proteins ==
All the functions of DNA depend on interactions with proteins. These protein interactions can be non-specific, or the protein can bind specifically to a single DNA sequence. Enzymes can also bind to DNA and of these, the polymerases that copy the DNA base sequence in transcription and DNA replication are particularly important.
=== DNA-binding proteins ===
Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions. Within chromosomes, DNA is held in complexes with structural proteins. These proteins organize the DNA into a compact structure called chromatin. In eukaryotes, this structure involves DNA binding to a complex of small basic proteins called histones, while in prokaryotes multiple types of proteins are involved. The histones form a disk-shaped complex called a nucleosome, which contains two complete turns of double-stranded DNA wrapped around its surface. These non-specific interactions are formed through basic residues in the histones, making ionic bonds to the acidic sugar-phosphate backbone of the DNA, and are thus largely independent of the base sequence. Chemical modifications of these basic amino acid residues include methylation, phosphorylation, and acetylation. These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA more or less accessible to transcription factors and changing the rate of transcription. Other non-specific DNA-binding proteins in chromatin include the high-mobility group proteins, which bind to bent or distorted DNA. These proteins are important in bending arrays of nucleosomes and arranging them into the larger structures that make up chromosomes.
A distinct group of DNA-binding proteins is the DNA-binding proteins that specifically bind single-stranded DNA. In humans, replication protein A is the best-understood member of this family and is used in processes where the double helix is separated, including DNA replication, recombination, and DNA repair. These binding proteins seem to stabilize single-stranded DNA and protect it from forming stem-loops or being degraded by nucleases.
In contrast, other proteins have evolved to bind to particular DNA sequences. The most intensively studied of these are the various transcription factors, which are proteins that regulate transcription. Each transcription factor binds to one particular set of DNA sequences and activates or inhibits the transcription of genes that have these sequences close to their promoters. The transcription factors do this in two ways. Firstly, they can bind the RNA polymerase responsible for transcription, either directly or through other mediator proteins; this locates the polymerase at the promoter and allows it to begin transcription. Alternatively, transcription factors can bind enzymes that modify the histones at the promoter. This changes the accessibility of the DNA template to the polymerase.
As these DNA targets can occur throughout an organism's genome, changes in the activity of one type of transcription factor can affect thousands of genes. Consequently, these proteins are often the targets of the signal transduction processes that control responses to environmental changes or cellular differentiation and development. The specificity of these transcription factors' interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowing them to "read" the DNA sequence. Most of these base-interactions are made in the major groove, where the bases are most accessible.
=== DNA-modifying enzymes ===
==== Nucleases and ligases ====
Nucleases are enzymes that cut DNA strands by catalyzing the hydrolysis of the phosphodiester bonds. Nucleases that hydrolyse nucleotides from the ends of DNA strands are called exonucleases, while endonucleases cut within strands. The most frequently used nucleases in molecular biology are the restriction endonucleases, which cut DNA at specific sequences. For instance, the EcoRV enzyme shown to the left recognizes the 6-base sequence 5′-GATATC-3′ and makes a cut at the horizontal line. In nature, these enzymes protect bacteria against phage infection by digesting the phage DNA when it enters the bacterial cell, acting as part of the restriction modification system. In technology, these sequence-specific nucleases are used in molecular cloning and DNA fingerprinting.
Enzymes called DNA ligases can rejoin cut or broken DNA strands. Ligases are particularly important in lagging strand DNA replication, as they join the short segments of DNA produced at the replication fork into a complete copy of the DNA template. They are also used in DNA repair and genetic recombination.
==== Topoisomerases and helicases ====
Topoisomerases are enzymes with both nuclease and ligase activity. These proteins change the amount of supercoiling in DNA. Some of these enzymes work by cutting the DNA helix and allowing one section to rotate, thereby reducing its level of supercoiling; the enzyme then seals the DNA break. Other types of these enzymes are capable of cutting one DNA helix and then passing a second strand of DNA through this break, before rejoining the helix. Topoisomerases are required for many processes involving DNA, such as DNA replication and transcription.
Helicases are proteins that are a type of molecular motor. They use the chemical energy in nucleoside triphosphates, predominantly adenosine triphosphate (ATP), to break hydrogen bonds between bases and unwind the DNA double helix into single strands. These enzymes are essential for most processes where enzymes need to access the DNA bases.
==== Polymerases ====
Polymerases are enzymes that synthesize polynucleotide chains from nucleoside triphosphates. The sequence of their products is created based on existing polynucleotide chains—which are called templates. These enzymes function by repeatedly adding a nucleotide to the 3′ hydroxyl group at the end of the growing polynucleotide chain. As a consequence, all polymerases work in a 5′ to 3′ direction. In the active site of these enzymes, the incoming nucleoside triphosphate base-pairs to the template: this allows polymerases to accurately synthesize the complementary strand of their template. Polymerases are classified according to the type of template that they use.
In DNA replication, DNA-dependent DNA polymerases make copies of DNA polynucleotide chains. To preserve biological information, it is essential that the sequence of bases in each copy are precisely complementary to the sequence of bases in the template strand. Many DNA polymerases have a proofreading activity. Here, the polymerase recognizes the occasional mistakes in the synthesis reaction by the lack of base pairing between the mismatched nucleotides. If a mismatch is detected, a 3′ to 5′ exonuclease activity is activated and the incorrect base removed. In most organisms, DNA polymerases function in a large complex called the replisome that contains multiple accessory subunits, such as the DNA clamp or helicases.
RNA-dependent DNA polymerases are a specialized class of polymerases that copy the sequence of an RNA strand into DNA. They include reverse transcriptase, which is a viral enzyme involved in the infection of cells by retroviruses, and telomerase, which is required for the replication of telomeres. For example, HIV reverse transcriptase is an enzyme for AIDS virus replication. Telomerase is an unusual polymerase because it contains its own RNA template as part of its structure. It synthesizes telomeres at the ends of chromosomes. Telomeres prevent fusion of the ends of neighboring chromosomes and protect chromosome ends from damage.
Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand into RNA. To begin transcribing a gene, the RNA polymerase binds to a sequence of DNA called a promoter and separates the DNA strands. It then copies the gene sequence into a messenger RNA transcript until it reaches a region of DNA called the terminator, where it halts and detaches from the DNA. As with human DNA-dependent DNA polymerases, RNA polymerase II, the enzyme that transcribes most of the genes in the human genome, operates as part of a large protein complex with multiple regulatory and accessory subunits.
== Genetic recombination ==
A DNA helix usually does not interact with other segments of DNA, and in human cells, the different chromosomes even occupy separate areas in the nucleus called "chromosome territories". This physical separation of different chromosomes is important for the ability of DNA to function as a stable repository for information, as one of the few times chromosomes interact is in chromosomal crossover which occurs during sexual reproduction, when genetic recombination occurs. Chromosomal crossover is when two DNA helices break, swap a section and then rejoin.
Recombination allows chromosomes to exchange genetic information and produces new combinations of genes, which increases the efficiency of natural selection and can be important in the rapid evolution of new proteins. Genetic recombination can also be involved in DNA repair, particularly in the cell's response to double-strand breaks.
The most common form of chromosomal crossover is homologous recombination, where the two chromosomes involved share very similar sequences. Non-homologous recombination can be damaging to cells, as it can produce chromosomal translocations and genetic abnormalities. The recombination reaction is catalyzed by enzymes known as recombinases, such as RAD51. The first step in recombination is a double-stranded break caused by either an endonuclease or damage to the DNA. A series of steps catalyzed in part by the recombinase then leads to joining of the two helices by at least one Holliday junction, in which a segment of a single strand in each helix is annealed to the complementary strand in the other helix. The Holliday junction is a tetrahedral junction structure that can be moved along the pair of chromosomes, swapping one strand for another. The recombination reaction is then halted by cleavage of the junction and re-ligation of the released DNA. Only strands of like polarity exchange DNA during recombination. There are two types of cleavage: east-west cleavage and north–south cleavage. The north–south cleavage nicks both strands of DNA, while the east–west cleavage has one strand of DNA intact. The formation of a Holliday junction during recombination makes it possible for genetic diversity, genes to exchange on chromosomes, and expression of wild-type viral genomes.
== Evolution ==
DNA contains the genetic information that allows all forms of life to function, grow and reproduce. However, it is unclear how long in the 4-billion-year history of life DNA has performed this function, as it has been proposed that the earliest forms of life may have used RNA as their genetic material. RNA may have acted as the central part of early cell metabolism as it can both transmit genetic information and carry out catalysis as part of ribozymes. This ancient RNA world where nucleic acid would have been used for both catalysis and genetics may have influenced the evolution of the current genetic code based on four nucleotide bases. This would occur, since the number of different bases in such an organism is a trade-off between a small number of bases increasing replication accuracy and a large number of bases increasing the catalytic efficiency of ribozymes. However, there is no direct evidence of ancient genetic systems, as recovery of DNA from most fossils is impossible because DNA survives in the environment for less than one million years, and slowly degrades into short fragments in solution. Claims for older DNA have been made, most notably a report of the isolation of a viable bacterium from a salt crystal 250 million years old, but these claims are controversial.
Building blocks of DNA (adenine, guanine, and related organic molecules) may have been formed extraterrestrially in outer space. Complex DNA and RNA organic compounds of life, including uracil, cytosine, and thymine, have also been formed in the laboratory under conditions mimicking those found in outer space, using starting chemicals, such as pyrimidine, found in meteorites. Pyrimidine, like polycyclic aromatic hydrocarbons (PAHs), the most carbon-rich chemical found in the universe, may have been formed in red giants or in interstellar cosmic dust and gas clouds.
Ancient DNA has been recovered from ancient organisms at a timescale where genome evolution can be directly observed, including from extinct organisms up to millions of years old, such as the woolly mammoth.
== Uses in technology ==
=== Genetic engineering ===
Methods have been developed to purify DNA from organisms, such as phenol-chloroform extraction, and to manipulate it in the laboratory, such as restriction digests and the polymerase chain reaction. Modern biology and biochemistry make intensive use of these techniques in recombinant DNA technology. Recombinant DNA is a man-made DNA sequence that has been assembled from other DNA sequences. They can be transformed into organisms in the form of plasmids or in the appropriate format, by using a viral vector. The genetically modified organisms produced can be used to produce products such as recombinant proteins, used in medical research, or be grown in agriculture.
=== DNA profiling ===
Forensic scientists can use DNA in blood, semen, skin, saliva or hair found at a crime scene to identify a matching DNA of an individual, such as a perpetrator. This process is formally termed DNA profiling, also called DNA fingerprinting. In DNA profiling, the lengths of variable sections of repetitive DNA, such as short tandem repeats and minisatellites, are compared between people. This method is usually an extremely reliable technique for identifying a matching DNA. However, identification can be complicated if the scene is contaminated with DNA from several people. DNA profiling was developed in 1984 by British geneticist Sir Alec Jeffreys, and first used in forensic science to convict Colin Pitchfork in the 1988 Enderby murders case.
The development of forensic science and the ability to now obtain genetic matching on minute samples of blood, skin, saliva, or hair has led to re-examining many cases. Evidence can now be uncovered that was scientifically impossible at the time of the original examination. Combined with the removal of the double jeopardy law in some places, this can allow cases to be reopened where prior trials have failed to produce sufficient evidence to convince a jury. People charged with serious crimes may be required to provide a sample of DNA for matching purposes. The most obvious defense to DNA matches obtained forensically is to claim that cross-contamination of evidence has occurred. This has resulted in meticulous strict handling procedures with new cases of serious crime.
DNA profiling is also used successfully to positively identify victims of mass casualty incidents, bodies or body parts in serious accidents, and individual victims in mass war graves, via matching to family members.
DNA profiling is also used in DNA paternity testing to determine if someone is the biological parent or grandparent of a child with the probability of parentage is typically 99.99% when the alleged parent is biologically related to the child. Normal DNA sequencing methods happen after birth, but there are new methods to test paternity while a mother is still pregnant.
=== DNA enzymes or catalytic DNA ===
Deoxyribozymes, also called DNAzymes or catalytic DNA, were first discovered in 1994. They are mostly single stranded DNA sequences isolated from a large pool of random DNA sequences through a combinatorial approach called in vitro selection or systematic evolution of ligands by exponential enrichment (SELEX). DNAzymes catalyze variety of chemical reactions including RNA-DNA cleavage, RNA-DNA ligation, amino acids phosphorylation-dephosphorylation, carbon-carbon bond formation, etc. DNAzymes can enhance catalytic rate of chemical reactions up to 100,000,000,000-fold over the uncatalyzed reaction. The most extensively studied class of DNAzymes is RNA-cleaving types which have been used to detect different metal ions and designing therapeutic agents. Several metal-specific DNAzymes have been reported including the GR-5 DNAzyme (lead-specific), the CA1-3 DNAzymes (copper-specific), the 39E DNAzyme (uranyl-specific) and the NaA43 DNAzyme (sodium-specific). The NaA43 DNAzyme, which is reported to be more than 10,000-fold selective for sodium over other metal ions, was used to make a real-time sodium sensor in cells.
=== Bioinformatics ===
Bioinformatics involves the development of techniques to store, data mine, search and manipulate biological data, including DNA nucleic acid sequence data. These have led to widely applied advances in computer science, especially string searching algorithms, machine learning, and database theory. String searching or matching algorithms, which find an occurrence of a sequence of letters inside a larger sequence of letters, were developed to search for specific sequences of nucleotides. The DNA sequence may be aligned with other DNA sequences to identify homologous sequences and locate the specific mutations that make them distinct. These techniques, especially multiple sequence alignment, are used in studying phylogenetic relationships and protein function. Data sets representing entire genomes' worth of DNA sequences, such as those produced by the Human Genome Project, are difficult to use without the annotations that identify the locations of genes and regulatory elements on each chromosome. Regions of DNA sequence that have the characteristic patterns associated with protein- or RNA-coding genes can be identified by gene finding algorithms, which allow researchers to predict the presence of particular gene products and their possible functions in an organism even before they have been isolated experimentally. Entire genomes may also be compared, which can shed light on the evolutionary history of particular organism and permit the examination of complex evolutionary events.
=== DNA nanotechnology ===
DNA nanotechnology uses the unique molecular recognition properties of DNA and other nucleic acids to create self-assembling branched DNA complexes with useful properties. DNA is thus used as a structural material rather than as a carrier of biological information. This has led to the creation of two-dimensional periodic lattices (both tile-based and using the DNA origami method) and three-dimensional structures in the shapes of polyhedra. Nanomechanical devices and algorithmic self-assembly have also been demonstrated, and these DNA structures have been used to template the arrangement of other molecules such as gold nanoparticles and streptavidin proteins. DNA and other nucleic acids are the basis of aptamers, synthetic oligonucleotide ligands for specific target molecules used in a range of biotechnology and biomedical applications.
=== History and anthropology ===
Because DNA collects mutations over time, which are then inherited, it contains historical information, and, by comparing DNA sequences, geneticists can infer the evolutionary history of organisms, their phylogeny. This field of phylogenetics is a powerful tool in evolutionary biology. If DNA sequences within a species are compared, population geneticists can learn the history of particular populations. This can be used in studies ranging from ecological genetics to anthropology.
=== Information storage ===
DNA as a storage device for information has enormous potential since it has much higher storage density compared to electronic devices. However, high costs, slow read and write times (memory latency), and insufficient reliability has prevented its practical use.
== History ==
DNA was first isolated by the Swiss physician Friedrich Miescher who, in 1869, discovered a microscopic substance in the pus of discarded surgical bandages. As it resided in the nuclei of cells, he called it "nuclein". In 1878, Albrecht Kossel isolated the non-protein component of "nuclein", nucleic acid, and later isolated its five primary nucleobases.
In 1909, Phoebus Levene identified the base, sugar, and phosphate nucleotide unit of RNA (then named "yeast nucleic acid"). In 1929, Levene identified deoxyribose sugar in "thymus nucleic acid" (DNA). Levene suggested that DNA consisted of a string of four nucleotide units linked together through the phosphate groups ("tetranucleotide hypothesis"). Levene thought the chain was short and the bases repeated in a fixed order. In 1927, Nikolai Koltsov proposed that inherited traits would be inherited via a "giant hereditary molecule" made up of "two mirror strands that would replicate in a semi-conservative fashion using each strand as a template". In 1928, Frederick Griffith in his experiment discovered that traits of the "smooth" form of Pneumococcus could be transferred to the "rough" form of the same bacteria by mixing killed "smooth" bacteria with the live "rough" form. This system provided the first clear suggestion that DNA carries genetic information.
In 1933, while studying virgin sea urchin eggs, Jean Brachet suggested that DNA is found in the cell nucleus and that RNA is present exclusively in the cytoplasm. At the time, "yeast nucleic acid" (RNA) was thought to occur only in plants, while "thymus nucleic acid" (DNA) only in animals. The latter was thought to be a tetramer, with the function of buffering cellular pH.
In 1937, William Astbury produced the first X-ray diffraction patterns that showed that DNA had a regular structure.
In 1943, Oswald Avery, along with co-workers Colin MacLeod and Maclyn McCarty, identified DNA as the transforming principle, supporting Griffith's suggestion (Avery–MacLeod–McCarty experiment). Erwin Chargaff developed and published observations now known as Chargaff's rules, stating that in DNA from any species of any organism, the amount of guanine should be equal to cytosine and the amount of adenine should be equal to thymine.
Late in 1951, Francis Crick started working with James Watson at the Cavendish Laboratory within the University of Cambridge. DNA's role in heredity was confirmed in 1952 when Alfred Hershey and Martha Chase in the Hershey–Chase experiment showed that DNA is the genetic material of the enterobacteria phage T2.
In May 1952, Raymond Gosling, a graduate student working under the supervision of Rosalind Franklin, took an X-ray diffraction image, labeled as "Photo 51", at high hydration levels of DNA. This photo was given to Watson and Crick by Maurice Wilkins and was critical to their obtaining the correct structure of DNA. Franklin told Crick and Watson that the backbones had to be on the outside. Before then, Linus Pauling, and Watson and Crick, had erroneous models with the chains inside and the bases pointing outwards. Franklin's identification of the space group for DNA crystals revealed to Crick that the two DNA strands were antiparallel. In February 1953, Linus Pauling and Robert Corey proposed a model for nucleic acids containing three intertwined chains, with the phosphates near the axis, and the bases on the outside. Watson and Crick completed their model, which is now accepted as the first correct model of the double helix of DNA. On 28 February 1953 Crick interrupted patrons' lunchtime at The Eagle pub in Cambridge, England to announce that he and Watson had "discovered the secret of life".
The 25 April 1953 issue of the journal Nature published a series of five articles giving the Watson and Crick double-helix structure DNA and evidence supporting it. The structure was reported in a letter titled "MOLECULAR STRUCTURE OF NUCLEIC ACIDS A Structure for Deoxyribose Nucleic Acid", in which they said, "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material." This letter was followed by a letter from Franklin and Gosling, which was the first publication of their own X-ray diffraction data and of their original analysis method. Then followed a letter by Wilkins and two of his colleagues, which contained an analysis of in vivo B-DNA X-ray patterns, and which supported the presence in vivo of the Watson and Crick structure.
In April 2023, scientists, based on new evidence, concluded that Rosalind Franklin was a contributor and "equal player" in the discovery process of DNA, rather than otherwise, as may have been presented subsequently after the time of the discovery.
In 1962, after Franklin's death, Watson, Crick, and Wilkins jointly received the Nobel Prize in Physiology or Medicine. Nobel Prizes are awarded only to living recipients. A debate continues about who should receive credit for the discovery.
In an influential presentation in 1957, Crick laid out the central dogma of molecular biology, which foretold the relationship between DNA, RNA, and proteins, and articulated the "adaptor hypothesis". Final confirmation of the replication mechanism that was implied by the double-helical structure followed in 1958 through the Meselson–Stahl experiment. Further work by Crick and co-workers showed that the genetic code was based on non-overlapping triplets of bases, called codons, allowing Har Gobind Khorana, Robert W. Holley, and Marshall Warren Nirenberg to decipher the genetic code. These findings represent the birth of molecular biology.
In 1986, DNA analysis was first used in a criminal investigation when police in the UK requested Alec Jeffreys of the University of Leicester to prove or disprove the involvement in a particular case of a suspect who claimed innocence in the matter. Although the suspect had already confessed to committing a recent rape-murder, he was denying any involvement in a similar crime committed three years earlier. Yet the details of the two cases were so alike that the police concluded both crimes had been committed by the same person. However, all charges against the suspect were dropped when Jeffreys' DNA testing exonerated the suspect — from both the earlier murder and the one to which he'd confessed. Further such DNA profiling led to positive identification of another suspect who, in 1988, was found guilty of both rape-murders.
== See also ==
== References ==
== Further reading ==
== External links ==
DNA binding site prediction on protein
DNA the Double Helix Game From the official Nobel Prize web site
DNA under electron microscope
Dolan DNA Learning Center
Double Helix: 50 years of DNA, Nature
Proteopedia DNA
Proteopedia Forms_of_DNA
ENCODE threads explorer ENCODE home page at Nature
Double Helix 1953–2003 National Centre for Biotechnology Education
Genetic Education Modules for Teachers – DNA from the Beginning Study Guide
PDB Molecule of the Month DNA
"Clue to chemistry of heredity found". The New York Times, June 1953. First American newspaper coverage of the discovery of the DNA structure
DNA from the Beginning Another DNA Learning Center site on DNA, genes, and heredity from Mendel to the human genome project.
The Register of Francis Crick Personal Papers 1938 – 2007 at Mandeville Special Collections Library, University of California, San Diego
Seven-page, handwritten letter that Crick sent to his 12-year-old son Michael in 1953 describing the structure of DNA. See Crick's medal goes under the hammer, Nature, 5 April 2013. | Wikipedia/Double-stranded_DNA |
Selective internal radiation therapy (SIRT), also known as transarterial radioembolization (TARE), radioembolization or intra-arterial microbrachytherapy is a form of radionuclide therapy used in interventional radiology to treat cancer. It is generally for selected patients with surgically unresectable cancers, especially hepatocellular carcinoma or metastasis to the liver. The treatment involves injecting tiny microspheres of radioactive material into the arteries that supply the tumor, where the spheres lodge in the small vessels of the tumor. Because this treatment combines radiotherapy with embolization, it is also called radioembolization. The chemotherapeutic analogue (combining chemotherapy with embolization) is called chemoembolization, of which transcatheter arterial chemoembolization (TACE) is the usual form.
== Principles ==
Radiation therapy is used to kill cancer cells; however, normal cells are also damaged in the process. Currently, therapeutic doses of radiation can be targeted to tumors with great accuracy using linear accelerators in radiation oncology; however, when irradiating using external beam radiotherapy, the beam will always need to travel through healthy tissue, and the normal liver tissue is very sensitive to radiation. The radiation sensitivity of the liver parenchyma limits the radiation dose that can be delivered via external beam radiotherapy. SIRT, on the other hand, involves the direct insertion of radioactive microspheres to a region, resulting in a local and targeted deposition of radioactive dose. It is therefore well-suited for treatment of liver tumors. Due to the local deposition, SIRT is regarded as a type of locoregional therapy (LRT).
The liver has a dual blood supply system; it receives blood from both the hepatic artery and the portal vein. The healthy liver tissue is mainly perfused by the portal vein, while most liver malignancies derive their blood supply from the hepatic artery. Therefore, locoregional therapies such as transarterial chemoembolization or radioembolization, can selectively be administered in the arteries that are supplying the tumors and will preferentially lead to deposition of the particles in the tumor, while sparing the healthy liver tissue from harmful side effects.
In addition, malignancies (including primary and many metastatic liver cancers) are often hypervascular; tumor blood supplies are increased compared to those of normal tissue, further leading to preferential deposition of particles in the tumors.
SIRT can be performed using several techniques, including whole liver treatment, lobar or segmental approaches. Whole liver SIRT targets the entire liver in one treatment and can be used when the disease is spread throughout the liver. Radiation lobectomy targets one of the two liver lobes and can be a good treatment option when only a single lobe is involved or when treating the whole liver in two separate treatments, one lobe at the time. The segmental approach, also called radiation segmentectomy, is a technique where a high dose of radiation is delivered in one or two Couinaud liver segments only. The high dose results in eradication of the tumor while damage to healthy liver tissue is contained to the targeted segments only. This approach results in effective necrosis of the targeted segments. Segmentectomy is only feasible when the tumor(s) are contained in one or two segments. Which technique is applied is determined by catheter placement. The more distally the catheter is placed, the more localized the technique.
== Therapeutic applications ==
Candidates for radioembolization include patients with:
Unresectable liver cancer of primary or secondary origin, such as hepatocellular carcinoma and liver-metastases from a different origin (e.g. colorectal cancer, breast cancer, neuroendocrine cancer, cholangiocarcinoma or soft tissue sarcomas)
No response or intolerance to regional or systemic chemotherapy
No eligibility for potentially curative options such as radiofrequency ablation.
SIRT is currently considered as a salvage therapy. It has been shown to be safe and effective in patients for whom surgery is not possible, and chemotherapy was not effective. Subsequently, several large phase III trials have been started to evaluate the efficacy of SIRT when used earlier in the treatment scheme or in combination treatments with systemic therapy.
SIRT, when added to first line therapy for patients with metastases of colorectal cancer, was evaluated in the SIRFLOX, FOXFIRE and FOXFIRE Global studies. For primary liver cancer (HCC), two large trials comparing SIRT with standard of care chemotherapy, Sorafenib, have been completed, namely the SARAH and SIRveNIB trials.
Results of these studies, published in 2017 and 2018, reported no superiority of SIRT over chemotherapy in terms of overall survival (SARAH, SIRveNIB, FOXFIRE). In the SIRFLOX study, better progression-free survival was also not observed. These trials did not give direct evidence supporting SIRT as a first-line treatment regime for liver cancer. However, these studies did show that SIRT is generally better tolerated than systemic therapy, with less severe adverse events. Simultaneously, for HCC, data derived from a large retrospective analysis showed promising results for SIRT as an earlier stage treatment, particularly with high dose radiation segmentectomy and lobectomy.
More studies and cohort analyses are underway to evaluate subgroups of patients who benefit from SIRT as a first-line or later treatment, or to evaluate the effect of SIRT in combination with chemotherapy (EPOCH, SIR-STEP, SORAMIC, STOP HCC).
For HCC patients currently ineligible for liver transplant, SIRT can sometimes be used to decreases tumor size allowing patients to be candidates for curative treatment. This is sometimes called bridging therapy.
When comparing SIRT with transarterial chemoembolization (TACE), several studies have shown favorable results for SIRT, such as longer time to progression, higher complete response rates and longer progression-free survival.
== Radionuclides and microspheres ==
There are currently three types of commercially available microsphere for SIRT. Two of these use the radionuclide yttrium-90 (90Y) and are made of either glass (TheraSphere) or resin (SIR-Spheres). The third type uses holmium-166 (166Ho) and is made of poly(l-lactic acid), PLLA, (QuiremSpheres). The therapeutic effect of all three types is based on local deposition of radiation dose by high-energy beta particles. All three types of microsphere are permanent implants and stay in the tissue even after radioactivity has decayed.
90Y, a pure beta emitter, has half-life 2.6 days, or 64.1 hours. 166Ho emits both beta and gamma rays emitter, with half-life 26.8 hours. Both 90Y and 166Ho have mean tissue penetration of a few millimeters. 90Y can be imaged using bremsstrahlung SPECT and positron emission tomography (PET). Bremsstrahlung SPECT uses of the approximately 23000 Bremsstrahlung photons per megabecquerel that are produced by interaction of beta particles with tissue. The positrons needed for PET imaging come from a small branch of the decay chain (branching ratio 32×10−6) that gives positrons. 90Y's low bremsstrahlung photon and positron yield make it difficult to perform quantitative imaging.
166Ho's additional gamma emission (81 KeV, 6.7%) makes 166Ho microspheres quantifiable using a gamma camera. Holmium is also paramagnetic, enabling visibility and quantifiability in MRI even after the radioactivity has decayed.
== Regulatory approval ==
=== United States ===
Theraspheres (glass 90Y microspheres) are FDA approved under a humanitarian device exemption for hepatocellular carcinoma (HCC). SIR-spheres (resin 90Y microspheres) are FDA approved under premarket approval for colorectal metastases in combination with chemotherapy.
=== Europe ===
SIR-Spheres were CE-marked as a medical device in 2002, for treating advanced inoperable liver tumors, and Theraspheres in 2014, for treating hepatic neoplasia.
QuiremSpheres (PLLA 166Ho microspheres) received their CE mark in April 2015 for treating unresectable liver tumors and are currently only available for the European market.
== Procedure ==
90Y microsphere treatment requires patient-individualized planning with cross-sectional imaging and arteriograms. Contrast computed tomography and/or contrast-enhanced magnetic resonance imaging of the liver is required to assess tumor and normal liver volumes, portal vein status, and extrahepatic tumor burden. Liver and kidney function tests should be performed; patients with irreversibly elevated serum bilirubin, AST and ALT are excluded, as these are markers of poor liver function. Use of iodinated contrast should be avoided or minimized in patients with chronic kidney disease. Tumor marker levels are also evaluated. Hepatic artery technetium (99mTc) macro aggregated albumin (MAA) scan is performed to evaluate hepatopulmonary shunting (resulting from hepatopulmonary syndrome). Therapeutic radioactive particles travelling through such a shunt can result in a high absorbed radiation dose to the lungs, possibly resulting in radiation pneumonitis. Lung dose >30 gray means increased risk of such pneumonitis.
Initial angiographic evaluation can include an abdominal aortogram, Superior mesenteric and Celiac arteriograms, and selective right and left liver arteriograms. These tests can show gastrointestinal vascular anatomy and flow characteristics. Extrahepatic vessels found on angiographic evaluation can be embolized, to prevent nontarget deposition of microspheres, that can lead to gastrointestinal ulcers. Or the catheter tip can be moved more distally, past the extrahepatic vessels. Once the branch of the hepatic artery supplying the tumor is identified and the tip of the catheter is selectively placed within the artery, the 90Y or 166Ho microspheres are infused. If preferred, particle infusion can be alternated with contrast infusion, to check for stasis or backflow. Radiation dose absorbed, depends on microsphere distribution within the tumor vascularization. Equal distribution is necessary to ensure tumor cells are not spared due to ≈2.5mm mean tissue penetration, with maximum penetration up to 11mm for 90Y or 8.7mm for 166Ho.
After treatment, for 90Y microspheres, bremsstrahlung SPECT or PET scanning may be done within 24 hours after radioembolization to evaluate the distribution. For 166Ho microspheres, quantitative SPECT or MRI can be done. Weeks after treatment, computed tomography or MRI can be done to evaluate anatomic changes. 166Ho microspheres are still visible on MRI after radioactivity has decayed, because holmium is paramagnetic. FDG positron emission tomography may also be done to evaluate changes in metabolic activity.
== Adverse effects ==
Complications include postradioembolization syndrome (PRS), hepatic complications, biliary complications, portal hypertension and lymphopenia. Complications due to extrahepatic deposition include radiation pneumonitis, gastrointestinal ulcers and vascular injury.
Postradioembolization syndrome (PRS) includes fatigue, nausea, vomiting, abdominal discomfort or pain, and cachexia, occurring in 20-70% of patients. Steroids and antiemetic agents may decrease the incidence of PRS.
Liver complications include cirrhosis leading to portal hypertension, radioembolization-induced liver disease (REILD), transient elevations in liver enzymes, and fulminant liver failure. REILD is characterized by jaundice, ascites, hyperbilirubinemia and hypoalbuminemia developing at least 2 weeks-4 months after SIRT, absent tumor progression or biliary obstruction. It can range from minor to fatal and is related to (over)exposure of healthy liver tissue to radiation.
Biliary complications include cholecystitis and biliary strictures.
== History ==
Investigation of yttrium-90 and other radioisotopes for cancer treatment began in the 1960s. Many key concepts, such as preferential blood supply and tumor vascularity, were discovered during this time. Reports of initial use of resin particles of 90Y in humans were published in the late 1970s. In the 1980s, the safety and feasibility of resin and glass yttrium-90 microsphere therapy for liver cancer were validated in a canine model. Clinical trials of yttrium-90 applied to the liver continued throughout the late 1980s to the 1990s, establishing the safety of the therapy. More recently, larger trials and RCTs have shown safety and efficacy of 90Y therapy for the treatment of both primary and metastatic liver malignancies.
Development of holmium-166 microspheres started in the 1990s. The intention was to develop a microsphere with therapeutic radiation dose similar to 90Y, but with better imaging properties, so that distribution of microspheres in the liver could be assessed more precisely. In the 2000s, development progressed to animal studies. 166Ho microspheres for SIRT were first used in humans in 2009, which was first published in 2012. Since then, several trials have been performed showing safety and efficacy of 166Ho SIRT, and more studies are ongoing.
== See also ==
Targeted alpha-particle therapy
Transcatheter arterial chemoembolization
== References ==
== External links ==
Phase III clinical trials of SIR-spheres
Phase III clinical trials of Therasphere | Wikipedia/Selective_internal_radiation_therapy |
Adjuvant therapy, also known as adjunct therapy, adjuvant care, or augmentation therapy, is a therapy that is given in addition to the primary or initial therapy to maximize its effectiveness. The surgeries and complex treatment regimens used in cancer therapy have led the term to be used mainly to describe adjuvant cancer treatments. An example of such adjuvant therapy is the additional treatment usually given after surgery where all detectable disease has been removed, but where there remains a statistical risk of relapse due to the presence of undetected disease. If known disease is left behind following surgery, then further treatment is not technically adjuvant.
An adjuvant used on its own specifically refers to an agent that improves the effect of a vaccine. Medications used to help primary medications are known as add-ons.
== History ==
The term "adjuvant therapy," derived from the Latin term adjuvāre, meaning "to help," was first coined by Paul Carbone and his team at the National Cancer Institute in 1963. In 1968, the National Surgical Adjuvant Breast and Bowel Project (NSABP) published its B-01 trial results for the first randomized trial that evaluated the effect of an adjuvant alkylating agent in breast cancer. The results indicated that the adjuvant therapy given after the initial radical mastectomy "significantly decreased recurrence rate in pre-menopausal women with four or more positive axillary lymph nodes."
The budding theory of using additional therapies to supplement primary surgery was put into practice by Gianni Bonadonna and his colleagues from the Instituto Tumori in Italy in 1973, where they conducted a randomized trial that demonstrated more favorable survival outcomes that accompanied use of Cyclophosphamide Methotrexate Fluorouracil (CMF) after the initial mastectomy.
In 1976, shortly after Bonadonna's landmark trial, Bernard Fisher at the University of Pittsburgh initiated a similar randomized trial that compared the survival of breast cancer patients treated with radiation after the initial mastectomy to those who only received the surgery. His results, published in 1985, indicated increased disease-free survival for the former group.
Despite the initial pushback from the breast cancer surgeons who believed that their radical mastectomies were sufficient in removing all traces of cancer, the success of Bonadonna's and Fisher's trials brought adjuvant therapy to the mainstream in oncology. Since then, the field of adjuvant therapy has expanded to include a range of adjuvant therapies to include chemotherapy, immunotherapy, hormone therapy, and radiation.
== Neoadjuvant therapy ==
Neoadjuvant therapy, in contrast to adjuvant therapy, is given before the main treatment. For example, systemic therapy for breast cancer that is given before removal of a breast is considered neoadjuvant chemotherapy. The most common reason for neoadjuvant therapy for cancer is to reduce the size of the tumor so as to facilitate more effective surgery.
In the context of breast cancer, neoadjuvant chemotherapy administered before surgery can improve survival in patients. If no active cancer cells are present in a tissue extracted from the tumor site after neoadjuvant therapy, physicians classify a case as "pathologic complete response" or "pCR." While response to therapy has been demonstrated to be a strong predictor of outcome, the medical community has still not reached a consensus in regard to the definition of pCR across various breast cancer subtypes. It remains unclear whether pCR can be used as a surrogate end point in breast cancer cases.
== Adjuvant cancer therapy ==
For example, radiotherapy or systemic therapy is commonly given as adjuvant treatment after surgery for breast cancer. Systemic therapy consists of chemotherapy, immunotherapy or biological response modifiers or hormone therapy. Oncologists use statistical evidence to assess the risk of disease relapse before deciding on the specific adjuvant therapy. The aim of adjuvant treatment is to improve disease-specific symptoms and overall survival. Because the treatment is essentially for a risk, rather than for provable disease, it is accepted that a proportion of patients who receive adjuvant therapy will already have been cured by their primary surgery.
Adjuvant systemic therapy and radiotherapy are often given following surgery for multiple types of cancer, including colon cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, and some gynaecological cancers. Some forms of cancer fail to benefit from adjuvant therapy, however. Such cancers include renal cell carcinoma, and certain forms of brain cancer.
Hyperthermia therapy or heat therapy is also a kind of adjuvant therapy that is sometimes given in combination with radiotherapy or chemotherapy to boost the effects of these conventional treatments in treating advanced cancers. Heating the tumour area sensitises it making it more responsive to the other therapies used. It is cost-effective and safe, and is seen to have a promising role in cancer treatment.
=== Controversy ===
A motif found throughout the history of cancer therapy is the tendency for overtreatment. From the time of its inception, the use of adjuvant therapy has received scrutiny for its adverse effects on the quality of life of cancer patients. For example, because side effects of adjuvant chemotherapy can range from nausea to loss of fertility, physicians regularly practice caution when prescribing chemotherapy.
In the context of melanoma, certain treatments, such as Ipilimumab, result in high grade adverse events, or immune-related adverse events, in 10-15% of patients that parallel the effects of metastatic melanoma itself. Similarly, several common adjuvant therapies are noted for having the potential of causing cardiovascular disease. In such cases, physicians must weigh the cost of recurrence against more immediate consequences and consider factors, like age and relative cardiovascular health of a patient, before prescribing certain types of adjuvant therapy.
One of the most notable side effects of adjuvant therapy is the loss of fertility. For pre-pubescent males, testicular tissue cryopreservation is an option for preserving future fertility. For post-pubescent males, this side effect can be assuaged through semen cryopreservation. For pre-menopausal females, options to preserve fertility are oftentimes much more complex. For example, breast cancer patients of fertile age oftentimes have to weigh the risks and benefits associated with starting an adjuvant therapy regimen after primary treatment. In the some low-risk, low-benefit situations, forgoing adjuvant treatment altogether can be a reasonable decision, but in cases where the risk of metastasis is high, patients may be forced to make a difficult decision. Though options for fertility preservation exist (e.g., embryo preservation, oocyte cryopreservation, ovarian suppression, etc.), they are more often than not time-consuming and costly.
As a result of complications that can stem from liberal use of adjuvant therapy, the philosophy surrounding the use of adjuvant therapy in the clinical setting has shifted towards the goal of doing as little harm as possible to patients. The standards for dose intensity of adjuvant treatments and treatment duration are regularly updated to optimize regimen efficiency while minimizing toxic side effects that patients must shoulder.
=== Concomitant or concurrent systemic cancer therapy ===
Concomitant or concurrent systemic cancer therapy refers to administering medical treatments at the same time as other therapies, such as radiation. Adjuvant hormonal therapy is given after prostate removal in prostate cancer, but there are concerns that the side effects, in particular the cardiovascular ones, may outweigh the risk of recurrence. In breast cancer, adjuvant therapy may consist of chemotherapy (doxorubicin, trastuzumab, paclitaxel, docetaxel, cyclophosphamide, fluorouracil, and methotrexate) and radiotherapy, especially after lumpectomy, and hormonal therapy (tamoxifen, letrozole). Adjuvant therapy in breast cancer is used in stage one and two breast cancer following lumpectomy, and in stage three breast cancer due to lymph node involvement.
In glioblastoma multiforme, adjuvant chemoradiotherapy is critical in the case of a completely removed tumor, as with no other therapy, recurrence occurs in 1–3 months.
In early stage one small cell lung carcinoma, adjuvant chemotherapy with gemcitabine, cisplatin, paclitaxel, docetaxel, and other chemotherapeutic agents, and adjuvant radiotherapy is administered to either the lung, to prevent a local recurrence, or the brain to prevent metastases.
In testicular cancer, adjuvant either radiotherapy or chemotherapy may be used following orchidectomy. Previously, mainly radiotherapy was used, as a full course of cytotoxic chemotherapy produced far more side effects then a course of external beam radiotherapy (EBRT). However, it has been found a single dose of carboplatin is as effective as EBRT in stage II testicular cancer, with only mild side effects (transient myelosuppressive action vs severe and prolonged myelosuppressive neutropenic illness in normal chemotherapy, and much less vomiting, diarrhea, mucositis, and no alopecia in 90% of cases.
Adjuvant therapy is particularly effective in certain types of cancer, including colorectal carcinoma, lung cancer, and medulloblastoma. In completely resected medulloblastoma, 5-year survival rate is 85% if adjuvant chemotherapy and/or craniospinal irradiation is performed, and just 10% if no adjuvant chemotherapy or craniospinal irradiation is used. Prophylactic cranial irradiation for acute lymphoblastic leukemia (ALL) is technically adjuvant, and most experts agree that cranial irradiation decreases risk of central nervous system (CNS) relapse in ALL and possibly acute myeloid leukemia (AML), but it can cause severe side effects, and adjuvant intrathecal methotrexate and hydrocortisone may be just as effective as cranial irradiation, without severe late effects, such as developmental disability, dementia, and increased risk for second malignancy.
=== Dose-dense chemotherapy ===
Dose-dense chemotherapy (DDC) has recently emerged as an effective method of adjuvant chemotherapy administration. DDC uses the Gompertz curve to explain tumor cell growth after initial surgery removes most of the tumor mass. Cancer cells that are left over after a surgery are typically rapidly dividing cells, leaving them the most vulnerable to chemotherapy. Standard chemotherapy regimens are usually administered every 3 weeks to allow normal cells time to recover. This practice has led scientists to the hypothesis that the recurrence of cancer after surgery and chemo may be due to the rapidly diving cells outpacing the rate of chemotherapy administration. DDC tries to circumvent this issue by giving chemotherapy every 2 weeks. To lessen the side effects of chemotherapy that can be exacerbated with more closely administered chemotherapy treatments, growth factors are typically given in conjunction with DDC to restore white blood cell counts. A recent 2018 meta-analysis of DDC clinical trials in early stage breast cancer patients indicated promising results in premenopausal women, but DDC has yet to become the standard of treatment in clinics.
=== Specific cancers ===
==== Malignant melanoma ====
The role of adjuvant therapy in malignant melanoma is and has been hotly debated by oncologists. In 1995 a multicenter study reported improved long-term and disease-free survival in melanoma patients using interferon alpha 2b as an adjuvant therapy. Thus, later that year the U.S. Food and Drug Administration (FDA) approved interferon alpha 2b for melanoma patients who are currently free of disease, to reduce the risk of recurrence. Since then, however, some doctors have argued that interferon treatment does not prolong survival or decrease the rate of relapse, but only causes harmful side effects. Those claims have not been validated by scientific research.
Adjuvant chemotherapy has been used in malignant melanoma, but there is little hard evidence to use chemotherapy in the adjuvant setting. However, melanoma is not a chemotherapy-resistant malignancy. Dacarbazine, temozolomide, and cisplatin all have a reproducible 10–20% response rate in metastatic melanoma.; however, these responses are often short-lived and almost never complete. Multiple studies have shown that adjuvant radiotherapy improves local recurrence rates in high-risk melanoma patients. The studies include at least two M.D. Anderson cancer center studies. However, none of the studies showed that adjuvant radiotherapy had a statistically significant survival benefit.
A number of studies are currently underway to determine whether immunomodulatory agents which have proven effective in the metastatic setting are of benefit as adjuvant therapy for patients with resected stage 3 or 4 disease.
==== Colorectal cancer ====
Adjuvant chemotherapy is effective in preventing the outgrowth of micrometastatic disease from colorectal cancer that has been removed surgically. Studies have shown that fluorouracil is an effective adjuvant chemotherapy among patients with microsatellite stability or low-frequency microsatellite instability, but not in patients with high-frequency microsatellite instability.
==== Pancreatic cancer ====
===== Exocrine =====
Exocrine pancreatic cancer has one of the lowest 5-year survival rates out of all cancers. Because of the poor outcomes associated with surgery alone, the role of adjuvant therapy has been extensively evaluated. A series of studies has established that 6 months of chemotherapy with either gemcitabine or fluorouracil, as compared with observation, improves overall survival. Newer trials incorporating immune checkpoint inhibitors such as the inhibitors to programmed death 1 (PD-1) and the PD-1 ligand PD-L1 are under way.
==== Lung Cancer ====
===== Non-small cell lung cancer (NSCLC) =====
In 2015, a comprehensive meta-analysis of 47 trials and 11,107 patients revealed that NSCLC patients benefit from adjuvant therapy in the form of chemotherapy and/or radiotherapy. The results found that patients given chemotherapy after the initial surgery lived 4% longer than those who did not receive chemotherapy. The toxicity resulting from adjuvant chemotherapy was believed to be manageable.
==== Bladder cancer ====
Neoadjuvant chemotherapy (NAC) followed by a radical cystectomy (RC) and pelvic lymph node dissection is current standard of care to treat muscle-invasive bladder cancer (MIBC). NAC was justified for use in MIBC due to a randomized control trial which showed an improved median overall survival (OS; 77 months vs. 46 months, p = 0.06) and downstaging of pathology (pT0 in 38% vs. 15%) in those who received cisplatin-based NAC followed by surgery vs. surgery alone. These findings were later substantiated by a meta-analysis of 11 clinical trials that showed a 5% and 9% absolute improvement in 5-year overall survival and disease free survival, respectively. Neoadjuvant platinum-based chemotherapy has been demonstrated to improve OS in advanced bladder cancer, but there exists some controversy in the administration. Unpredictable patient response remains the drawback of NAC therapy. While it may shrink tumors in some patients, others may not respond to the treatment at all. It has been demonstrated that a delay in surgery of greater than 12 weeks from the time of diagnosis can decrease OS. Thus, the timing for NAC becomes critical, as a course of NAC therapy could delay a RC and allow the tumor to grow and further metastasize.
Micometastases cannot be ruled out in locally advanced disease, and surgery alone is not always sufficient for complete cancer control. In certain situations, acquiring precise pathologic staging can make adjuvant chemotherapy (AC) an appealing option. Stage specific pathologic treatment and reduced time to surgery can predict prognosis and the absolute OS benefits in patients with at least cT3 disease A systematic review that studied 7,056 patients showed there was a known 9-11% absolute survival benefit at five years attributable to earlier administration of AC; there was a survival benefit seen with earlier administration, as well as a benefit that persisted when compared to controls who received no AC. One limitation of AC is that poor postoperative healing or complications can limit early administration, leading to a potential propagation of potential micrometastases, early recurrence, or reduction in cancer-specific survival. Enhanced recovery after surgery protocols have recently improved perioperative care and may make earlier time to AC administration less challenging. The recent approval of adjuvant immunotherapy for patients with adverse pathology may make earlier adjuvant administration more tolerable, and be provided to patients who received NAC prior to their RC.
==== Breast cancer ====
It has been known for at least 30 years that adjuvant chemotherapy increases the relapse-free survival rate for patients with breast cancer In 2001 after a national consensus conference, a US National Institute of Health panel concluded: "Because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status."
Agents used include:
However, ethical concerns have been raised about the magnitude of benefit of this therapy since it involves further treatment of patients without knowing the possibility of relapse. Dr. Bernard Fisher, among the first to conduct a clinical trial evaluating the efficacy of adjuvant therapy on patients with breast cancer, described it as a "value judgement" in which the potential benefits must be evaluated against the toxicity and cost of treatment and other potential side effects.
Often related to fear of side effects, more recent work has indicated that women do not take adjuvant therapy as prescribed or may stop before they should. A study in 2023 exploring the extent to which an information leaflet could help women to understand the benefits and to reduce their concerns and found that quotes from other women with breast cancer contributes to more positive beliefs.
==== Combination adjuvant chemotherapy for breast cancer ====
Giving two or more chemotherapeutic agents at once may decrease the chances of recurrence of the cancer, and increase overall survival in patients with breast cancer. Commonly used combination chemotherapy regimens used include:
Doxorubicin and cyclophosphamide
Doxorubicin and cyclophosphamide followed by docetaxel
Doxorubicin and cyclophosphamide followed by cyclophosphamide, methotrexate, and fluorouracil
Cyclophosphamide, methotrexate, and fluorouracil.
Docetaxel and cyclophosphamide.
Docetaxel, doxorubicin, and cyclophosphamide
Cyclophosphamide, epirubicin, and fluorouracil.
==== Ovarian Cancer ====
Roughly 15% of ovarian cancers are detected at the early stage, at which the 5-year survival rate is 92%. A Norwegian meta-analysis of 22 randomized studies involving early-stage ovarian cancer revealed the likelihood that 8 out of 10 women treated with cisplatin after the initial surgery were overtreated. Patients diagnosed at an early stage who were treated with cisplatin immediately after surgery fared worse than patients who were left untreated. An additional surgical focus for young women with early-stage cancers is on the conservation of the contralateral ovary for the preservation of fertility.
Most cases of ovarian cancers are detected at the advanced stages, when the survival is greatly reduced.
==== Cervical cancer ====
In early stage cervical cancers, research suggests that adjuvant platinum-based chemotherapy after chemo-radiation may improve survival. For advanced cervical cancers, further research is needed to determine the efficacy, toxicity and effect on the quality of life of adjuvant chemotherapy.
==== Endometrial cancer ====
Since most early-stage endometrial cancer cases are diagnosed early and are typically curable with surgery, adjuvant therapy is only given after surveillance and histological factors determine that a patient is at high risk for recurrence. Adjuvant pelvic radiation therapy has received scrutiny for its use in women under 60, as studies have indicated decreased survival and increased risk of second malignancies following treatment.
In advanced-stage endometrial cancer, adjuvant therapy is typically radiation, chemotherapy, or a combination of the two. While advanced-stage cancer makes up only about 15% of diagnoses, it accounts for 50% of deaths from endometrial cancer. Patients who undergo radiation and/or chemotherapy treatment will sometimes experience modest benefits before relapse.
==== Testicular cancer ====
===== Stage I =====
For seminoma, the three standard options are: active surveillance, adjuvant radiotherapy, or adjuvant chemotherapy.
For non-seminoma, the options include: active surveillance, adjuvant chemotherapy and retroperitoneal lymph node dissection.
As is the case for all reproductive cancers, a degree of caution is taken when deciding to use adjuvant therapy to treat early stage testicular cancer. Though the 5-year survival rates for stage I testicular cancers is approximately 99%, there still exists controversy over whether to overtreat stage I patients to prevent relapse or to wait until patients experience relapse. Patients treated with standard chemotherapy regimens can experience "second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems." As such to minimize overtreatment and avoid potential long-term toxicity caused by adjuvant therapy, most patients today are treated with active surveillance.
=== Side effects of adjuvant cancer therapy ===
Depending on what form of treatment is used, adjuvant therapy can have side effects, like all therapy for neoplasms. Chemotherapy frequently causes vomiting, nausea, alopecia, mucositis, myelosuppression particularly neutropenia, sometimes resulting in septicaemia. Some chemotherapeutic agents can cause acute myeloid leukaemia, in particular the alkylating agents. Rarely, this risk may outweigh the risk of recurrence of the primary tumor. Depending on the agents used, side effects such as chemotherapy-induced peripheral neuropathy, leukoencephalopathy, bladder damage, constipation or diarrhea, hemorrhage, or post-chemotherapy cognitive impairment. Radiotherapy causes radiation dermatitis and fatigue, and, depending on the area being irradiated, may have other side effects. For instance, radiotherapy to the brain can cause memory loss, headache, alopecia, and radiation necrosis of the brain. If the abdomen or spine is irradiated, nausea, vomiting, diarrhea, and dysphagia can occur. If the pelvis is irradiated, prostatitis, proctitis, dysuria, metritis, diarrhea, and abdominal pain can occur. Adjuvant hormonal therapy for prostate cancer may cause cardiovascular disease, and other, possibly severe, side effects.
== See also ==
Analgesic adjuvant
== References == | Wikipedia/Adjuvant_radiation_therapy |
Cobalt therapy is the medical use of gamma rays from the radioisotope cobalt-60 to treat conditions such as cancer. Beginning in the 1950s, cobalt-60 was widely used in external beam radiotherapy (teletherapy) machines, which produced a beam of gamma rays which was directed into the patient's body to kill tumor tissue. Because these "cobalt machines" were expensive and required specialist support, they were often housed in cobalt units. Cobalt therapy was a revolutionary advance in radiotherapy in the post-World War II period but is now being replaced by other technologies such as linear accelerators.
== History ==
Before the development of medical linear accelerators in the 1970s, the only artificial radiation source used for teletherapy was the x-ray tube. Researchers found ordinary x-ray tubes, which used voltages of 50-150 keV, could treat superficial tumors, but did not have the energy to reach tumors deep in the body. To have the penetrating ability to reach deep-seated tumors without subjecting healthy tissue to dangerous radiation doses required rays with energy around a million electron volts (MeV), called "megavoltage" radiation. To produce a significant amount of MeV x-rays required potentials on the tube of 3-5 million volts (3-5 megavolts), necessitating huge, expensive x-ray machines. By the late 1930s these were being built, but they were available at only a few hospitals.
Radioisotopes produced gamma rays in the megavolt range, but prior to World War II virtually the only radioisotope available for radiotherapy was naturally occurring radium (producing 1-2 MeV gamma rays), which was extremely expensive due to its low occurrence in ores. In 1937 the price of radium US$25,000 (equivalent to $546,817 in 2024) per gram, and the total worldwide supply of radium available for beam radiotherapy (teletherapy) was 50 grams.
The invention of the nuclear reactor in the Manhattan Project during World War II made possible the creation of artificial radioisotopes for radiotherapy. Cobalt-60, produced by neutron irradiation of ordinary cobalt metal in a reactor, is a high activity gamma-ray emitter, emitting 1.17 and 1.33 MeV gamma rays with an activity of 44 TBq/g (1,200 Ci/g). The main reason for its wide use in radiotherapy is that it has a longer half-life, 5.27 years, than many other gamma emitters. However, this half-life still requires cobalt sources to be replaced about every 5 years.
In 1949, Dr. Harold E. Johns of the University of Saskatchewan sent a request to the National Research Council (NRC) of Canada asking it to produce cobalt-60 isotopes for use in a cobalt therapy unit prototype. Two cobalt-60 apparatuses were then built, one in Saskatoon in the cancer wing of the University of Saskatchewan and the other in London, Ontario. Johns collected depth-dose data at the University of Saskatchewan which would later become the world standard. The first patient to be treated with cobalt-60 radiation was treated on October 27, 1951, at the War Memorial Children's Hospital in London, Ontario. In 1961 cobalt therapy was expected to replace X-ray radiotherapy.: 14 In 1966, Walt Disney's lung cancer was treated with this procedure, but could not prevent his death.
Dr. Glenn T. Seaborg, chairman of the United States Atomic Energy Commission, Nobel Prize winner and former chancellor of the University of California, dedicated the first cobalt facility of the new Radiation Therapy and Nuclear Medicine Wing of the Cedars of Lebanon Hospital on January 11, 1963 supervised by Dr. Henry L. Jaffe, Director of the new department. A pioneer in the use of the nicknamed "cobalt bomb" the Cedars unit was licensed in 1948 by the Atomic Energy Commission.
== Current use ==
The role of the cobalt unit has partly been replaced by the linear accelerator, which can generate higher-energy radiation, and does not produce the radioactive waste that radioisotopes do with their attendant disposal problems. Cobalt treatment still has a useful role to play in certain applications and is still in widespread use worldwide, since the machinery is relatively reliable and simple to maintain compared to the modern linear accelerator.
== Isotope ==
As used in radiotherapy, cobalt units produce stable, dichromatic beams of 1.17 and 1.33 MeV, resulting in an average beam energy of 1.25 MeV. Cobalt-60 has a half-life of 5.2713 years.: 39
== See also ==
Gamma knife
== References ==
== External links ==
public domain image of cobalt machine | Wikipedia/Cobalt_therapy |
In radiotherapy, radiation treatment planning (RTP) is the process in which a team consisting of radiation oncologists, radiation therapist, medical physicists and medical dosimetrists plan the appropriate external beam radiotherapy or internal brachytherapy treatment technique for a patient with cancer.
== History ==
In the early days of radiotherapy planning was performed on 2D x-ray images, often by hand and with manual calculations. Computerised treatment planning systems began to be used in the 1970s to improve the accuracy and speed of dose calculations.
By the 1990s CT scans, more powerful computers, improved dose calculation algorithms and Multileaf collimators (MLCs) lead to 3D conformal planning (3DCRT), categorised as a Level 2 technique by the European Dynarad consortium. 3DCRT uses MLCs to shape the radiotherapy beam to closely match the shape of a target tumour, reducing the dose to healthy surrounding tissue.
Level 3 techniques such as IMRT and VMAT utilise inverse planning to provide further improved dose distributions (i.e. better coverage of target tumours and sparing of healthy tissue). These methods are growing in use, particularly for cancers in certain locations which have been shown to derive the greatest benefits.
== Image guided planning ==
Typically, medical imaging is used to form a virtual patient for a computer-aided design procedure. A CT scan is often the primary image set for treatment planning while magnetic resonance imaging provides excellent secondary image set for soft tissue contouring. Positron emission tomography is less commonly used and reserved for cases where specific uptake studies can enhance planning target volume delineation. Modern treatment planning systems provide tools for multimodality image matching, also known as image coregistration or fusion. Treatment simulations are used to plan the geometric, radiological, and dosimetric aspects of the therapy using radiation transport simulations and optimization. For intensity modulated radiation therapy (IMRT), this process involves selecting the appropriate beam type (which may include photons, electrons and protons), energy (e.g. 6, 18 megaelectronvolt (MeV) photons) and physical arrangements. In brachytherapy planning involves selecting the appropriate catheter positions and source dwell times
(in HDR brachytherapy) or seed positions (in LDR brachytherapy).
The more formal optimization process is typically referred to as forward planning and inverse planning.
Plans are often assessed with the aid of dose-volume histograms, allowing the clinician to evaluate the uniformity of the dose to the diseased tissue (tumor) and sparing of healthy structures.
=== Forward planning ===
In forward planning, the planner places beams into a radiotherapy treatment planning system that can deliver sufficient radiation to a tumour while both sparing critical organs and minimising the dose to healthy tissue. The required decisions include how many radiation beams to use, which angles each will be delivered from, whether attenuating wedges be used, and which MLC configuration will be used to shape the radiation from each beam.
Once the treatment planner has made an initial plan, the treatment planning system calculates the required monitor units to deliver a prescribed dose to a specific area, and the distribution of dose in the body this will create. The dose distribution in the patient is dependent on the anatomy and beam modifiers such as wedges, specialized collimation, field sizes, tumor depth, etc. The information from a prior CT scan of the patient allows more accurate modelling of the behaviour of the radiation as it travels through the patient's tissues. Different dose calculation models are available, including pencil beam, convolution-superposition and monte carlo simulation, with precision versus computation time being the relevant trade-off.
This type of planning is only sufficiently adept to handle relatively simple cases in which the tumour has a simple shape and is not near any critical organs.
=== Inverse planning ===
In inverse planning a radiation oncologist defines a patient's critical organs and tumour, after which a planner gives target doses and importance factors for each. Then, an optimisation program is run to find the treatment plan which best matches all the input criteria.
In contrast to the manual trial-and-error process of forward planning, inverse planning uses the optimiser to solve the Inverse Problem as set up by the planner.
== See also ==
Brachytherapy planning
Image-guided radiation therapy
== References == | Wikipedia/Treatment_planning |
Acoustic radiation force (ARF) is a physical phenomenon resulting from the interaction of an acoustic wave with an obstacle placed along its path. Generally, the force exerted on the obstacle is evaluated by integrating the acoustic radiation pressure (due to the presence of the sonic wave) over its time-varying surface.
The magnitude of the force exerted by an acoustic plane wave at any given location can be calculated as:
|
F
r
a
d
|
=
2
α
I
c
{\displaystyle |F^{\rm {rad}}|={\frac {2\alpha I}{c}}}
where
|
F
r
a
d
|
{\displaystyle |F^{\rm {rad}}|}
is a force per unit volume, here expressed in kg/(s2cm2);
α
{\displaystyle \alpha }
is the absorption coefficient in Np/cm (nepers per cm);
I
{\displaystyle I}
is the temporal average intensity of the acoustic wave at the given location in W/cm2; and
c
{\displaystyle c}
is the speed of sound in the medium in cm/s.
The effect of frequency on acoustic radiation force is taken into account via intensity (higher pressures are more difficult to attain at higher frequencies) and absorption (higher frequencies have a higher absorption rate). As a reference, water has an acoustic absorption of 0.002 dB/(MHz2cm).(page number?) Acoustic radiation forces on compressible particles such as bubbles are also known as Bjerknes forces, and are generated through a different mechanism, which does not require sound absorption or reflection. Acoustic radiation forces can also be controlled through sub-wavelength patterning of the surface of the object.
When a particle is exposed to an acoustic standing wave it will experience a time-averaged force known as the primary acoustic radiation force (
F
p
r
{\displaystyle F_{pr}}
). In a rectangular microfluidic channel with coplanar walls which acts as a resonance chamber, the incoming acoustic wave can be approximated as a resonant, standing pressure wave of the form:
p
1
=
p
a
cos
k
z
{\displaystyle p_{1}=p_{a}\cos {kz}}
.where
k
{\displaystyle k}
is the wave number.
For a compressible, spherical and micrometre-sized particle (of radius
a
{\displaystyle a}
) suspended in an inviscid fluid in a rectangular micro-channel with a 1D planar standing ultrasonic wave of wavelength
λ
{\displaystyle \lambda }
, the expression for the primary radiation force (at the far-field region where
a
≪
λ
{\displaystyle a\ll \lambda }
）becomes then :
F
p
r
1
D
=
4
π
Φ
(
κ
~
,
ρ
~
)
a
3
k
E
a
c
sin
2
k
z
{\displaystyle F_{pr}^{\rm {1D}}=4\pi \Phi ({\tilde {\kappa }},{\tilde {\rho }})a^{3}kE_{ac}\sin {2kz}}
Φ
(
κ
~
,
ρ
~
)
=
1
3
[
5
ρ
~
−
2
2
ρ
~
+
1
−
κ
~
]
{\displaystyle \Phi ({\tilde {\kappa }},{\tilde {\rho }})={1 \over 3}\left[{5{\tilde {\rho }}-2 \over 2{\tilde {\rho }}+1}-{\tilde {\kappa }}\right]}
E
a
c
=
1
4
κ
f
p
a
2
=
p
a
2
4
ρ
f
c
f
2
{\displaystyle E_{\rm {ac}}={1 \over 4}\kappa _{f}p_{a}^{2}={p_{a}^{2} \over 4\rho _{f}c_{f}^{2}}}
where
Φ
{\displaystyle \Phi }
is the acoustic contrast factor
κ
~
{\displaystyle {\tilde {\kappa }}}
is relative compressibility between the particle
κ
p
{\displaystyle \kappa _{p}}
and the surrounding fluid
κ
f
{\displaystyle \kappa _{f}}
:
κ
~
=
κ
p
/
κ
f
{\displaystyle {\tilde {\kappa }}=\kappa _{p}/\kappa _{f}}
ρ
~
{\displaystyle {\tilde {\rho }}}
is relative density between the particle
ρ
p
{\displaystyle \rho _{p}}
and the surrounding fluid
ρ
f
{\displaystyle \rho _{f}}
:
ρ
~
=
ρ
p
/
ρ
f
{\displaystyle {\tilde {\rho }}=\rho _{p}/\rho _{f}}
E
a
c
{\displaystyle E_{\rm {ac}}}
is the acoustic energy density
The factor
sin
2
k
z
{\displaystyle \sin {2kz}}
makes the radiation force period doubled and phase shifted relative to the pressure wave
p
a
cos
k
z
{\displaystyle p_{a}\cos {kz}}
c
f
{\displaystyle c_{f}}
is the speed of sound in the fluid
== See also ==
Acoustic tweezers
Radiation pressure
== References == | Wikipedia/Acoustic_radiation_force |
In radiation therapy, bolus is a material which has properties equivalent to tissue when irradiated. It is widely used in practice to reduce or alter dosing for targeted radiation therapy.
== Compensating for missing tissue or irregular tissue shape ==
It must be possible to mould the bolus to fill the tissue space. Lincolnshire and Spier's bolus, which is loosely packed in polyethylene bags, is suitable as the bolus bags take the shape of the skin surface these bags are easily smoothed to achieve a flat surface.
== Modifying dose at the skin surface and at depth ==
A specific thickness of bolus can be applied to the skin to alter the dose received at depth in the tissue and on the skin surface. A typical example of this is the application of a defined thickness of bolus to a chest wall for post-mastectomy chest wall treatment, to increase the skin dose. The thickness of bolus applied is dependent on the skin dose required and the angle of incidence of the treatment beams. For example, if oblique 6 MV beams are used for tangential pair, 1 cm of bolus effectively becomes 1.5 cm, i.e., "full bolus".
When a full bolus is applied, bolus thickness equal to the depth of the build-up region removes the skin-sparing effect of a megavoltage x-ray beam. On the other hand, there are boluses that do not require the selection of specific thicknesses to treat a certain depth. These types of boluses have densities higher than water but can be calculated from CT images by the Treatment Planning System (TPS). One of these boluses is commonly known as high-density and high-adaptation bolus (e.g., eXaSkin and eXaSkin Plus).
== Pliable bolus ==
Suitable material must be pliable and easily moulded to the skin surface, but retain a constant thickness. One example includes paraffin gauze.
== Rigid bolus ==
For smaller areas which do not require the bolus to be moulded over the skin, Perspex can be used. The use of Perspex bolus is advantageous for electron set-ups because it is transparent. Since the f.s.d. for most electron fields is 95 cm, so that the movements of the couch are not isocentric, inaccuracies may arise for aligning angled fields when an opaque bolus is inserted.
== Positioning bolus in the treatment beam ==
To ensure that the patient receives the required dose, bolus of the right thickness must be placed correctly. Therefore, bolus requirements must be clearly documented in the setup sheets of the treatment card. When using bolus to compensate for missing tissue, the whole of the bolussed area must be level with the point on the patient where the f.s.d. is set, to ensure dose homogeneity.
When the bolus is used to reduce the skin-sparing effect, the bolus does not necessarily need to touch the skin all over the bolussed area as the scatter is of sufficiently high energy to be unaffected by an air gap. However, it is important that the bolus is uniform thickness. Some bolus materials are easily squashed and must be carefully measured at regular intervals.
== References ==
Perez and Brady's Principles and Practice of Radiation Oncology | Wikipedia/Bolus_(radiation_therapy) |
In radiotherapy, radiation treatment planning (RTP) is the process in which a team consisting of radiation oncologists, radiation therapist, medical physicists and medical dosimetrists plan the appropriate external beam radiotherapy or internal brachytherapy treatment technique for a patient with cancer.
== History ==
In the early days of radiotherapy planning was performed on 2D x-ray images, often by hand and with manual calculations. Computerised treatment planning systems began to be used in the 1970s to improve the accuracy and speed of dose calculations.
By the 1990s CT scans, more powerful computers, improved dose calculation algorithms and Multileaf collimators (MLCs) lead to 3D conformal planning (3DCRT), categorised as a Level 2 technique by the European Dynarad consortium. 3DCRT uses MLCs to shape the radiotherapy beam to closely match the shape of a target tumour, reducing the dose to healthy surrounding tissue.
Level 3 techniques such as IMRT and VMAT utilise inverse planning to provide further improved dose distributions (i.e. better coverage of target tumours and sparing of healthy tissue). These methods are growing in use, particularly for cancers in certain locations which have been shown to derive the greatest benefits.
== Image guided planning ==
Typically, medical imaging is used to form a virtual patient for a computer-aided design procedure. A CT scan is often the primary image set for treatment planning while magnetic resonance imaging provides excellent secondary image set for soft tissue contouring. Positron emission tomography is less commonly used and reserved for cases where specific uptake studies can enhance planning target volume delineation. Modern treatment planning systems provide tools for multimodality image matching, also known as image coregistration or fusion. Treatment simulations are used to plan the geometric, radiological, and dosimetric aspects of the therapy using radiation transport simulations and optimization. For intensity modulated radiation therapy (IMRT), this process involves selecting the appropriate beam type (which may include photons, electrons and protons), energy (e.g. 6, 18 megaelectronvolt (MeV) photons) and physical arrangements. In brachytherapy planning involves selecting the appropriate catheter positions and source dwell times
(in HDR brachytherapy) or seed positions (in LDR brachytherapy).
The more formal optimization process is typically referred to as forward planning and inverse planning.
Plans are often assessed with the aid of dose-volume histograms, allowing the clinician to evaluate the uniformity of the dose to the diseased tissue (tumor) and sparing of healthy structures.
=== Forward planning ===
In forward planning, the planner places beams into a radiotherapy treatment planning system that can deliver sufficient radiation to a tumour while both sparing critical organs and minimising the dose to healthy tissue. The required decisions include how many radiation beams to use, which angles each will be delivered from, whether attenuating wedges be used, and which MLC configuration will be used to shape the radiation from each beam.
Once the treatment planner has made an initial plan, the treatment planning system calculates the required monitor units to deliver a prescribed dose to a specific area, and the distribution of dose in the body this will create. The dose distribution in the patient is dependent on the anatomy and beam modifiers such as wedges, specialized collimation, field sizes, tumor depth, etc. The information from a prior CT scan of the patient allows more accurate modelling of the behaviour of the radiation as it travels through the patient's tissues. Different dose calculation models are available, including pencil beam, convolution-superposition and monte carlo simulation, with precision versus computation time being the relevant trade-off.
This type of planning is only sufficiently adept to handle relatively simple cases in which the tumour has a simple shape and is not near any critical organs.
=== Inverse planning ===
In inverse planning a radiation oncologist defines a patient's critical organs and tumour, after which a planner gives target doses and importance factors for each. Then, an optimisation program is run to find the treatment plan which best matches all the input criteria.
In contrast to the manual trial-and-error process of forward planning, inverse planning uses the optimiser to solve the Inverse Problem as set up by the planner.
== See also ==
Brachytherapy planning
Image-guided radiation therapy
== References == | Wikipedia/Radiation_treatment_planning |
(Redirected from "Pelvic Radiation Disease")
Radiation enteropathy is a syndrome that may develop following abdominal or pelvic radiation therapy for cancer. Many affected people are cancer survivors who had treatment for cervical cancer or prostate cancer. It has also been termed pelvic radiation disease with radiation proctitis being one of its principal features and radiation-induced lumbar plexopathy (RILP) being a rare consequence.
== Signs and symptoms ==
People who have been treated with radiotherapy for pelvic and other abdominal cancers frequently develop gastrointestinal symptoms.
These include:
rectal bleeding
diarrhea and steatorrhea
other defecation disorders including fecal urgency and incontinence.
nutritional deficiencies and weight loss
abdominal pain and bloating
nausea, vomiting and fatigue
Gastrointestinal symptoms are often found together with those in other systems including genitourinary disorders and sexual dysfunction. The burden of symptoms substantially impairs the patients' quality of life.
Nausea, vomiting, fatigue, and diarrhea may happen early during the course of radiotherapy. Radiation enteropathy represents the longer-term, chronic effects that may be found after a latent period most commonly of 6 months to 3 years after the end of treatment. In some cases, it does not become a problem for 20–30 years after successful curative therapy.
=== Associated conditions ===
Small intestinal bacterial overgrowth
Exocrine pancreatic insufficiency
Bile acid diarrhea
Urinary urgency
Sexual dysfunction
== Causes ==
A large number of people receive abdominal and or pelvic radiotherapy as part of their cancer treatment with 60–80% experiencing gastrointestinal symptoms. This is used in standard therapeutic regimens for cervical cancer, prostate cancer, rectal cancer, anal cancer, lymphoma and other abdominal malignancies. Symptoms can be made worse by the effects of surgery, chemotherapy or other drugs given to treat the cancer. Improved methods of radiotherapy have reduced the exposure of non-involved tissues to radiation, concentrating the effects on the cancer. However, as the parts of the intestine such as the ileum and the rectum are immediately adjacent to the cancers, it is impossible to avoid some radiation effects. Previous intestinal surgery, obesity, diabetes, tobacco smoking and vascular disorders increase the chances of developing enteropathy.
== Pathology ==
=== Acute intestinal injury ===
Early radiation enteropathy is very common during or immediately after the course of radiotherapy. This involves cell death, mucosal inflammation and epithelial barrier dysfunction. This injury is termed mucositis and results in symptoms of nausea, vomiting, fatigue, diarrhea and abdominal pain. It recovers within a few weeks or months.
=== Long-term effects of radiation ===
The delayed effects, found 3 months or more after radiation therapy, produce pathology which includes intestinal epithelial mucosal atrophy, vascular sclerosis, and progressive fibrosis of the intestinal wall, among other changes in intestinal neuroendocrine and immune cells and in the gut microbiota. These changes may produce dysmotility, strictures, malabsorption and bleeding. Problems in the terminal ileum and rectum predominate.
== Diagnosis ==
Multiple disorders are found in patients with radiation enteropathy, so guidance including an algorithmic approach to their investigation has been developed. This includes a holistic assessment with investigations including upper endoscopy, colonoscopy, breath tests and other nutritional and gastrointestinal tests. Full investigation is important as many cancer survivors of radiation therapy develop other causes for their symptoms such as colonic polyps, diverticular disease or hemorrhoids.
== Prevention ==
Prevention of radiation injury to the small bowel is a key aim of techniques such as brachytherapy, field size, multiple field arrangements, conformal radiotherapy techniques and intensity-modulated radiotherapy. Medications including ACE inhibitors, statins and probiotics have also been studied and reviewed.
== Treatment ==
In people presenting with symptoms compatible with radiation enteropathy, the initial step is to identify what is responsible for causing the symptoms. Management is best with a multidisciplinary team including gastroenterologists, nurses, dietitians, surgeons and others. Medical treatments include the use of hyperbaric oxygen which has beneficial effects in radiation proctitis or anal damage. Nutritional therapies include treatments directed at specific malabsorptive disorders such as low fat diets and vitamin B12 or vitamin D supplements, together with bile acid sequestrants for bile acid diarrhea and possibly antibiotics for small intestinal bacterial overgrowth. Probiotics have all been suggested as another therapeutic avenue.
Endoscopic therapies including argon plasma coagulation have been used for bleeding telangiectasia in radiation proctitis and at other intestinal sites, although there is a rick of perforation.
Surgical treatment may be needed for intestinal obstruction, fistulae, or perforation, which can happen in more severe cases. These can be fatal if patients present as an emergency, but with improved radiotherapy techniques are now less common.
A systematic review has found there is some promising evidence for non-surgical interventions for late rectal damage, however due to low quality evidence no conclusions could be drawn. Optimal treatment usually produces significant improvements in quality of life.
== Prevalence ==
An increasing number of people are now surviving cancer, with improved treatments producing cure of the malignancy (cancer survivors). There are now over 14 million such people in the US, and this figure is expected to increase to 18 million by 2022. More than half are survivors of abdominal or pelvic cancers, with about 300,000 people receiving abdominal and pelvic radiation each year. It has been estimated there are 1.6 million people in the US with post-radiation intestinal dysfunction, a greater number than those with inflammatory bowel disease such as Crohn's disease or ulcerative colitis.
== Research ==
New agents have been identified in animal studies that may have effects on intestinal radiation injury. The research approach in humans has been reviewed.
== See also ==
Neurogenic bowel dysfunction
== References ==
== External links == | Wikipedia/Pelvic_radiation_disease |
Particle therapy is a form of external beam radiotherapy using beams of energetic neutrons, protons, or other heavier positive ions for cancer treatment. The most common type of particle therapy as of August 2021 is proton therapy.
In contrast to X-rays (photon beams) used in older radiotherapy, particle beams exhibit a Bragg peak in energy loss through the body, delivering their maximum radiation dose at or near the tumor and minimizing damage to surrounding normal tissues.
Particle therapy is also referred to more technically as hadron therapy, excluding photon and electron therapy. Neutron capture therapy, which depends on a secondary nuclear reaction, is also not considered here. Muon therapy, a rare type of particle therapy not within the categories above, has also been studied theoretically; however, muons are still most commonly used for imaging, rather than therapy.
== Method ==
Particle therapy works by aiming energetic ionizing particles at the target tumor. These particles damage the DNA of tissue cells, ultimately causing their death. Because of their reduced ability to repair DNA, cancerous cells are particularly vulnerable to such damage.
The figure shows how beams of electrons, X-rays or protons of different energies (expressed in MeV) penetrate human tissue. Electrons have a short range and are therefore only of interest close to the skin (see electron therapy). Bremsstrahlung X-rays penetrate more deeply, but the dose absorbed by the tissue then shows the typical exponential decay with increasing thickness. For protons and heavier ions, on the other hand, the dose increases while the particle penetrates the tissue and loses energy continuously. Hence the dose increases with increasing thickness up to the Bragg peak that occurs near the end of the particle's range. Beyond the Bragg peak, the dose drops to zero (for protons) or almost zero (for heavier ions).
The advantage of this energy deposition profile is that less energy is deposited into the healthy tissue surrounding the target tissue. This enables higher dose prescription to the tumor, theoretically leading to a higher local control rate, as well as achieving a low toxicity rate.
The ions are first accelerated by means of a cyclotron or synchrotron. The final energy of the emerging particle beam defines the depth of penetration, and hence, the location of the maximum energy deposition. Since it is easy to deflect the beam by means of electro-magnets in a transverse direction, it is possible to employ a raster scan method, i.e., to scan the target area quickly, as the electron beam scans a TV tube. If, in addition, the beam energy and hence the depth of penetration is varied, an entire target volume can be covered in three dimensions, providing an irradiation exactly following the shape of the tumor. This is one of the great advantages compared to conventional X-ray therapy.
At the end of 2008, 28 treatment facilities were in operation worldwide and over 70,000 patients had been treated by means of pions, protons and heavier ions. Most of this therapy has been conducted using protons.
At the end of 2013, 105,000 patients had been treated with proton beams, and approximately 13,000 patients had received carbon-ion therapy.
As of April 1, 2015, for proton beam therapy, there are 49 facilities in the world, including 14 in the US with another 29 facilities under construction. For Carbon-ion therapy, there are eight centers operating and four under construction. Carbon-ion therapy centers exist in Japan, Germany, Italy, and China. Two US federal agencies are hoping to stimulate the establishment of at least one US heavy-ion therapy center.
== Proton therapy ==
Proton therapy is a type of particle therapy that uses a beam of protons to irradiate diseased tissue, most often to treat cancer. The chief advantage of proton therapy over other types of external beam radiotherapy (e.g., radiation therapy, or photon therapy) is that the dose of protons is deposited over a narrow range of depth, which results in minimal entry, exit, or scattered radiation dose to healthy nearby tissues. High dose rates are key in cancer treatment advancements. PSI demonstrated that for cyclotron-based proton therapy facility using momentum cooling, it is possible to achieve remarkable dose rates of 952 Gy/s and 2105 Gy/s at the Bragg peak (in water) for 70 MeV and 230 MeV beams, respectively. When combined with field-specific ridge filters, Bragg peak-based FLASH proton therapy becomes feasible.
== Fast-neutron therapy ==
Fast neutron therapy utilizes high energy neutrons typically between 50 and 70 MeV to treat cancer. Most fast neutron therapy beams are produced by reactors, cyclotrons (d+Be) and linear accelerators. Neutron therapy is currently available in Germany, Russia, South Africa and the United States. In the United States, the only treatment center still operational is in Seattle, Washington. The Seattle center use a cyclotron which produces a proton beam impinging upon a beryllium target.
== Carbon ion radiotherapy ==
Carbon ion therapy (C-ion RT) was pioneered at the National Institute of Radiological Sciences (NIRS) in Chiba, Japan, which began treating patients with carbon ion beams in 1994. This facility was the first to utilize carbon ions clinically, marking a significant advancement in particle therapy for cancer treatment. The therapeutic advantages of carbon ions were recognized earlier, but NIRS was instrumental in establishing its clinical application.
C-ion RT uses particles more massive than protons or neutrons. Carbon ion radiotherapy has increasingly garnered scientific attention as technological delivery options have improved and clinical studies have demonstrated its treatment advantages for many cancers such as prostate, head and neck, lung, and liver cancers, bone and soft tissue sarcomas, locally recurrent rectal cancer, and pancreatic cancer, including locally advanced disease. It also has clear advantages to treat otherwise intractable hypoxic and radio-resistant cancers while opening the door for substantially hypo-fractionated treatment of normal and radio-sensitive disease.
By mid 2017, more than 15,000 patients have been treated worldwide in over 8 operational centers. Japan has been a conspicuous leader in this field. There are five heavy-ion radiotherapy facilities in operation and plans exist to construct several more facilities in the near future. In Germany this type of treatment is available at the Heidelberg Ion-Beam Therapy Center (HIT) and at the Marburg Ion-Beam Therapy Center (MIT). In Italy the National Centre of Oncological Hadrontherapy (CNAO) provides this treatment. Austria will open a CIRT center in 2017, with centers in South Korea, Taiwan, and China soon to open. No CIRT facility now operates in the United States but several are in various states of development.
== Biological advantages of heavy-ion radiotherapy ==
From a radiation biology standpoint, there is considerable rationale to support use of heavy-ion beams in treating cancer patients. All proton and other heavy ion beam therapies exhibit a defined Bragg peak in the body so they deliver their maximum lethal dosage at or near the tumor. This minimizes harmful radiation to the surrounding normal tissues. However, carbon-ions are heavier than protons and so provide a higher relative biological effectiveness (RBE), which increases with depth to reach the maximum at the end of the beam's range. Thus the RBE of a carbon ion beam increases as the ions advance deeper into the tumor-lying region. CIRT provides the highest linear energy transfer (LET) of any currently available form of clinical radiation. This high energy delivery to the tumor results in many double-strand DNA breaks which are very difficult for the tumor to repair. Conventional radiation produces principally single strand DNA breaks which can allow many of the tumor cells to survive. The higher outright cell mortality produced by CIRT may also provide a clearer antigen signature to stimulate the patient's immune system.
== Particle therapy of moving targets ==
The precision of particle therapy of tumors situated in thorax and abdominal region is strongly affected by the target motion. The mitigation of its negative influence requires advanced techniques of tumor position monitoring (e.g., fluoroscopic imaging of implanted radio-opaque fiducial markers or electromagnetic detection of inserted transponders) and irradiation (gating, rescanning, gated rescanning and tumor tracking).
== References ==
== External links ==
Touro University announces first combined particle therapy center in U.S.
PTCOG annual conference | Wikipedia/Charged_particle_therapy |
Intraoperative electron radiation therapy is the application of electron radiation directly to the residual tumor or tumor bed during cancer surgery. Electron beams are useful for intraoperative radiation treatment because, depending on the electron energy, the dose falls off rapidly behind the target site, therefore sparing underlying healthy tissue.
IOERT has been called "precision radiotherapy," because the physician has direct visualization of the tumor and can exclude normal tissue from the field while protecting critical structures within the field and underlying the target volume. One advantage of IOERT is that it can be given at the time of surgery when microscopic residual tumor cells are most vulnerable to destruction. Also, IOERT is often used in combination with external beam radiotherapy (EBR) because it results in less integral doses and shorter treatment times.
== Medical uses ==
IOERT has a long history of clinical applications, with promising results, in the management of solid tumors (e.g., pancreatic cancer, locally advanced and recurrent rectal cancer, breast tumors, sarcomas, and selected gynaecologic and genitourinary malignancies, neuroblastomas and brain tumors. In virtually every tumor site, electron IORT improves local control, reducing the need for additional surgeries or interventions. The following is a list of disease sites currently treated by IOERT:
=== Breast cancer ===
Since 1975, breast cancer rates have declined in the U.S., largely due to mammograms and the use of adjuvant treatments such as radiotherapy. Local recurrence rates are greatly reduced by postoperative radiotherapy, which translates into improved survival: Preventing four local recurrences can prevent one breast cancer death. In one of the largest published studies so far called (ELIOT), researchers found that after treating 574 patients with full-dose IOERT with 21 Gy, at a median follow-up of 20 months, there was an in-breast tumor recurrence rate of only 1.05%. Other studies show that IOERT provides acceptable results when treating breast cancer in low-risk patients. More research is needed for defining the optimal dose of IOERT, alone or in combination with EBRT, and for determining when it may be appropriate to use it as part of the treatment for higher risk patients.
=== Colorectal cancer ===
Over the past 30 years, treatment of locally advanced colorectal cancer has evolved, particularly in the area of local control – stopping the spread of cancer from the tumor site. IOERT shows promising results. When combined with preoperative external beam irradiation plus chemotherapy and maximal surgical resection, it may be a successful component in the treatment of high-risk patients with locally advanced primary or locally recurrent cancers.
=== Gynecological cancer ===
Studies suggest that electron IORT may play an important and useful role in the treatment of patients with locally advanced and recurrent gynecologic cancers, especially for patients with locally recurrent cancer after treatment for their primary lesion. Further research into radiation doses and how to best combine IOERT with other interventions will help to define the sequencing of treatment and the patients who would most benefit from receiving electron IORT, as part of the multimodality treatment of this disease.
=== Head and neck cancer ===
Head and neck cancers are often difficult to treat and have a high rate of recurrence or metastasis. IOERT is an effective means of treating locally advanced or recurrent head and neck cancers. Furthermore, research shows that a boost given by IOERT reduces the ability for surviving tumor cells to replicate, creating extra time for healing of the surgical wound before EBRT is administered.
=== Pancreatic cancer ===
In the U.S., pancreatic cancer is the fourth leading cause of cancer death, even though there has been a slight improvement in mortality rates in recent years. Although the optimal treatment plan remains debated, a combination of radiotherapy and chemotherapy is favored in the U.S. As part of a multimodality treatment, IOERT appears to reduce local recurrence when combined with EBRT, chemoradiation, and surgical resection.
=== Soft tissue sarcomas ===
Soft tissue sarcomas can be effectively treated by electron IORT, which appears to be gaining acceptance as the current practice for sarcomas in combination with EBRT (preferably preoperative) and maximal resection. Used together, IOERT and EBRT appear to be improving local control, and this method is being refined so that it can effectively be used in combination with other interventions if indicated. In studies regarding the delivery of therapeutic radiation in the limb-sparing approach to extremity soft tissue sarcomas, electron IORT has been called ‘precision radiotherapy’ by some, because the treating physician has direct visualization of the tumor or surgical cavity and can manually exclude normal tissue from the field.
== History ==
Spanish and German doctors, in 1905 and 1915 respectively, used intraoperative radiation therapy (IORT) in an attempt to eradicate residual tumors left behind after surgical resection. However, radiation equipment in the early twentieth-century could only deliver low energy X-rays, which had relatively poor penetration; high doses of radiation could not be applied externally without doing unacceptable damage to normal tissues. IORT treatments with low energy or "orthovoltage" X-rays gained advocates throughout the 1930s and 1940s, but the results were inconsistent. The X-rays penetrated beyond the tumor bed to the normal tissues beneath, had poor dose distributions, and took a relatively long time to administer. The technique was largely abandoned in the late 1950s with the advent of megavoltage radiation equipment, which enabled the delivery of more penetrating external radiation.
In 1965, the modern era of IOERT began in Japan at Kyoto University where patients were treated with electrons generated by a betatron Compared with other forms of IORT such as orthovoltage X-ray beams, electron beams improved IOERT dose distributions, limited penetration beyond the tumor, and delivered the required dose much more rapidly. Normal tissue beneath the tumor bed could be protected and shielded, if required, and the treatment took only a few minutes to deliver. These advantages made electrons the preferred radiation for IOERT. The technique gained favor in Japan. Other Japanese hospitals initiated IOERT using electron beams, principally generated from linear particle accelerators. At most institutions, patients were operated on in the operating room (OR) and were transported to the radiation facility for treatment.
With the Japanese IOERT technique, relatively large single doses of radiation were administered during surgery, and most patients received no follow-up external radiation treatment. Even though this reduced the overall dose that could potentially be delivered to the tumor site, the early Japanese results were impressive, particularly for gastric cancer.
The Japanese experience was encouraging enough for several U.S. centers to institute IOERT programs. The first one began at Howard University in 1976 and followed the Japanese protocol of a large, single dose. Howard built a standard radiation therapy facility with one room that could be used as an OR as well as for conventional treatment. Because the radiation equipment was also used for conventional therapy, the competition for the machine limited the number of patients that could be scheduled for IOERT.
In 1978, Massachusetts General Hospital (MGH) started an IORT program. The MGH doctors scheduled one of their conventional therapy rooms for IOERT one afternoon a week, performed surgery in the OR, and transported the patient to the radiation therapy room during surgery. This used the radiation equipment more efficiently and required no additional capital outlay. However, about 30-50% of the patients planned for IOERT were found to be unsuitable candidates for IORT at the time of surgery, mainly because the disease had spread to adjacent organs. This factor, combined with the risks and complexities of moving a patient during surgery, severely limited the number of patients who could be treated using the MGH method of IOERT. Consequently, conventional fractionated external beam irradiation was added to the IOERT dose, either prior to or subsequent to the surgery, in the MGH IOERT program.
The National Cancer Institute (NCI) started an IOERT program in 1979. Their approach combined maximal surgical resection and IOERT and, in most cases, did not include conventional external beam therapy as part of the treatment. Because the NCI protocol relied on IOERT radiation alone, the IOERT fields were often very large, sometimes requiring two or three adjacent and overlapping fields to cover the tumor site. While the NCI results for these very large tumors were not encouraging, they showed that even the combination of aggressive surgery and large IOERT fields had acceptable toxicity. Furthermore, they introduced several technical innovations to IOERT, including the use of television for simultaneous periscopic viewing of the tumor by the surgical team.
In 1981 the Mayo Clinic tried yet another arrangement. They built an OR adjacent to the radiation therapy department. Potential IOERT patients underwent surgery in the regular OR suite. If they were found to be candidates for IOERT, a second surgical procedure was scheduled in the OR adjacent to the radiation facility. By scheduling only those patients known to be suitable for IOERT, they made more efficient use of their radiation therapy machine, but at the cost of subjecting patients to a second surgery. Subsequently, the Mayo Clinic remodeled an OR and installed a conventional radiation therapy machine with its required massive shield walls, and the clinic now routinely treats over 100 IORT patients per year. After 1985, Siemens Medical Systems offered a specialized LINAC for IOERT. It was designed to be used in the OR, but it weighed more than eight tons and required about 100 tons of shielding. This proved to be too expensive an approach for the medical community, and only seven of these specialized units were ever sold.
Dedicating an OR to IOERT increases the number of patients that can be treated and eliminates the risks of double surgeries and moving a patient during surgery. It also eliminates the complex logistics involved in moving patients from the OR to the therapy room and back to the OR. However, this solution has its own disadvantages: Remodeling an OR and purchasing an accelerator is expensive. Moreover, IORT is restricted to that one, specialized OR. Even so, the Mayo Clinic model demonstrated that when therapy equipment is located within an OR, the number of IOERT procedures will increase. In 1985, IOERT began in Italy and involved a specialized method to facilitate surgery followed by transport to the radiotherapy treatment room. Around the same time in France, another IOERT method was developed using the Lyon intra-operative device.
In 1982 the Joint Center for Radiation Therapy (JCRT), at Harvard Medical School, attempted to reduce the cost of performing IORT in an OR by using orthovoltage X-rays to provide the intraoperative dose, which was similar to the approach used in Germany in 1915. But this was less than ideal. While the shielding costs and the cost and weight of the equipment compared favorably with conventional electron accelerators, dose distributions were inferior; treatment times were longer; and bones received a higher radiation dose. For these reasons, the centers rejected IO orthovoltage (X-rays) radiation therapy machines. In addition, these orthovoltage machines (300 kvp) were not designed to be mobile.
=== Advent of Portable Linear Accelerators ===
In the 1990s, electron IORT experienced resurgence, due to the development of mobile linear accelerators that used electron beams—the Mobetron, LIAC, and NOVAC-7 -- and the increasing use of IOERT to treat breast cancer. Prior to the invention of portable LINACs for IOERT, clinicians could only treat IORT patients in specially shielded operating rooms, which were expensive to build, or in a radiotherapy room, which required transporting the anesthetized patient from the OR to the LINAC for treatment. These factors were major obstructions to the widespread adoption of IORT because they added significant cost to treatment as well as logistical complications to surgery, including an increased risk of infection to the patient.
Because portable LINACs for IOERT produced electron beams of energy less than or equal to 12 MeV and did not use bending magnets, the secondary radiation emitted was so low that it didn’t require permanent shielding in the operating room. This greatly reduced the cost of either constructing a new OR or retrofitting an old one. By using mobile units, the possibility of treating patients with IORT was no longer restricted to the availability of special shielded operating rooms, but could be done in regular unshielded ORs.
Currently, the Mobetron, LIAC, and NOVAC-7 linear accelerators are improving patient care by delivering intraoperative radiation electron beam therapy to cancer patients during surgery. All three units are compact and mobile. Invented in the U.S. in 1997, the Mobetron uses X-band technology and a soft docking system. The LIAC and NOVAC-7 are robotic devices developed in Italy that use S-band technology and a hard-docking system. The NOVAC-7 became available for clinical use in the 1990s while the LIAC was introduced to a clinical environment in 2003.
Other non-IOERT mobile units have been developed as well. In 1998, a technique called TARGIT (targeted intraoperative radio therapy) was designed at the University College London for treating the tumor bed after wide local excision (lumpectomy) of breast cancer. TARGIT uses a miniature and mobile X-ray source that emits low energy X-ray radiation (max. 50 kV) in isotropic distribution. (IO)-brachytherapy with MammoSite is also used to treat breast cancer.
Interest in this treatment technique is growing, due in part to the development of LINAC for IOERT by factories.
== See also ==
External beam radiotherapy (EBRT)
Intraoperative radiation therapy (IORT)
Targeted intraoperative radiotherapy (TARGIT)
== References ==
== External links ==
Internal radiation therapy, cancer.org Archived 2010-06-27 at the Wayback Machine | Wikipedia/Intraoperative_electron_radiation_therapy |
Radioimmunotherapy (RIT) uses an antibody labeled with a radionuclide to deliver cytotoxic radiation to a target cell. It is a form of unsealed source radiotherapy. In cancer therapy, an antibody with specificity for a tumor-associated antigen is used to deliver a lethal dose of radiation to the tumor cells. The ability for the antibody to specifically bind to a tumor-associated antigen increases the dose delivered to the tumor cells while decreasing the dose to normal tissues. By its nature, RIT requires a tumor cell to express an antigen that is unique to the neoplasm or is not accessible in normal cells.
== History of available agents ==
131I tositumomab and 90Y ibritumomab tiuxetan were the first agents of radioimmunotherapy, and they were approved for the treatment of refractory non-Hodgkin's lymphoma. This means they are used in patients whose lymphoma is refractory to conventional chemotherapy and the monoclonal antibody rituximab.
=== Agents in clinical development ===
A set of radioimmunotherapy drugs that rely upon an alpha-emitting isotope (e.g., bismuth-213 or, preferably, actinium-225), rather than a beta emitter, as the killing source of radiation is being developed. Several phase II clinical trials for the treatment of acute myeloid leukemia have been carried out using alpha-emitting RITs.
90Y-FF-21101 is a monoclonal antibody against P-cadherin radiolabeled with yttrium-90. It is one of several RIT treatments under investigation intending to treat solid tumors. A phase I clinical trial began in 2015.
== Other applications (non-approved indications) ==
Other types of cancer for which RIT has therapeutic potential include prostate cancer, metastatic melanoma, ovarian cancer, neoplastic meningitis, leukemia, high-grade brain glioma, and metastatic colorectal cancer.
Components of the extracellular matrix and the tumor microenvironment can also be targeted by radioimmunotherapy, such as Netrin-1 (an axon guidance protein) and FAP (a marker for cancer associated fibroblasts).
== References ==
== External links ==
Radioimmunotherapy at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Radioimmunotherapy.org | Wikipedia/Radioimmunotherapy |
Neoadjuvant therapy is the administration of therapeutic agents before a main treatment. One example is neoadjuvant hormone therapy prior to radical radiotherapy for adenocarcinoma of the prostate. Neoadjuvant therapy aims to reduce the size or extent of the cancer before using radical treatment intervention, thus both making procedures easier and more likely to succeed and reducing the consequences of a more extensive treatment technique, which would be required if the tumor were not reduced in size or extent.
Another related concept is that neoadjuvant therapy acts on micrometastatic disease. The downstaging is then a surrogate marker of efficacy on undetected dissemination, resulting in improved longtime survival compared to the surgery-alone strategy.
This systemic therapy (chemotherapy, immunotherapy or hormone therapy) or radiation therapy is commonly used in cancers that are locally advanced, and clinicians plan an operation at a later stage, such as pancreatic cancer. The use of such therapy can effectively reduce the difficulty and morbidity of more extensive procedures.
The use of therapy can turn a tumor from untreatable to treatable by shrinking the volume. Often, it is unclear which surrounding structures are directly involved in the disease and which are just showing signs of inflammation. By administering therapy, a distinction can often be made. Some doctors give the therapy in the hope that a response is seen, and they can then decide what is the best course of action. In some cases, magnetic resonance imaging can predict the response of a patient to neoadjuvant therapy, for example in ovarian cancer.
Not everyone is suitable for neoadjuvant therapy because it can be extremely toxic. Some patients react so severely that further treatments, especially surgery, are precluded, and the patient is rendered unfit for anesthetic.
== See also ==
Adjuvant chemotherapy
== References ==
== Further reading == | Wikipedia/Neoadjuvant_therapy |
Intraoperative radiation therapy (IORT) is radiation therapy that is administered during surgery directly in the operating room (hence intraoperative).
Usually therapeutic levels of radiation are delivered to the tumor bed while the area is exposed during surgery. IORT is typically a component in the multidisciplinary treatment of locally advanced and recurrent cancer, in combination with external beam radiation, surgery, and chemotherapy. As a growing trend in recent years, IORT can also be used in earlier stage cancers such as prostate and breast cancer.
== Medical uses ==
IORT was found to be useful and feasible in the multidisciplinary management of many solid tumors but further studies are needed to determine the benefit more precisely. Single-institution experiences have suggested a role of IORT e.g. in brain tumors and cerebral metastases, locally advanced and recurrent rectal cancer, skin cancer, retroperitoneal sarcoma, pancreatic cancer, and selected gynaecologic and genitourinary malignancies. For local recurrences, irradiation with IORT is, besides brachytherapy, the only radiotherapeutic option if repeated EBRT is no longer possible. Generally, the normal tissue tolerance does not allow a second full-dose course of EBRT, even after years.
=== Breast cancer ===
On 25 July 2014, the UK National Institute for Health and Care Excellence (NICE) gave provisional recommendation for the use of TARGIT IORT with Intrabeam in the UK National Health Service. The 2015 update of guidelines of the Association of Gynecological Oncology (AGO), an autonomous community of the German Society of Gynecology and Obstetrics (DGGG) and the German Cancer Society includes TARGIT IORT during lumpectomy as a recommended option for women with a T1, Grade 1 or 2, ER positive breast cancer.
== Rationale ==
The rationale for IORT is to deliver a high dose of radiation precisely to the targeted area with minimal exposure of surrounding tissues which are displaced or shielded during the IORT. Conventional radiation techniques such as external beam radiotherapy (EBRT) following surgical removal of the tumor have several drawbacks: The tumor bed where the highest dose should be applied is frequently missed due to the complex localization of the wound cavity even when modern radiotherapy planning is used. Additionally, the usual delay between the surgical removal of the tumor and EBRT may allow a repopulation of the tumor cells. These potentially harmful effects can be avoided by delivering the radiation more precisely to the targeted tissues leading to immediate sterilization of residual tumor cells. Another aspect is that wound fluid has a stimulating effect on tumor cells. IORT was found to inhibit the stimulating effects of wound fluid.
== Methods ==
Several methods are used to deliver IORT. IORT can be delivered using electron beams (electron IORT), orthovoltage (250–300 kV) X-rays (X-ray IORT), high-dose-rate brachytherapy (HDR-IORT), or low-energy (50 kV) x-rays (low-energy IORT).
=== Electron IORT ===
While IORT was first used in clinical practice in 1905, the modern era of IORT began with the introduction of electron IORT in the mid-1960s by transporting patients from the OR after the tumor was removed to the radiation department to receive their electron IORT. Electron IORT has the advantages of being able to carefully control the depth of radiation penetration while providing a very uniform dose to the tumor bed. Applied with energies in the range of 3 MeV to 12 MeV, electron IORT can treat to depths of up to 4 cm over areas as large as 300 cm² (i.e. a 10 cm diameter circle) and takes only 1–3 minutes to deliver the prescribed radiation dose. A few hospitals built shielded operation rooms in which a conventional linear accelerator was installed to deliver the IORT radiation. This eliminated the complex logistics involved with patient transportation, but was so costly that only a few hospitals were able to use this approach. The breakthrough came in 1997, with the introduction of a miniaturized, self-shielded, mobile linear accelerator (Mobetron, IntraOp Corporation, US) and a mobile but unshielded linear accelerator (Novac, Liac–SIT, Italy). More than 75,000 patients have been treated with electron IORT, almost half of them since the introduction of mobile electron IORT technology.
=== X-ray IORT ===
Early practitioners of IORT treated primarily abdominal malignancies using superficial X-rays (75–125 kV) and later orthovoltage x-rays (up to 300 kV in energy) prior to the advent of technology that enabled high-energy electrons. For the first 75 years, X-ray IORT was used mostly for palliation, but there were a few anecdotal reports of long-term survivors. In the early 1980s, when the use of electron IORT was increasing and showed promising results for certain indications, a handful of hospitals installed othovoltage units in lightly shielded ORs to see if this lower cost approach could achieve comparable results to that of electron IORT. This approach was less costly than building a shielded OR for an electron IORT unit and eliminated the logistics involved with patient transportation. However, it had a number of problems that limited its appeal. X-ray IORT has a poor uniformity of dose as a function of depth of penetration, the radiation does not stop at a pre-defined depth but continues to deposit radiation to underlying structures, and can do damage to boney structures if too high a dose is delivered. Despite its long use (since the 1930s), fewer than 1000 patients have been treated with this approach, and it is no longer offered at most centers.
=== HDR-IORT ===
This technique was developed in the late 1980s in an attempt to combine the dosimetric advantages of high-dose rate brachytherapy with the challenges of treating some complex anatomic surfaces with IORT. It has the advantage of being lower cost than dedicated electron IORT systems, since many radiation centers already have an HDR system that can be transported to the OR when HDR-IORT is needed. HDR-IORT can also treat very large and convoluted surfaces. However, it does require a shielded OR or a shielded room in the OR complex to deliver the HDR-IORT. The depth of penetration is very limited, typically either ½ cm to 1 cm depth, sometimes requiring extensive surgery due to the limited penetration of the radiation. Treatments tend to be 40 minutes or longer, resulting in greater OR time, more anesthesia and greater blood loss when compared to electron IORT. There are about 10 to 20 active centers using HDR-IORT for locally advanced and recurrent disease, and approximately 2000 patients have received this treatment, mostly for colorectal cancer, head and neck cancer, and gynecologic cancer.
=== Low-energy IORT (50 kV) ===
Intrabeam, (Carl Zeiss AG, Germany) received FDA and CE approval in 1999 and is a miniature mobile X-ray source which emits low-energy X-ray radiation (max. 50 kV) in isotropic distribution. Due to the higher ionization density caused by soft X-ray radiation in the tissue, the relative biological effectiveness (RBE) of low-energy X-rays on tumor cells is higher when compared to high-energy X-rays or gamma rays which are delivered by linear accelerators. The radiation which is produced by low-energy mobile radiation systems has a limited range. For this reason, conventional walls are regarded sufficient to stop the radiation scatter produced in the operating room and no extra measures for radiation protection are necessary. This makes IORT accessible for more hospitals. Targeted intra-operative radiotherapy is a low-energy IORT technique. Evaluation of the long-term outcomes in patients who were treated with TARGIT-IORT for breast cancer confirmed that it is as effective as whole breast external beam radiotherapy in controlling cancer, and also reduces deaths from other causes as shown in a large international randomised clinical trial published in the British Medical Journal.
== See also ==
Brachytherapy
External beam radiotherapy (EBRT)
Intraoperative electron radiation therapy (IOERT)
Targeted intra-operative radiotherapy (TARGIT-IORT)
== References ==
== External links ==
Intraoperative radiation therapy Cancer Treatment Centers of America
Internal radiation therapy, cancer.org
Intraoperative radiation therapy Mayo Clinic
Report of AAPM Radiation Therapy IORT Committee Task Group No. 72 | Wikipedia/Intraoperative_radiation_therapy |
Image-guided radiation therapy (IGRT) is the process of frequent imaging, during a course of radiation treatment, used to direct the treatment, position the patient, and compare to the pre-therapy imaging from the treatment plan. Immediately prior to, or during, a treatment fraction, the patient is localized in the treatment room in the same position as planned from the reference imaging dataset. An example of IGRT would include comparison of a cone beam computed tomography (CBCT) dataset, acquired on the treatment machine, with the computed tomography (CT) dataset from planning. IGRT would also include matching planar kilovoltage (kV) radiographs or megavoltage (MV) images with digital reconstructed radiographs (DRRs) from the planning CT.
This process is distinct from the use of imaging to delineate targets and organs in the planning process of radiation therapy. However, there is a connection between the imaging processes as IGRT relies directly on the imaging modalities from planning as the reference coordinates for localizing the patient. The variety of medical imaging technologies used in planning includes x-ray computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) among others.
IGRT can help to reduce errors in set-up and positioning, allow the margins around target tissue when planning to be reduced, and enable treatment to be adapted during its course, with the aim of overall improving outcomes.
== Goals and clinical benefits ==
The goal of the IGRT process is to improve the accuracy of the radiation field placement, and to reduce the exposure of healthy tissue during radiation treatments. In years past, larger planning target volume (PTV) margins were used to compensate for localization errors during treatment. This resulted in healthy human tissues receiving unnecessary doses of radiation during treatment. PTV margins are the most widely used method to account for geometric uncertainties. By improving accuracy through IGRT, radiation is decreased to surrounding healthy tissues, allowing for increased radiation to the tumour for control.
Currently, certain radiation therapy techniques employ the process of intensity-modulated radiotherapy (IMRT). This form of radiation treatment uses computers and linear accelerators to sculpt a three-dimensional radiation dose map, specific to the target's location, shape and motion characteristics. Because of the level of precision required for IMRT, detailed data must be gathered about tumour locations. The single most important area of innovation in clinical practice is the reduction of the planning target volume margins around the location. The ability to avoid more normal tissue (and thus potentially employ dose escalation strategies) is a direct by-product of the ability to execute therapy with the most accuracy.
Modern, advanced radiotherapy techniques such as proton and charged particle radiotherapy enable superior precision in the dose delivery and spatial distribution of the effective dose. Today, those possibilities add new challenges to IGRT, concerning required accuracy and reliability. Suitable approaches are therefore a matter of intense research.
IGRT increases the amount of data collected throughout the course of therapy. Over the course of time, whether for an individual or a population of patients, this information will allow for the continued assessment and further refinement of treatment techniques. The clinical benefit for the patient is the ability to monitor and adapt to changes that may occur during the course of radiation treatment. Such changes can include tumor shrinkage or expansion, or changes in shape of the tumor and surrounding anatomy.
The precision of IGRT is significantly improved when technologies that were originally developed for image-guided surgery, such as the N-localizer and Sturm-Pastyr localizer, are used in conjunction with these medical imaging technologies. SRT provides a Non-Surgical Alternative for Non-Melanoma Skin Cancer & an Effective Solution for Keloids.
Sensus Healthcare is a manufacturer and distributor of this device With a compact 30”x30” footprint, the mobile unit delivers a precise and calibrated dose of SRT that penetrates only five millimeters below the skin’s surface—making it one of the safest and most effective alternative cancer treatments available. Unlike more powerful radiotherapy devices, the SRT-100™ carefully destroys malignant skin cancer cells while preserving healthy tissue.
== Rationale ==
Radiation therapy is a local treatment that is designed to treat the defined tumour and spare the surrounding normal tissue from receiving doses above specified dose tolerances. There are many factors that may contribute to differences between the planned dose distribution and the delivered dose distribution. One such factor is uncertainty in patient position on the treatment unit. IGRT is a component of the radiation therapy process that incorporates imaging coordinates from the treatment plan to be delivered in order to ensure the patient is properly aligned in the treatment room.
The localization information provided through IGRT approaches can also be used to facilitate robust treatment planning strategies and enable patient modelling, which is beyond the scope of this article.
== History of "guidance" for treatment ==
=== Surface and skin marks ===
In general, at the time of 'planning' (whether a clinical mark up or a full simulation) the intended area for treatment is outlined by the radiation oncologist. Once the area of treatment was determined, marks were placed on the skin. The purpose of the ink marks was to align and position the patient daily for treatment to improve reproducibility of field placement. By aligning the markings with the radiation field (or its representation) in the radiation therapy treatment room, the correct placement of the treatment field could be identified.
Over time, with improvement in technology – light fields with cross hairs, isocentric lasers – and with the shift to the practice of 'tattooing' – a procedure where ink markings are replaced with a permanent mark by the application of ink just under the first layer of skin using a needle in documented locations - the reproducibility of the patient's setup improved.
=== Portal imaging ===
Portal imaging is the acquisition of images using a radiation beam that is being used for giving radiation treatment to a patient. If not all of the radiation beam is absorbed or scattered in the patient, the portion that passes through may be measured and used to produce images of the patient.
It is difficult to establish the initial use of portal imaging to define radiation field placement. From the early days of radiation therapy, X-rays or gamma rays were used to develop large format radiographic films for inspection. With the introduction of cobalt-60 machines in the 1950s, radiation went deeper inside the body, but with lower contrast and poor subjective visibility. Today, using advancements in digital imaging devices, the use of electronic portal imaging has developed into both a tool for accurate field placement and as a quality assurance tool for review by radiation oncologists during check film reviews.
=== Electronic portal imaging ===
Electronic portal imaging is the process of using digital imaging, such as a CCD video camera, liquid ion chamber and amorphous silicon flat panel detectors to create a digital image with improved quality and contrast over traditional portal imaging. The benefit of the system is the ability to capture images, for review and guidance, digitally. These systems are in use throughout clinical practice. Current reviews of Electronic Portal Imaging Devices (EPID) show acceptable results in imaging irradiations and in most clinical practice, provide sufficiently large fields-of-view. kV is not a portal imaging feature.
== Imaging for treatment guidance ==
=== Fluoroscopy ===
Fluoroscopy is an imaging technique that uses a fluoroscope, in coordination with either a screen or image-capturing device to create real-time images of patients' internal structures.
=== Digital X-ray ===
Digital X-ray equipment mounted in the radiation treatment device is often used to picture the patient’s internal anatomy at time before or during treatment, which then can be compared to the original planning CT series. Usage of an orthogonal set-up of two radiographic axes is common, to provide means for highly accurate patient position verification.
=== Computed tomography (CT) ===
A medical imaging method employing tomography where digital geometry processing is used to generate a three-dimensional image of the internal structures of an object from a large series of two-dimensional X-ray images taken around a single axis of rotation. CT produces a volume of data, which can be manipulated, through a process known as windowing, in order to demonstrate various structures based on their ability to attenuate and prevent transmission of the incident X-ray beam.
=== Conventional CT ===
With the growing recognition of the utility of CT imaging in using guidance strategies to match treatment volume position and treatment field placement, several systems have been designed that place an actual conventional 2-D CT machine in the treatment room alongside the treatment linear accelerator. The advantage is that the conventional CT provides accurate measure of tissue attenuation, which is important for dose calculation (e.g. CT on rails).
=== Cone beam ===
Cone-beam computed tomography (CBCT) based image guided systems have been integrated with medical linear accelerators to great success. With improvements in flat-panel technology, CBCT has been able to provide volumetric imaging, and allows for radiographic or fluoroscopic monitoring throughout the treatment process. Cone beam CT acquires many projections over the entire volume of interest in each projection. Using reconstruction strategies pioneered by Feldkamp, the 2D projections are reconstructed into a 3D volume analogous to the CT planning dataset.
=== MVCT ===
Megavoltage computed tomography (MVCT) is a medical imaging technique that uses the Megavoltage range of X-rays to create an image of bony structures or surrogate structures within the body. The original rational for MVCT was spurred by the need for accurate density estimates for treatment planning. Both patient and target structure localization were secondary uses. A test unit using a single linear detector, consisting of 75 cadmium tungstate crystals, was mounted on the linear accelerator gantry. The test results indicated a spatial resolution of .5mm, and a contrast resolution of 5% using this method. While another approach could involve integrating the system directly into the MLA, it would limit the number of revolutions to a number prohibitive to regular use.
=== Optical tracking ===
Optical tracking entails the use of a camera to relay positional information of objects within its inherent coordinate system by means of a subset of the electromagnetic spectrum of wavelengths spanning ultra-violet, visible, and infrared light. Optical navigation has been in use for the last 10 years within image-guided surgery (neurosurgery, ENT, and orthopaedic) and has increased in prevalence within radiotherapy to provide real-time feedback through visual cues on graphical user interfaces (GUIs). For the latter, a method of calibration is used to align the camera's native coordinate system with that of the isocentric reference frame of the radiation treatment delivery room. Optically tracked tools are then used to identify the positions of patient reference set-up points and these are compared to their location within the planning CT coordinate system. A computation based on least-squares methodology is performed using these two sets of coordinates to determine a treatment couch translation that will result in the alignment of the patient's planned isocenter with that of the treatment room. These tools can also be used for intra-fraction monitoring of patient position by placing an optically tracked tool on a region of interest to either initiate radiation delivery (i.e. gating regimes) or action (i.e. repositioning). Alternatively, products such as AlignRT (from Vision RT) allow for real time feedback by imaging the patient directly and tracking the skin surface of the patient.
=== MRI ===
The first clinically active MRI-guided radiation therapy machine, the ViewRay device, was installed in St. Louis, MO, at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. Treatment of the first patients was announced in February 2014. Other radiation therapy machines which incorporate real-time MRI tracking of tumors are currently in development. MRI-guided radiation therapy enables clinicians to see a patient's internal anatomy in real-time using continual soft-tissue imaging and allows them to keep the radiation beams on target when the tumour moves during treatment.
=== Ultrasound ===
Ultrasound is used for daily patient setup. It is useful for soft tissue such as the breast and prostate. The BAT (Best Nomos) and Clarity (Elekta) systems are the two main systems currently being used. The Clarity system has been further developed to enable intra-fraction prostate motion tracking via trans-perineal imaging.
=== Electromagnetic transponders ===
While not IGRT per se, electromagnetic transponder systems seek to serve exactly the same clinical function as CBCT or kV X-ray, yet provide for more temporally continuous analysis of setup error analogous to that of the optical tracking strategies. Hence, this technology (although entailing the use of no "images") is usually classified as an IGRT approach.
== Correction strategies for patient positioning during IGRT ==
There are two basic correction strategies used while determining the most beneficial patient position and beam structure: on-line and off-line correction. Both serve their purposes in the clinical setting, and have their own merits. Generally, a combination of the both strategies is employed. Often, a patient will receive corrections to their treatment via on-line strategies during their first radiation session, and physicians make subsequent adjustments off-line during check film rounds.
=== On-line ===
The On-line strategy makes adjustment to patient and beam position during the treatment process, based on continuously updated information throughout the procedure. The on-line approach requires a high-level of integration of both software and hardware. The advantage of this strategy is a reduction in both systematic and random errors. An example is the use of a marker-based program in the treatment of prostate cancer at Princess Margaret Hospital. Gold markers are implanted into the prostate to provide a surrogate position of the gland. Prior to each day's treatment, portal imaging system results are returned. If the center of the mass has moved greater than 3mm, then the couch is readjusted and a subsequent reference image is created. Other clinics correct for any positional errors, never allowing for >1 mm error in any measured axes.
=== Off-line ===
The Off-line strategy determines the best patient position through accumulated data gathered during treatment sessions, almost always initial treatments. Physicians and staff measure the accuracy of treatment and devise treatment guidelines during using information from the images. The strategy requires greater coordination than on-line strategies. However, the use of off-line strategies does reduce the risk of systematic error. The risk of random error may still persist, however.
== Future areas of study ==
The debate between the benefits of on-line versus off-line strategies continues to be contended.
Whether further research into biological functions and movements can create a better understanding of tumor movement in the body before, between and during treatment.
When rules or algorithms are used, large variations in PTV margins can be reduced. Margin "recipes" are being developed that will create linear equations and algorithms that account for "normal" variations. These rules are created from a normal population, and are applied to the treatment plan off-line. Possible side effects include random errors from uniqueness of the target
With a greater amount of data being collected, how systems must will be established for the categorizing and storing of information.
== See also ==
== References ==
== Further reading ==
Cossmann, Peter H. Advances in Image-guided Radiotherapy - The Future is in Motion. European Oncology Review 2005 - July (2005)
Sharpe, MB; T Craig; DJ Moseley (2007) [2007]. "Image Guidance: Treatment Target Localization Systems in IMRT-IGRT-SBRT – Advances in the Treatment Planning and Delivery of Radiotherapy.". Frontiers in Radiation Therapy Oncology. Vol. 40. Madison, WI: Karger. ISBN 978-3-8055-8199-8. | Wikipedia/Image-guided_radiation_therapy |
Electron therapy or electron beam therapy (EBT) is a kind of external beam radiotherapy where electrons are directed to a tumor site for medical treatment of cancer.
== Equipment ==
Electron beam therapy is performed using a medical linear accelerator. The same device can also be used to produce high energy photon beams. When electrons are required, the X-ray target is retracted out of the beam and the electron beam is collimated with a piece of apparatus known as an applicator or an additional collimating insert, constructed from a low melting point alloy.
== Properties ==
Electron beams have a finite range, after which dose falls off rapidly. Therefore, they spare deeper healthy tissue. The depth of the treatment is selected by the appropriate energy. Unlike photon beams there is no surface sparing effect, so electron therapy is used when the target extends to the patient's skin.
== Indications ==
Electron beam therapy is used in the treatment of superficial tumors like cancer of skin regions, or total skin (e.g. mycosis fungoides), diseases of the limbs (e.g. melanoma and lymphoma), nodal irradiation, and it may also be used to boost the radiation dose to the surgical bed after mastectomy or lumpectomy. For deeper regions intraoperative electron radiation therapy might be applied.
== See also ==
Intraoperative electron radiation therapy (IOERT)
External beam radiotherapy (EBRT)
Proton therapy
== References ==
Eric E. Klein: "Electron-Beam Therapy: Dosimetry, Planning, and Techniques" in: Edward C. Halperin, Carlos A. Perez, Luther W. Brady (ed.): Perez and Brady's Principles and Practice of Radiation Oncology, 5th. edition, 2008 | Wikipedia/Electron_therapy |
Peptide receptor radionuclide therapy (PRRT) is a type of radionuclide therapy, using a radiopharmaceutical that targets peptide receptors to deliver localised treatment, typically for neuroendocrine tumours (NETs).
== Mechanism ==
A key advantage of PRRT over other methods of radiotherapy is the ability to target delivery of therapeutic radionuclides directly to the tumour or target site. This works because some tumours have an abundance (overexpression) of peptide receptors, compared to normal tissue. A radioactive substance can be combined with a relevant peptide (or its analogue) so that it preferentially binds to the tumour. With a gamma emitter as the radionuclide, the technique can be used for imaging with a gamma camera or PET scanner to locate tumours. When paired with alpha or beta emitters, therapy can be achieved, as in PRRT.
The current generation of PRRT targets somatostatin receptors, with a range of analogue materials such as octreotide and other DOTA compounds. These are combined with indium-111, lutetium-177 or yttrium-90 for treatment. 111In is primarily used for imaging alone, however in addition to its gamma emission there are also Auger electrons emitted, which can have a therapeutic effect in high doses.
PRRT radiopharmaceuticals are constructed with three components; the radionuclide, chelator, and somatostatin analogue (peptide). The radionuclide delivers the actual therapeutic effect (or emission, such as photons, for imaging). The chelator is the essential link between the radionuclide and peptide. For 177Lu and 90Y this is typically DOTA (tetracarboxylic acid, and its variants) and DTPA (pentetic acid) for 111In. Other chelators known as NOTA (triazacyclononane triacetic acid) and HYNIC (hydrazinonicotinamide) have also been experimented with, albeit more for imaging applications. The somatostatin analogue affects biodistribution of the radionuclide, and therefore how effectively any treatment effect can be targeted. Changes affect which somatostatin receptor is most strongly targeted. For example, DOTA-lanreotide (DOTALAN) has a lower affinity for receptor 2 and a higher affinity for receptor 5 compared to DOTA-octreotide (DOTATOC).
== Applications ==
The body of research on the effectiveness of current PRRT is promising, but limited. Complete or partial treatment response has been seen in 20-30% of patients in trials treated with 177Lu-DOTATATE or 90Y-DOTATOC, among the most widely used PRRT drugs. When it comes to comparing these two PRRT, Y-labeled and Lu-labeled PRRTs, it appears that Y-labeled is more effective for larger tumors, while Lu-labeled is better for smaller and primary tumors. The lack of ɤ-emission with Y-labeled PPRTs is also an important difference between Lu peptides and Y peptide. In particular, with Y-labeled PRRT it becomes difficult to set up a dose of radiations specific to the patient's needs. In most cases PRRT is used for cancers of the gastroenteropancreatic and bronchial tracts, and in some cases phaeochromocytoma, paraganglioma, neuroblastoma or medullary thyroid carcinoma. Various approaches to approve effectiveness and limit side effects are being investigated, including radiosensitising drugs, fractionation regimes and new radionuclides. Alpha emitters, which have much shorter ranges in tissue (limiting the effect on nearby healthy tissue), such as bismuth-213 or actinium-225 labelled DOTATOC are of particular interest.
A comparative cohort study of 1051 neuroendocrine tumor patients undergoing 90Y-DOTATOC (n=910) or 177Lu-DOTATOC (n=141) reported no significant difference in overall survival between the groups. However, patients with high tumor accumulation and multiple lesions seemed to benefit from 90Y-DOTATOC, while patients with low tumor burden, solitary lesions and extra-hepatic disease experienced more favorable outcome on 177Lu-DOTATOC. There were significantly fewer cases of transitory hematotoxicity in the 177Lu-DOTATOC group compared with the 90Y-DOTATOC group (1.4% versus 10.1%, p=0.001).
The randomized controlled phase III Neuroendocrine Tumors Therapy (NETTER-1) trial evaluated the efficacy and safety of 177Lu-DOTATATE as compared with high-dose octreotide long-acting repeatable (LAR) in patients with advanced progressive somatostatin-receptor positive midgut neuroendocrine tumors. Patients were randomly assigned to receive either 177Lu-DOTATATE and octreotide LAR at a dose of 30 mg every four weeks for symptom control (n=116) or to only receive octreotide LAR at a dose of 60 mg every four weeks (n=113, control group). In total, 200 out of the 231 patients entered long-term follow-up. Final overall survival in the intention-to-treat population was median 48.0 months in the 177Lu-DOTATATE group versus median 36.3 months in the control group (p=0.30). In other words, there was numerical difference of 11.7 months, not reaching statistical significance. 177Lu-DOTATATE was associated with limited acute toxic effects. In neuroendocrine tumor patients with advanced well-differentiated disease and progression on somatostatin analogs, 177Lu-DOTATATE is likely to reduce the risk of disease progression and be associated with quality-of-life benefits.
== Dosimetry ==
Therapeutic PRRT treatments typically involve several gigabecquerels (GBq) of activity. Several radiopharmaceuticals allow simultaneous imaging and therapy, enabling precise dosimetric estimates to be made. For example, the bremsstrahlung emission from 90Y and gamma emissions from 177Lu can be detected by a gamma camera. In other cases, imaging can be performed by labelling a suitable radionuclide to the same peptide as used for therapy. Radionuclides that can be used for imaging include gallium-68, technetium-99m and fluorine-18.
Currently used peptides can result in high kidney doses, as the radiopharmaceutical is retained for relatively long periods. Renal protection is therefore used in some cases, taking the form of alternative substances that reduce the uptake of the kidneys.
== Availability ==
PRRT is not yet widely available, with various radiopharmaceuticals at different stages of clinical trials. The cost of small volume production of the relevant radionuclides is high. The cost of Lutathera, a commercial 177Lu-DOTATATE product, has been quoted by the manufacturer as £71,500 (€80,000 or $94,000 in July 2018) for 4 administrations of 7.4 GBq.
=== United States ===
177Lu-DOTATATE (international nonproprietary name: lutetium (177Lu) oxodotreotide) was approved by the FDA in early 2018, for treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
=== Europe ===
Marketing authorisation for 177Lu-DOTATATE was granted by the European Medicines Agency on 26 September 2017. 90Y-DOTATOC (international nonproprietary name: yttrium (90Y) edotreotide) and 177Lu-DOTATOC are designated as orphan drugs, but have not yet received marketing authorisation.
==== United Kingdom ====
In guidance published in August 2018, lutetium (177Lu) oxodotreotide was recommended by NICE for treating unresectable or metastatic neuroendocrine tumours.
=== Turkey ===
The first therapies in Turkey using 177Lu-DOTATATE PRRT were carried out in early 2014, for treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) at the Istanbul University-Cerrahpaşa.
=== Australia ===
Research in Australia into the use of lutetium-177-labelled antibodies for various cancers began in the Department of Nuclear Medicine at Fremantle Hospital and Health Service (FHHS), Fremantle, Australia in the late 1990s. The first therapies in Australia using 177Lu-DOTATATE PRRT for NET began in February 2005 on a trial basis under the Therapeutic Goods Administration's (TGA) Special Access Scheme (SAS) and compassionate usage of unapproved therapeutic goods. Shortly after this, 177Lu-DOTATATE PRRT was provided to Western Australian NET patients on a routine basis under the SAS, as well as under various on-going research trials.
In Australia, most centres synthesise the lutetium-177 peptide on-site from lutetium-177 chloride and the appropriate peptide.
== Side effects ==
Like any form of radiotherapy, ionising radiation can harm healthy tissue as well as the intended treatment target. Radiation from lutetium (177Lu) oxodotreotide can cause damage when the medicine passes through tubules in the kidney. Arginine/lysine can be used to reduce renal radiation exposure during peptide receptor radionuclide therapy with lutetium (177Lu) oxodotreotide.
== See also ==
Nuclear medicine
Targeted alpha-particle therapy
== References == | Wikipedia/Peptide_receptor_radionuclide_therapy |
The trachea (pl.: tracheae or tracheas), also known as the windpipe, is a cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air, and so is present in almost all animals' lungs. The trachea extends from the larynx and branches into the two primary bronchi. At the top of the trachea, the cricoid cartilage attaches it to the larynx. The trachea is formed by a number of horseshoe-shaped rings, joined together vertically by overlying ligaments, and by the trachealis muscle at their ends. The epiglottis closes the opening to the larynx during swallowing.
The trachea begins to form in the second month of embryo development, becoming longer and more fixed in its position over time. Its epithelium is lined with column-shaped cells that have hair-like extensions called cilia, with scattered goblet cells that produce protective mucins. The trachea can be affected by inflammation or infection, usually as a result of a viral illness affecting other parts of the respiratory tract, such as the larynx and bronchi, called croup, that can result in a cough. Infection with bacteria usually affects the trachea only and can cause narrowing or even obstruction. As a major part of the respiratory tract, the trachea, when obstructed, prevents air from entering the lungs; thus, a tracheostomy may be required. Additionally, during surgery, if mechanical ventilation is required during anaesthesia, a tube is inserted into the trachea: this is called tracheal intubation.
The word trachea is used to define a very different organ in invertebrates than in vertebrates. Insects have an open respiratory system made up of spiracles, tracheae, and tracheoles to transport metabolic gases to and from tissues.
== Structure ==
An adult's trachea has an inner diameter of about 1.5 to 2 centimetres (1⁄2 to 3⁄4 in) and a length of about 10 to 11 cm (4 to 4+1⁄4 in), wider in males than females. The trachea begins at the lower edge of the cricoid cartilage of the larynx at the level of sixth cervical vertebra (C6) and ends at the carina, the point where the trachea branches into left and right main bronchi., at the level of the fourth thoracic vertebra (T4), although its position may change with breathing. The trachea is surrounded by 16–20 rings of hyaline cartilage; these 'rings' are 4 millimetres high in the adult, incomplete and C-shaped. Ligaments connect the rings. The trachealis muscle connects the ends of the incomplete rings and runs along the back wall of the trachea. Also adventitia, which is the outermost layer of connective tissue that surrounds the hyaline cartilage, contributes to the trachea's ability to bend and stretch with movement.
Although trachea is a midline structure, it can be displaced normally to the right by the aortic arch.
=== Nearby structures ===
The trachea passes by many structures of the neck and chest (thorax) along its course.
In front of the upper trachea lies connective tissue and skin. Several other structures pass over or sit on the trachea; the jugular arch, which joins the two anterior jugular veins, sits in front of the upper part of the trachea. The sternohyoid and sternothyroid muscles stretch along its length. The thyroid gland also stretches across the upper trachea, with the isthmus overlying the second to fourth rings, and the lobes stretching to the level of the fifth or sixth cartilage. The blood vessels of the thyroid rest on the trachea next to the isthmus; superior thyroid arteries join just above it, and the inferior thyroid veins below it. In front of the lower trachea lies the manubrium of the sternum, the remnants of the thymus in adults. To the front left lie the large blood vessels the aortic arch and its branches the left common carotid artery and the brachiocephalic trunk; and the left brachiocephalic vein. The deep cardiac plexus and lymph nodes are also positioned in front of the lower trachea.
Behind the trachea, along its length, sits the oesophagus, followed by connective tissue and the vertebral column. To its sides run the carotid arteries and inferior thyroid arteries; and to its sides on its back surface run the recurrent laryngeal nerves in the upper trachea, and the vagus nerves in the lower trachea.
The trachealis muscle contracts during coughing, reducing the size of the lumen of the trachea.
=== Blood and lymphatic supply ===
The upper part of trachea receives and drains blood through the inferior thyroid arteries and veins; the lower trachea receives blood from bronchial arteries. Arteries that supply the trachea do so via small branches that supply the trachea from the sides. As the branches approach the wall of the trachea, they split into inferior and superior branches, which join with the branches of the arteries above and below; these then split into branches that supply the anterior and posterior parts of the trachea. The inferior thyroid arteries arise just below the isthmus of the thyroid, which sits atop the trachea. These arteries join (anastamoses) with ascending branches of the bronchial arteries, which are direct branches from the aorta, to supply blood to the trachea. The lymphatic vessels of the trachea drain into the pretracheal nodes that lie in front of the trachea, and paratracheal lymph nodes that lie beside it.
=== Development ===
In the fourth week of development of the human embryo as the respiratory bud grows, the trachea separates from the foregut through the formation of ridges which eventually separate the trachea from the oesophagus, the tracheoesophageal septum. This separates the future trachea from the oesophagus and divides the foregut tube into the laryngotracheal tube. By the start of the fifth week, the left and right main bronchi have begun to form, initially as buds at the terminal end of the trachea.
The trachea is no more than 4 mm in diameter during the first year of life, expanding to its adult diameter of approximately 2 cm by late childhood. The trachea is more circular and more vertical in children compared to adults, varies more in size, and also varies more in its position in relation to its surrounding structures.
=== Microanatomy ===
The trachea is lined with a layer of interspersed layers of column-shaped cells with cilia. The epithelium contains goblet cells, which are glandular, column-shaped cells that produce mucins, the main component of mucus. Mucus helps to moisten and protect the airways. Mucus lines the ciliated cells of the trachea to trap inhaled foreign particles that the cilia then waft upward toward the larynx and then the pharynx where it can be either swallowed into the stomach or expelled as phlegm. This self-clearing mechanism is termed mucociliary clearance. Directly beneath this mucus layer lies the submucosa layer which is composed primarily of fibrous connective tissue and connects the mucosa to the rings of hyaline cartilage beneath.
The trachea is surrounded by 16 to 20 rings of hyaline cartilage; these 'rings' are incomplete and C-shaped. Two or more of the cartilages often unite, partially or completely, and they are sometimes bifurcated at their extremities. The rings are generally highly elastic but they may calcify with age.
== Function ==
The trachea's main function is to transport air to and from the lungs. It also helps to warm, humidify, and filter the air before it reaches the lungs.
The trachea is made up of rings of cartilage, which help to keep it open and prevent it from collapsing. The inside of the trachea is lined with a mucous membrane, which produces mucus to help trap dirt and dust particles. The cilia, which are tiny hairs that line the mucous membrane, help to move the mucus and trapped particles up and out of the trachea.
== Clinical significance ==
=== Inflammation and infection ===
Inflammation of the trachea is known as tracheitis, usually due to an infection. It is usually caused by viral infections, with bacterial infections occurring almost entirely in children. Most commonly, infections occur with inflammation of other parts of the respiratory tract, such as the larynx and bronchi, known as croup, however bacterial infections may also affect the trachea alone, although they are often associated with a recent viral infection. Viruses that cause croup are generally the parainfluenza viruses 1–3, with influenza viruses A and B also causing croup, but usually causing more serious infections; bacteria may also cause croup and include Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Causes of bacterial infection of the trachea are most commonly Staphylococcus aureus and Streptococcus pneumoniae. In patients who are in hospital, additional bacteria that may cause tracheitis include Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
A person affected with tracheitis may start with symptoms that suggest an upper respiratory tract infection such as a cough, sore throat, or coryzal symptoms such as a runny nose. Fevers may develop and an affected child may develop difficulty breathing and sepsis. Swelling of the airway can cause narrowing of the airway, causing a hoarse breathing sound called stridor, or even cause complete blockage. Up to 80% of people affected by bacterial tracheitis require the use of mechanical ventilation, and treatment may include endoscopy for the purposes of acquiring microbiological specimens for culture and sensitivity, as well as removal of any dead tissue associated with the infection. Treatment in such situations usually includes antibiotics.
=== Narrowing ===
A trachea may be narrowed or compressed, usually a result of enlarged nearby lymph nodes; cancers of the trachea or nearby structures; large thyroid goitres; or rarely as a result of other processes such as unusually swollen blood vessels. Scarring from tracheobronchial injury or intubation; or inflammation associated with granulomatosis with polyangiitis may also cause a narrowing of the trachea (tracheal stenosis). Obstruction invariably causes a harsh breathing sound known as stridor. A camera inserted via the mouth down into the trachea, called bronchoscopy, may be performed to investigate the cause of an obstruction. Management of obstructions depends on the cause. Obstructions as a result of malignancy may be managed with surgery, chemotherapy or radiotherapy. A stent may be inserted over the obstruction. Benign lesions, such as narrowing resulting from scarring, are likely to be surgically excised.
One cause of narrowing is tracheomalacia, which is the tendency for the trachea to collapse when there is increased external pressure, such as when airflow is increased during breathing in or out, due to decreased compliance. It can be due to congenital causes, or due to things that develop after birth, such as compression from nearby masses or swelling, or trauma. Congenital tracheomalacia can occur by itself or in association with other abnormalities such as bronchomalacia or laryngomalacia, and abnormal connections between the trachea and the oesophagus, amongst others. Congenital tracheomalacia often improves without specific intervention; when required, interventions may include beta agonists and muscarinic agonists, which enhance the tone of the smooth muscle surrounding the trachea; positive pressure ventilation, or surgery, which may include the placement of a stent, or the removal of the affected part of the trachea. In dogs, particularly miniature dogs and toy dogs, tracheomalacia, as well as bronchomalacia, can lead to tracheal collapse, which often presents with a honking goose-like cough.
=== Injury ===
The trachea may be injured by trauma such as in a vehicle accident, or intentionally by another wilfully inflicting damage for example as practiced in some martial arts.
=== Intubation ===
Tracheal intubation refers to the insertion of a tube down the trachea. This procedure is commonly performed during surgery, in order to ensure a person receives enough oxygen when sedated. The catheter is connected to a machine that monitors the airflow, oxygenation and several other metrics. This is often one of the responsibilities of an anaesthetist during surgery.
In an emergency, or when tracheal intubation is deemed impossible, a tracheotomy is often performed to insert a tube for ventilation, usually when needed for particular types of surgery to be carried out so that the airway can be kept open. The provision of the opening via a tracheotomy is called a tracheostomy. Another method procedure can be carried, in an emergency situation, and this is a cricothyrotomy.
=== Congenital disorders ===
Tracheal agenesis is a rare birth defect in which the trachea fails to develop. The defect is usually fatal though sometimes surgical intervention has been successful.
A tracheoesophageal fistula is a congenital defect in which the trachea and esophagus are abnormally connected (a fistula). This is because of abnormalities in the separation between the trachea and oesophagus during development. This occurs in approximately 1 in 3,000 births, and the most common abnormalities is a separation of the upper and lower ends of the oesophagus, with the upper end finishing in a closed pouch. Other abnormalities may be associated with this, including cardiac abnormalities, or VACTERL syndrome. Such fistulas may be detected before a baby is born because of excess amniotic fluid; after birth, they are often associated with pneumonitis and pneumonia because of aspiration of food contents. Congenital fistulas are often treated by surgical repair. In adults, fistulas may occur because of erosion into the trachea from nearby malignant tumours, which erode into both the trachea and the oesophagus. Initially, these often result in coughing from swallowed contents of the oesophagus that are aspirated through the trachea, often progressing to fatal pneumonia; there is rarely a curative treatment. A tracheo-oesophageal puncture is a surgically created hole between the trachea and the esophagus in a person who has had their larynx removed. Air travels upwards from the surgical connection to the upper oesophagus and the pharynx, creating vibrations that create sound that can be used for speech. The purpose of the puncture is to restore a person's ability to speak after the vocal cords have been removed.
Sometimes as an anatomical variation one or more of the tracheal rings are formed as complete rings, rather than horseshoe shaped rings. These O rings are smaller than the normal C-shaped rings and can cause narrowing (stenosis) of the trachea, resulting in breathing difficulties. An operation called a slide tracheoplasty can open up the rings and rejoin them as wider rings, shortening the length of the trachea. Slide tracheoplasty is said to be the best option in treating tracheal stenosis.
Mounier-Kuhn syndrome is a rare congenital disorder of an abnormally enlarged trachea, characterised by absent elastic fibres, smooth muscle thinning, and a tendency to get recurrent respiratory tract infections.
=== Replacement ===
From 2008, operations have experimentally replaced tracheas, with those grown from stem cells, or with synthetic substitutes, however this is regarded as experimental and there is no standardised method. Difficulties with ensuring adequate blood supply to the replaced trachea is considered a major challenge to any replacement. Additionally, no evidence has been found to support the placement of stem cells taken from bone marrow on the trachea as a way of stimulating tissue regeneration, and such a method remains hypothetical.
In January 2021, surgeons at Mount Sinai Hospital in New York performed the first complete trachea transplantation. The 18-hour procedure included harvesting a trachea from a donor and implanting it in the patient, connecting numerous veins and arteries to provide sufficient blood flow to the organ.
== Other animals ==
Allowing for variations in the length of the neck, the trachea in other mammals is, in general, similar to that in humans. Generally, it is also similar to the reptilian trachea.
=== Vertebrates ===
In birds, the trachea runs from the pharynx to the syrinx, from which the primary bronchi diverge. Swans have an unusually elongated trachea, part of which is coiled beneath the sternum; this may act as a resonator to amplify sound. In some birds, the tracheal rings are complete, and may even be ossified.
In amphibians, the trachea is normally extremely short, and leads directly into the lungs, without clear primary bronchi. A longer trachea is, however, found in some long-necked salamanders, and in caecilians. While there are irregular cartilagenous nodules on the amphibian trachea, these do not form the rings found in amniotes.
The only vertebrates to have lungs, but no trachea, are the lungfish and the Polypterus, in which the lungs arise directly from the pharynx.
=== Invertebrates ===
The word trachea is used to define a very different organ in invertebrates than in vertebrates. Insects have an open respiratory system made up of spiracles, tracheae, and tracheoles to transport metabolic gases to and from tissues. The distribution of spiracles can vary greatly among the many orders of insects, but in general each segment of the body can have only one pair of spiracles, each of which connects to an atrium and has a relatively large tracheal tube behind it. The tracheae are invaginations of the cuticular exoskeleton that branch (anastomose) throughout the body with diameters from only a few micrometres up to 0.8 mm. Diffusion of oxygen and carbon dioxide takes place across the walls of the smallest tubes, called tracheoles, which penetrate tissues and even indent individual cells. Gas may be conducted through the respiratory system by means of active ventilation or passive diffusion. Unlike vertebrates, insects do not generally carry oxygen in their hemolymph.
This is one of the factors that may limit their size.
A tracheal tube may contain ridge-like circumferential rings of taenidia in various geometries such as loops or helices. Taenidia provide strength and flexibility to the trachea. In the head, thorax, or abdomen, tracheae may also be connected to air sacs. Many insects, such as grasshoppers and bees, which actively pump the air sacs in their abdomen, are able to control the flow of air through their body. In some aquatic insects, the tracheae exchange gas through the body wall directly, in the form of a gill, or function essentially as normal, via a plastron. Note that despite being internal, the tracheae of arthropods are lined with cuticular tissue and are shed during moulting (ecdysis).
== Additional images ==
== References == | Wikipedia/Vertebrate_trachea |
Adjuvant therapy, also known as adjunct therapy, adjuvant care, or augmentation therapy, is a therapy that is given in addition to the primary or initial therapy to maximize its effectiveness. The surgeries and complex treatment regimens used in cancer therapy have led the term to be used mainly to describe adjuvant cancer treatments. An example of such adjuvant therapy is the additional treatment usually given after surgery where all detectable disease has been removed, but where there remains a statistical risk of relapse due to the presence of undetected disease. If known disease is left behind following surgery, then further treatment is not technically adjuvant.
An adjuvant used on its own specifically refers to an agent that improves the effect of a vaccine. Medications used to help primary medications are known as add-ons.
== History ==
The term "adjuvant therapy," derived from the Latin term adjuvāre, meaning "to help," was first coined by Paul Carbone and his team at the National Cancer Institute in 1963. In 1968, the National Surgical Adjuvant Breast and Bowel Project (NSABP) published its B-01 trial results for the first randomized trial that evaluated the effect of an adjuvant alkylating agent in breast cancer. The results indicated that the adjuvant therapy given after the initial radical mastectomy "significantly decreased recurrence rate in pre-menopausal women with four or more positive axillary lymph nodes."
The budding theory of using additional therapies to supplement primary surgery was put into practice by Gianni Bonadonna and his colleagues from the Instituto Tumori in Italy in 1973, where they conducted a randomized trial that demonstrated more favorable survival outcomes that accompanied use of Cyclophosphamide Methotrexate Fluorouracil (CMF) after the initial mastectomy.
In 1976, shortly after Bonadonna's landmark trial, Bernard Fisher at the University of Pittsburgh initiated a similar randomized trial that compared the survival of breast cancer patients treated with radiation after the initial mastectomy to those who only received the surgery. His results, published in 1985, indicated increased disease-free survival for the former group.
Despite the initial pushback from the breast cancer surgeons who believed that their radical mastectomies were sufficient in removing all traces of cancer, the success of Bonadonna's and Fisher's trials brought adjuvant therapy to the mainstream in oncology. Since then, the field of adjuvant therapy has expanded to include a range of adjuvant therapies to include chemotherapy, immunotherapy, hormone therapy, and radiation.
== Neoadjuvant therapy ==
Neoadjuvant therapy, in contrast to adjuvant therapy, is given before the main treatment. For example, systemic therapy for breast cancer that is given before removal of a breast is considered neoadjuvant chemotherapy. The most common reason for neoadjuvant therapy for cancer is to reduce the size of the tumor so as to facilitate more effective surgery.
In the context of breast cancer, neoadjuvant chemotherapy administered before surgery can improve survival in patients. If no active cancer cells are present in a tissue extracted from the tumor site after neoadjuvant therapy, physicians classify a case as "pathologic complete response" or "pCR." While response to therapy has been demonstrated to be a strong predictor of outcome, the medical community has still not reached a consensus in regard to the definition of pCR across various breast cancer subtypes. It remains unclear whether pCR can be used as a surrogate end point in breast cancer cases.
== Adjuvant cancer therapy ==
For example, radiotherapy or systemic therapy is commonly given as adjuvant treatment after surgery for breast cancer. Systemic therapy consists of chemotherapy, immunotherapy or biological response modifiers or hormone therapy. Oncologists use statistical evidence to assess the risk of disease relapse before deciding on the specific adjuvant therapy. The aim of adjuvant treatment is to improve disease-specific symptoms and overall survival. Because the treatment is essentially for a risk, rather than for provable disease, it is accepted that a proportion of patients who receive adjuvant therapy will already have been cured by their primary surgery.
Adjuvant systemic therapy and radiotherapy are often given following surgery for multiple types of cancer, including colon cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, and some gynaecological cancers. Some forms of cancer fail to benefit from adjuvant therapy, however. Such cancers include renal cell carcinoma, and certain forms of brain cancer.
Hyperthermia therapy or heat therapy is also a kind of adjuvant therapy that is sometimes given in combination with radiotherapy or chemotherapy to boost the effects of these conventional treatments in treating advanced cancers. Heating the tumour area sensitises it making it more responsive to the other therapies used. It is cost-effective and safe, and is seen to have a promising role in cancer treatment.
=== Controversy ===
A motif found throughout the history of cancer therapy is the tendency for overtreatment. From the time of its inception, the use of adjuvant therapy has received scrutiny for its adverse effects on the quality of life of cancer patients. For example, because side effects of adjuvant chemotherapy can range from nausea to loss of fertility, physicians regularly practice caution when prescribing chemotherapy.
In the context of melanoma, certain treatments, such as Ipilimumab, result in high grade adverse events, or immune-related adverse events, in 10-15% of patients that parallel the effects of metastatic melanoma itself. Similarly, several common adjuvant therapies are noted for having the potential of causing cardiovascular disease. In such cases, physicians must weigh the cost of recurrence against more immediate consequences and consider factors, like age and relative cardiovascular health of a patient, before prescribing certain types of adjuvant therapy.
One of the most notable side effects of adjuvant therapy is the loss of fertility. For pre-pubescent males, testicular tissue cryopreservation is an option for preserving future fertility. For post-pubescent males, this side effect can be assuaged through semen cryopreservation. For pre-menopausal females, options to preserve fertility are oftentimes much more complex. For example, breast cancer patients of fertile age oftentimes have to weigh the risks and benefits associated with starting an adjuvant therapy regimen after primary treatment. In the some low-risk, low-benefit situations, forgoing adjuvant treatment altogether can be a reasonable decision, but in cases where the risk of metastasis is high, patients may be forced to make a difficult decision. Though options for fertility preservation exist (e.g., embryo preservation, oocyte cryopreservation, ovarian suppression, etc.), they are more often than not time-consuming and costly.
As a result of complications that can stem from liberal use of adjuvant therapy, the philosophy surrounding the use of adjuvant therapy in the clinical setting has shifted towards the goal of doing as little harm as possible to patients. The standards for dose intensity of adjuvant treatments and treatment duration are regularly updated to optimize regimen efficiency while minimizing toxic side effects that patients must shoulder.
=== Concomitant or concurrent systemic cancer therapy ===
Concomitant or concurrent systemic cancer therapy refers to administering medical treatments at the same time as other therapies, such as radiation. Adjuvant hormonal therapy is given after prostate removal in prostate cancer, but there are concerns that the side effects, in particular the cardiovascular ones, may outweigh the risk of recurrence. In breast cancer, adjuvant therapy may consist of chemotherapy (doxorubicin, trastuzumab, paclitaxel, docetaxel, cyclophosphamide, fluorouracil, and methotrexate) and radiotherapy, especially after lumpectomy, and hormonal therapy (tamoxifen, letrozole). Adjuvant therapy in breast cancer is used in stage one and two breast cancer following lumpectomy, and in stage three breast cancer due to lymph node involvement.
In glioblastoma multiforme, adjuvant chemoradiotherapy is critical in the case of a completely removed tumor, as with no other therapy, recurrence occurs in 1–3 months.
In early stage one small cell lung carcinoma, adjuvant chemotherapy with gemcitabine, cisplatin, paclitaxel, docetaxel, and other chemotherapeutic agents, and adjuvant radiotherapy is administered to either the lung, to prevent a local recurrence, or the brain to prevent metastases.
In testicular cancer, adjuvant either radiotherapy or chemotherapy may be used following orchidectomy. Previously, mainly radiotherapy was used, as a full course of cytotoxic chemotherapy produced far more side effects then a course of external beam radiotherapy (EBRT). However, it has been found a single dose of carboplatin is as effective as EBRT in stage II testicular cancer, with only mild side effects (transient myelosuppressive action vs severe and prolonged myelosuppressive neutropenic illness in normal chemotherapy, and much less vomiting, diarrhea, mucositis, and no alopecia in 90% of cases.
Adjuvant therapy is particularly effective in certain types of cancer, including colorectal carcinoma, lung cancer, and medulloblastoma. In completely resected medulloblastoma, 5-year survival rate is 85% if adjuvant chemotherapy and/or craniospinal irradiation is performed, and just 10% if no adjuvant chemotherapy or craniospinal irradiation is used. Prophylactic cranial irradiation for acute lymphoblastic leukemia (ALL) is technically adjuvant, and most experts agree that cranial irradiation decreases risk of central nervous system (CNS) relapse in ALL and possibly acute myeloid leukemia (AML), but it can cause severe side effects, and adjuvant intrathecal methotrexate and hydrocortisone may be just as effective as cranial irradiation, without severe late effects, such as developmental disability, dementia, and increased risk for second malignancy.
=== Dose-dense chemotherapy ===
Dose-dense chemotherapy (DDC) has recently emerged as an effective method of adjuvant chemotherapy administration. DDC uses the Gompertz curve to explain tumor cell growth after initial surgery removes most of the tumor mass. Cancer cells that are left over after a surgery are typically rapidly dividing cells, leaving them the most vulnerable to chemotherapy. Standard chemotherapy regimens are usually administered every 3 weeks to allow normal cells time to recover. This practice has led scientists to the hypothesis that the recurrence of cancer after surgery and chemo may be due to the rapidly diving cells outpacing the rate of chemotherapy administration. DDC tries to circumvent this issue by giving chemotherapy every 2 weeks. To lessen the side effects of chemotherapy that can be exacerbated with more closely administered chemotherapy treatments, growth factors are typically given in conjunction with DDC to restore white blood cell counts. A recent 2018 meta-analysis of DDC clinical trials in early stage breast cancer patients indicated promising results in premenopausal women, but DDC has yet to become the standard of treatment in clinics.
=== Specific cancers ===
==== Malignant melanoma ====
The role of adjuvant therapy in malignant melanoma is and has been hotly debated by oncologists. In 1995 a multicenter study reported improved long-term and disease-free survival in melanoma patients using interferon alpha 2b as an adjuvant therapy. Thus, later that year the U.S. Food and Drug Administration (FDA) approved interferon alpha 2b for melanoma patients who are currently free of disease, to reduce the risk of recurrence. Since then, however, some doctors have argued that interferon treatment does not prolong survival or decrease the rate of relapse, but only causes harmful side effects. Those claims have not been validated by scientific research.
Adjuvant chemotherapy has been used in malignant melanoma, but there is little hard evidence to use chemotherapy in the adjuvant setting. However, melanoma is not a chemotherapy-resistant malignancy. Dacarbazine, temozolomide, and cisplatin all have a reproducible 10–20% response rate in metastatic melanoma.; however, these responses are often short-lived and almost never complete. Multiple studies have shown that adjuvant radiotherapy improves local recurrence rates in high-risk melanoma patients. The studies include at least two M.D. Anderson cancer center studies. However, none of the studies showed that adjuvant radiotherapy had a statistically significant survival benefit.
A number of studies are currently underway to determine whether immunomodulatory agents which have proven effective in the metastatic setting are of benefit as adjuvant therapy for patients with resected stage 3 or 4 disease.
==== Colorectal cancer ====
Adjuvant chemotherapy is effective in preventing the outgrowth of micrometastatic disease from colorectal cancer that has been removed surgically. Studies have shown that fluorouracil is an effective adjuvant chemotherapy among patients with microsatellite stability or low-frequency microsatellite instability, but not in patients with high-frequency microsatellite instability.
==== Pancreatic cancer ====
===== Exocrine =====
Exocrine pancreatic cancer has one of the lowest 5-year survival rates out of all cancers. Because of the poor outcomes associated with surgery alone, the role of adjuvant therapy has been extensively evaluated. A series of studies has established that 6 months of chemotherapy with either gemcitabine or fluorouracil, as compared with observation, improves overall survival. Newer trials incorporating immune checkpoint inhibitors such as the inhibitors to programmed death 1 (PD-1) and the PD-1 ligand PD-L1 are under way.
==== Lung Cancer ====
===== Non-small cell lung cancer (NSCLC) =====
In 2015, a comprehensive meta-analysis of 47 trials and 11,107 patients revealed that NSCLC patients benefit from adjuvant therapy in the form of chemotherapy and/or radiotherapy. The results found that patients given chemotherapy after the initial surgery lived 4% longer than those who did not receive chemotherapy. The toxicity resulting from adjuvant chemotherapy was believed to be manageable.
==== Bladder cancer ====
Neoadjuvant chemotherapy (NAC) followed by a radical cystectomy (RC) and pelvic lymph node dissection is current standard of care to treat muscle-invasive bladder cancer (MIBC). NAC was justified for use in MIBC due to a randomized control trial which showed an improved median overall survival (OS; 77 months vs. 46 months, p = 0.06) and downstaging of pathology (pT0 in 38% vs. 15%) in those who received cisplatin-based NAC followed by surgery vs. surgery alone. These findings were later substantiated by a meta-analysis of 11 clinical trials that showed a 5% and 9% absolute improvement in 5-year overall survival and disease free survival, respectively. Neoadjuvant platinum-based chemotherapy has been demonstrated to improve OS in advanced bladder cancer, but there exists some controversy in the administration. Unpredictable patient response remains the drawback of NAC therapy. While it may shrink tumors in some patients, others may not respond to the treatment at all. It has been demonstrated that a delay in surgery of greater than 12 weeks from the time of diagnosis can decrease OS. Thus, the timing for NAC becomes critical, as a course of NAC therapy could delay a RC and allow the tumor to grow and further metastasize.
Micometastases cannot be ruled out in locally advanced disease, and surgery alone is not always sufficient for complete cancer control. In certain situations, acquiring precise pathologic staging can make adjuvant chemotherapy (AC) an appealing option. Stage specific pathologic treatment and reduced time to surgery can predict prognosis and the absolute OS benefits in patients with at least cT3 disease A systematic review that studied 7,056 patients showed there was a known 9-11% absolute survival benefit at five years attributable to earlier administration of AC; there was a survival benefit seen with earlier administration, as well as a benefit that persisted when compared to controls who received no AC. One limitation of AC is that poor postoperative healing or complications can limit early administration, leading to a potential propagation of potential micrometastases, early recurrence, or reduction in cancer-specific survival. Enhanced recovery after surgery protocols have recently improved perioperative care and may make earlier time to AC administration less challenging. The recent approval of adjuvant immunotherapy for patients with adverse pathology may make earlier adjuvant administration more tolerable, and be provided to patients who received NAC prior to their RC.
==== Breast cancer ====
It has been known for at least 30 years that adjuvant chemotherapy increases the relapse-free survival rate for patients with breast cancer In 2001 after a national consensus conference, a US National Institute of Health panel concluded: "Because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status."
Agents used include:
However, ethical concerns have been raised about the magnitude of benefit of this therapy since it involves further treatment of patients without knowing the possibility of relapse. Dr. Bernard Fisher, among the first to conduct a clinical trial evaluating the efficacy of adjuvant therapy on patients with breast cancer, described it as a "value judgement" in which the potential benefits must be evaluated against the toxicity and cost of treatment and other potential side effects.
Often related to fear of side effects, more recent work has indicated that women do not take adjuvant therapy as prescribed or may stop before they should. A study in 2023 exploring the extent to which an information leaflet could help women to understand the benefits and to reduce their concerns and found that quotes from other women with breast cancer contributes to more positive beliefs.
==== Combination adjuvant chemotherapy for breast cancer ====
Giving two or more chemotherapeutic agents at once may decrease the chances of recurrence of the cancer, and increase overall survival in patients with breast cancer. Commonly used combination chemotherapy regimens used include:
Doxorubicin and cyclophosphamide
Doxorubicin and cyclophosphamide followed by docetaxel
Doxorubicin and cyclophosphamide followed by cyclophosphamide, methotrexate, and fluorouracil
Cyclophosphamide, methotrexate, and fluorouracil.
Docetaxel and cyclophosphamide.
Docetaxel, doxorubicin, and cyclophosphamide
Cyclophosphamide, epirubicin, and fluorouracil.
==== Ovarian Cancer ====
Roughly 15% of ovarian cancers are detected at the early stage, at which the 5-year survival rate is 92%. A Norwegian meta-analysis of 22 randomized studies involving early-stage ovarian cancer revealed the likelihood that 8 out of 10 women treated with cisplatin after the initial surgery were overtreated. Patients diagnosed at an early stage who were treated with cisplatin immediately after surgery fared worse than patients who were left untreated. An additional surgical focus for young women with early-stage cancers is on the conservation of the contralateral ovary for the preservation of fertility.
Most cases of ovarian cancers are detected at the advanced stages, when the survival is greatly reduced.
==== Cervical cancer ====
In early stage cervical cancers, research suggests that adjuvant platinum-based chemotherapy after chemo-radiation may improve survival. For advanced cervical cancers, further research is needed to determine the efficacy, toxicity and effect on the quality of life of adjuvant chemotherapy.
==== Endometrial cancer ====
Since most early-stage endometrial cancer cases are diagnosed early and are typically curable with surgery, adjuvant therapy is only given after surveillance and histological factors determine that a patient is at high risk for recurrence. Adjuvant pelvic radiation therapy has received scrutiny for its use in women under 60, as studies have indicated decreased survival and increased risk of second malignancies following treatment.
In advanced-stage endometrial cancer, adjuvant therapy is typically radiation, chemotherapy, or a combination of the two. While advanced-stage cancer makes up only about 15% of diagnoses, it accounts for 50% of deaths from endometrial cancer. Patients who undergo radiation and/or chemotherapy treatment will sometimes experience modest benefits before relapse.
==== Testicular cancer ====
===== Stage I =====
For seminoma, the three standard options are: active surveillance, adjuvant radiotherapy, or adjuvant chemotherapy.
For non-seminoma, the options include: active surveillance, adjuvant chemotherapy and retroperitoneal lymph node dissection.
As is the case for all reproductive cancers, a degree of caution is taken when deciding to use adjuvant therapy to treat early stage testicular cancer. Though the 5-year survival rates for stage I testicular cancers is approximately 99%, there still exists controversy over whether to overtreat stage I patients to prevent relapse or to wait until patients experience relapse. Patients treated with standard chemotherapy regimens can experience "second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems." As such to minimize overtreatment and avoid potential long-term toxicity caused by adjuvant therapy, most patients today are treated with active surveillance.
=== Side effects of adjuvant cancer therapy ===
Depending on what form of treatment is used, adjuvant therapy can have side effects, like all therapy for neoplasms. Chemotherapy frequently causes vomiting, nausea, alopecia, mucositis, myelosuppression particularly neutropenia, sometimes resulting in septicaemia. Some chemotherapeutic agents can cause acute myeloid leukaemia, in particular the alkylating agents. Rarely, this risk may outweigh the risk of recurrence of the primary tumor. Depending on the agents used, side effects such as chemotherapy-induced peripheral neuropathy, leukoencephalopathy, bladder damage, constipation or diarrhea, hemorrhage, or post-chemotherapy cognitive impairment. Radiotherapy causes radiation dermatitis and fatigue, and, depending on the area being irradiated, may have other side effects. For instance, radiotherapy to the brain can cause memory loss, headache, alopecia, and radiation necrosis of the brain. If the abdomen or spine is irradiated, nausea, vomiting, diarrhea, and dysphagia can occur. If the pelvis is irradiated, prostatitis, proctitis, dysuria, metritis, diarrhea, and abdominal pain can occur. Adjuvant hormonal therapy for prostate cancer may cause cardiovascular disease, and other, possibly severe, side effects.
== See also ==
Analgesic adjuvant
== References == | Wikipedia/Adjuvant_therapy |
In radiotherapy, radiation treatment planning (RTP) is the process in which a team consisting of radiation oncologists, radiation therapist, medical physicists and medical dosimetrists plan the appropriate external beam radiotherapy or internal brachytherapy treatment technique for a patient with cancer.
== History ==
In the early days of radiotherapy planning was performed on 2D x-ray images, often by hand and with manual calculations. Computerised treatment planning systems began to be used in the 1970s to improve the accuracy and speed of dose calculations.
By the 1990s CT scans, more powerful computers, improved dose calculation algorithms and Multileaf collimators (MLCs) lead to 3D conformal planning (3DCRT), categorised as a Level 2 technique by the European Dynarad consortium. 3DCRT uses MLCs to shape the radiotherapy beam to closely match the shape of a target tumour, reducing the dose to healthy surrounding tissue.
Level 3 techniques such as IMRT and VMAT utilise inverse planning to provide further improved dose distributions (i.e. better coverage of target tumours and sparing of healthy tissue). These methods are growing in use, particularly for cancers in certain locations which have been shown to derive the greatest benefits.
== Image guided planning ==
Typically, medical imaging is used to form a virtual patient for a computer-aided design procedure. A CT scan is often the primary image set for treatment planning while magnetic resonance imaging provides excellent secondary image set for soft tissue contouring. Positron emission tomography is less commonly used and reserved for cases where specific uptake studies can enhance planning target volume delineation. Modern treatment planning systems provide tools for multimodality image matching, also known as image coregistration or fusion. Treatment simulations are used to plan the geometric, radiological, and dosimetric aspects of the therapy using radiation transport simulations and optimization. For intensity modulated radiation therapy (IMRT), this process involves selecting the appropriate beam type (which may include photons, electrons and protons), energy (e.g. 6, 18 megaelectronvolt (MeV) photons) and physical arrangements. In brachytherapy planning involves selecting the appropriate catheter positions and source dwell times
(in HDR brachytherapy) or seed positions (in LDR brachytherapy).
The more formal optimization process is typically referred to as forward planning and inverse planning.
Plans are often assessed with the aid of dose-volume histograms, allowing the clinician to evaluate the uniformity of the dose to the diseased tissue (tumor) and sparing of healthy structures.
=== Forward planning ===
In forward planning, the planner places beams into a radiotherapy treatment planning system that can deliver sufficient radiation to a tumour while both sparing critical organs and minimising the dose to healthy tissue. The required decisions include how many radiation beams to use, which angles each will be delivered from, whether attenuating wedges be used, and which MLC configuration will be used to shape the radiation from each beam.
Once the treatment planner has made an initial plan, the treatment planning system calculates the required monitor units to deliver a prescribed dose to a specific area, and the distribution of dose in the body this will create. The dose distribution in the patient is dependent on the anatomy and beam modifiers such as wedges, specialized collimation, field sizes, tumor depth, etc. The information from a prior CT scan of the patient allows more accurate modelling of the behaviour of the radiation as it travels through the patient's tissues. Different dose calculation models are available, including pencil beam, convolution-superposition and monte carlo simulation, with precision versus computation time being the relevant trade-off.
This type of planning is only sufficiently adept to handle relatively simple cases in which the tumour has a simple shape and is not near any critical organs.
=== Inverse planning ===
In inverse planning a radiation oncologist defines a patient's critical organs and tumour, after which a planner gives target doses and importance factors for each. Then, an optimisation program is run to find the treatment plan which best matches all the input criteria.
In contrast to the manual trial-and-error process of forward planning, inverse planning uses the optimiser to solve the Inverse Problem as set up by the planner.
== See also ==
Brachytherapy planning
Image-guided radiation therapy
== References == | Wikipedia/Treatment_Planning |
External beam radiation therapy (EBRT) is a form of radiotherapy that utilizes a high-energy collimated beam of ionizing radiation, from a source outside the body, to target and kill cancer cells. The radiotherapy beam is composed of particles, which are focussed in a particular direction of travel using collimators. Each radiotherapy beam consists of one type of particle intended for use in treatment, though most beams contain some contamination by other particle types.
Radiotherapy beams are classified by the particle they are intended to deliver, such as photons (as x-rays or gamma rays), electrons, and heavy ions; x-rays and electron beams are by far the most widely used sources for external beam radiotherapy. Orthovoltage ("superficial") X-rays are used for treating skin cancer and superficial structures. Megavoltage X-rays are used to treat deep-seated tumors (e.g. bladder, bowel, prostate, lung, or brain), whereas megavoltage electron beams are typically used to treat superficial lesions extending to a depth of approximately 5 cm. A small number of centers operate experimental and pilot programs employing beams of heavier particles, particularly protons, owing to the rapid decrease in absorbed dose beneath the depth of the target.
Teletherapy is the most common form of radiotherapy (radiation therapy). The patient sits or lies on a couch and an external source of ionizing radiation is pointed at a particular part of the body. In contrast to brachytherapy (sealed source radiotherapy) and unsealed source radiotherapy, in which the radiation source is inside the body, external beam radiotherapy directs the radiation at the tumor from outside the body.
== X-rays and gamma rays ==
Conventionally, the energy of diagnostic and therapeutic gamma- and X-rays is on the order of kiloelectronvolts (keV) or megaelectronvolts (MeV), and the energy of therapeutic electrons is on the order of megaelectronvolts. The beam is made up of a spectrum of energies: the maximum energy is approximately equal to the beam's maximum electric potential within a linear accelerator times the electron charge. For instance, a 1 megavolt beam will produce photons with a maximum energy around 1 MeV. In practice, the mean X-ray energy is about one-third of the maximum energy. Beam quality and hardness may be improved by X-ray filters, which improves the homogeneity of the X-ray spectrum.
Medically useful X-rays are produced when electrons are accelerated to energies at which either the photoelectric effect predominates (for diagnostic use, since the photoelectric effect offers comparatively excellent contrast with effective atomic number Z) or Compton scattering and pair production predominate (at energies above approximately 200 keV for the former and 1 MeV for the latter), for therapeutic X-ray beams. Some examples of X-ray energies used in medicine are:
Very low-energy superficial X-rays – 35 to 60 keV (mammography, which prioritizes soft-tissue contrast, uses very low-energy kV X-rays)
Superficial radiotherapy X-rays – 60 to 150 keV
Diagnostic X-rays – 20 to 150 keV (mammography to CT); this is the range of photon energies at which the photoelectric effect, which gives maximal soft-tissue contrast, predominates.
Orthovoltage X-rays – 200 to 500 keV
Supervoltage X-rays – 500 to 1000 keV
Megavoltage X-rays – 1 to 25 MeV (in practice, nominal energies above 15 MeV are unusual in clinical practice).
Megavoltage X-rays are by far most common in radiotherapy for the treatment of a wide range of cancers. Superficial and orthovoltage X-rays have application for the treatment of cancers at or close to the skin surface. Typically, higher-energy megavoltage X-rays are chosen when it is desirable to maximize "skin-sparing" (since the relative dose to the skin is lower for such high-energy beams).
Medically useful photon beams can also be derived from a radioactive source such as iridium-192, caesium-137, or cobalt-60. (Radium-226 has also been used as such a source in the past, though has been replaced in this capacity by less harmful radioisotopes.) Such photon beams, derived from radioactive decay, are approximately monochromatic, in contrast to the continuous bremsstrahlung spectrum from a linac. These decays include the emission of gamma rays, whose energy is isotope-specific and ranges between 300 keV and 1.5 MeV.
Superficial radiation therapy machines produce low energy x-rays in the same energy range as diagnostic x-ray machines, 20–150 keV, to treat skin conditions. Orthovoltage X-ray machines produce higher energy x-rays in the range 200–500 keV. Radiation from orthovoltage x-ray machines has been called "deep" due to its greater penetrating ability, allowing it to treat tumors at depths unreachable by lower-energy "superficial" radiation. Orthovoltage units have essentially the same design as diagnostic X-ray machines and are generally limited to photon energies less than 600 keV. X-rays with energies on the order of 1 MeV are generated in Linear accelerators ("linacs"). The first use of a linac for medical radiotherapy was in 1953. Commercially available medical linacs produce X-rays and electrons with an energy range from 4 MeV up to around 25 MeV. The X-rays themselves are produced by the rapid deceleration of electrons in a target material, typically a tungsten alloy, which produces an X-ray spectrum via bremsstrahlung radiation. The shape and intensity of the beam produced by a linac may be modified or collimated by a variety of means. Thus, conventional, conformal, intensity-modulated, tomographic, and stereotactic radiotherapy are all provided using specially-modified linear accelerators.
Cobalt units use radiation from cobalt-60, which emits two gamma rays at energies of 1.17 and 1.33 MeV, a dichromatic beam with an average energy of 1.25 MeV. The role of the cobalt unit has largely been replaced by the linear accelerator, which can generate higher energy radiation. Nonetheless, cobalt treatment still retains some applications, such as the Gamma Knife, since the machinery is relatively reliable and simple to maintain compared to the modern linear accelerator.
=== Sources and properties of X-rays ===
Bremsstrahlung X-rays are produced by bombarding energetic cathode rays (electrons) onto a target made of a material with high atomic number, such as tungsten. The target acts as a sort of transducer, converting part of the electrons' kinetic energy into energetic photons. Kilovoltage X-rays are typically produced using an X-ray tube, in which electrons travel through a vacuum from a hot cathode to a cold anode, which also acts as the target. However, it is impractical to produce megavoltage X-rays using this method; instead, a linear accelerator is most commonly used to produce X-rays of such energy. X-ray emission is more forward-directed at megavoltage energies and more laterally-directed at kilovoltage energies. Consequently, kilovoltage X-rays tend to be produced using a reflection-type target, in which the radiation is emitted back from the target's surface, while megavoltage X-rays tend to be produced with a transmission target in which the X-rays are emitted on the side opposite that of electron incidence. Reflection type targets exhibit the heel effect and can use a rotating anode to aid in heat dissipation.
Compton scattering is the dominant interaction between a megavoltage beam and the patient, while the photoelectric effect dominates at keV energies. Additionally, Compton scattering is much less dependent on atomic number than the photoelectric effect; while kilovoltage beams enhance the distinction between muscle and bone in medical imaging, megavoltage beams suppress that distinction to the advantage of teletherapy. Pair production and photoneutron production increase at higher energies, only becoming significant at energies on the order of 1 MeV.
X-ray energy in the keV range is described by the electrical voltage used to produce it. For instance, a 100 kVp beam is produced by a 100 kV voltage applied to an X-ray tube and will have a maximum photon energy of 100 keV. However, the beam's spectrum can be affected by other factors as well, such as the voltage waveform and external X-ray filtration. These factors are reflected in the beam's half-value layer (HVL), measured in-air under conditions of "good geometry". A typical superficial X-ray energy might be 100 kVp per 3 mmAl – "100 kilovolts applied to the X-ray tube with a measured half-value layer of 3 millimeters of aluminum". The half-value layer for orthovoltage beams is more typically measured using copper; a typical orthovoltage energy is 250 kVp per 2 mmCu. For X-rays in the MeV range, an actual voltage of the same magnitude is not used in production of the beam. A 6 MV beam contains photons of no more than 1 MeV, rather than 6 MeV; the energy of such a beam is instead generally characterized by measuring the ratio of the beam's intensity at varying depths in a medium.
Kilovoltage beams do not exhibit a build-up effect and thus deposit their maximum dose at the surface, i.e. dmax = 0 or D0 = 100%. Conversely, megavoltage beams do exhibit the buildup effect deposit; they deposit their maximum dose at some depth below the surface, i.e. dmax > 0. The depth of dose maximum is governed by the range of the electrons liberated upstream during Compton scattering. At depths beyond dmax, the dose profile of all X-ray beams decreases roughly exponentially with depth. Though actual values of dmax are influenced by various factors, the following are representative benchmark values.
== Electrons ==
X-rays are generated by bombarding a high atomic number material with electrons. If the target is removed (and the beam current decreased). a high energy electron beam is obtained. Electron beams are useful for treating superficial lesions, because the maximum dose deposition occurs near the surface and thereafter decreases rapidly with depth, sparing underlying tissue. Electron beams usually have nominal energies in the range of 4–20 MeV, corresponding to a treatment range of approximately 1–5 cm (in water-equivalent tissue). Energies above 18 MeV are rarely used. Although the X-ray target is removed in electron mode, the beam must be fanned out by sets of thin scattering foils in order to achieve flat and symmetric dose profiles in the treated tissue.
Many linear accelerators can produce both electrons and x-rays.
== Hadron therapy ==
Hadron therapy involves the therapeutic use of protons, neutrons, and heavier ions (fully ionized atomic nuclei). Of these, proton therapy is by far the most common, though still rare compared to other forms of external beam radiotherapy, since it requires large and expensive equipment. The gantry (the part that rotates around the patient) is a multi-story structure, and a proton therapy system can cost (as of 2009) up to US$150 million.
== Multi-leaf collimator ==
Modern linear accelerators are equipped with multileaf collimators (MLCs), which can move within the radiation field as the linac gantry rotates, and block the field as necessary according to the gantry position. This technology allows radiotherapy treatment planners great flexibility in shielding organs-at-risk (OARSs), while ensuring that the prescribed dose is delivered to the target organs. A typical multi-leaf collimator consists of two sets of 40 to 160 leaves, each around 5–10 mm thick and several centimetres long in the other two dimensions. Each leaf in the MLC is aligned parallel to the radiation field and can be moved independently to block part of the field, adapting it to the shape of the tumor (by adjusting the position of the leaves), thus minimizing the amount of healthy tissue subject to radiation exposure. On older linacs without MLCs, this must be accomplished manually using several hand-crafted blocks.
== Intensity modulated radiation therapy ==
Intensity modulated radiation therapy (IMRT) is an advanced radiotherapy technique used to minimize the amount of normal tissue being irradiated in the treatment field. In some systems, this intensity modulation is achieved by moving the leaves in the MLC during the course of treatment, thereby delivering a radiation field with a non-uniform (i.e., modulated) intensity. Using IMRT, radiation oncologists are able to split the radiation beam into many beamlets and vary the intensity of each beamlet, and doctors are often able to further limit the amount of radiation received by healthy tissue near the tumor. Doctors have found that this sometimes allows them to safely give a higher dose of radiation to the tumor, potentially increasing the chance of successful treatment.
=== Volumetric modulated arc therapy ===
Volumetric modulated arc therapy (VMAT) is an extension of IMRT characterized by a linear accelerator rotating around the patient. This means that rather than radiation entering the patient at only a small number of fixed angles, it can enter at many angles. This can be beneficial for some treatment sites in which the target volume is surrounded by a number, allowing directed treatment without exposing nearby organs to heightened radiation levels.
=== Flattening filter free ===
The intensity of the X-rays produced in a megavoltage linac is much higher in the centre of the beam compared to the edges. To offset this central peak, a flattening filter is used. A flattening filter is cone-shaped so as to compensate for the forward bias in the momentum of incident electrons (and is typically made from a metal such as tungsten); after an X-ray beam passes through the flattening filter, it has a more uniform profile. This simplifies treatment planning, though significantly reduces the intensity of the beam. With greater computing power and more efficient treatment planning algorithms, the need for simpler treatment planning techniques – such as "forward planning", in which the planner directly instructs the linac on how to deliver the prescribed treatment – is reduced. This has led to increased interest in flattening filter free (FFF) treatments.
FFF treatments have been found to have an increased maximum dose rate, allowing reduced treatment times and a reduction in the effect of patient motion on the delivery of the treatment. This makes FFF an area of particular interest in stereotactic treatments. For instance, in treatment of breast cancer, the reduced treatment time may reduce patient movement and breast treatments where there is the potential to reduce breathing motion.
== Image-guided radiation therapy ==
Image-guided radiation therapy (IGRT) augments radiotherapy with imaging to increase the accuracy and precision of target localization, thereby reducing the amount of healthy tissue in the treatment field. To allow patients to benefit from sophisticated treatment techniques as IMRT or hadron therapy, patient alignment accuracies with an error margin of at most 0.5 mm are desirable. Therefore, methods such as stereoscopic digital kilovoltage imaging-based patient position verification (PPVS), and alignment estimation based on in-situ cone-beam computed tomography (CT), enrich the range of modern IGRT approaches.
== See also ==
Brachytherapy
Cyberknife
Gamma Knife, a type of radiosurgery
Intraoperative electron radiation therapy
Intraoperative radiation therapy
Neutron capture therapy of cancer
Radiation therapy
Tomotherapy
== References ==
== General references ==
Radiotherapy physics in practice, edited by JR Williams and DI Thwaites, Oxford University Press UK (2nd edition 2000), ISBN 0-19-262878-X
Linear Particle Accelerator (Linac) Animation by Ionactive
http://www.myradiotherapy.com
Superficial radiation therapy
National Institute of Radiological Science (Japan) | Wikipedia/Teletherapy |
Breast-conserving surgery refers to an operation that aims to remove breast cancer while avoiding a mastectomy. Different forms of this operation include: lumpectomy (tylectomy), wide local excision, segmental resection, and quadrantectomy. Breast-conserving surgery has been increasingly accepted as an alternative to mastectomy in specific patients, as it provides tumor removal while maintaining an acceptable cosmetic outcome. This page reviews the history of this operation, important considerations in decision making and patient selection, and the emerging field of oncoplastic breast conservation surgery.
== Medical uses ==
For clinical stages I and II breast cancer, breast-conserving surgery, with radiotherapy and possibly chemotherapy may be indicated if one or two sentinel lymph nodes are found to have cancer which is not extensive. In this case, the sentinel lymph nodes would be examined, and lymphadenectomy as further evaluation is not indicated as this result from the sentinel lymph nodes is sufficient to recommend treatment.
Breast-conserving surgery may also be used in cases of biopsy-proven invasive breast cancer or biopsy-proven ductal carcinoma in situ. In the assessment of the tumor, the surgeon should assess the ability to resect the tumor with clear margins while providing a cosmetic result that is acceptable to the patient.
For screening detected lesions that are non-palpable, preoperative lesion localization by a breast radiologist is required in order to accurately identify the tumor intraoperatively and excise it with adequate margins. Preoperative localization was traditionally performed using a steel guidewire; however, novel tumor markers have emerged such as radioactive seeds, radiofrequency reflectors and magnetic seeds.
Shared decision-making is an important consideration in breast-conserving surgery. It is estimated that between 50% and 70% of patients are active participants in the decision-making of breast cancer surgery. The time following a cancer diagnosis may be filled with fear, vulnerability, and a sense of being overwhelmed at the amount of information being provided by physicians as well as accessed on the internet. Each patient has their own set of unique characteristics, which may make it challenging to read information online and apply that information to a specific individual circumstance. In addition, there are several important misconceptions regarding breast-conservation surgery for patients and clinicians to keep in mind.
In appropriately selected patients, mastectomy and breast-conserving surgery have equivalent survival rates.
Undergoing mastectomy does not eliminate the risk for recurrent or new cancer.
Radiation therapy may still be needed following breast-conservation surgery.
The decision regarding the need for chemotherapy is independent from the surgical options.
== Contraindications ==
Absolute contraindications, which are reasons why the procedure absolutely cannot be done, include:
Pregnancy is an absolute contraindication to the use of breast irradiation. In some cases, it may be possible to perform breast-conserving surgery in the third trimester and treat the patient with radiation after delivery.
Two or more primary tumors in separate quadrants of the breast or with diffuse malignant-appearing microcalcifications.
A history of prior therapeutic irradiation to the breast that would require re-treatment to an excessively high total dose.
Persistent positive margins after reasonable surgical attempts: the importance of a single focally positive microscopic margin needs further study and may not be an absolute contraindication.
Inflammatory breast cancer
Diffuse or indeterminate micro-calcifications on mammography
Relative contraindications encompass situations of higher risk of complications to the patient that may be outweighed by other considerations, such as the benefit to the patient. Relative contraindications include:
Previous breast radiation therapy
Connective tissue disease such as Scleroderma, Sjogren Syndrome, Lupus, and Rheumatoid arthritis may result in an increased risk of radiation toxicity.
Very large tumor size relative to breast volume.
== Oncoplastic surgery ==
Oncoplastic surgery is an important consideration in breast-conserving surgery that integrates plastic surgery principles into breast cancer surgery in order to preserve aesthetic outcomes and quality of life, without compromising local control of the cancer. It is based on three surgical principles: ideal breast cancer surgery with free tumor margins, immediate breast reconstruction, and immediate symmetry with the other breast. Oncoplastic approaches to breast-conserving surgery may require a close partnership among surgeons who specialize in surgical oncology and plastic surgery. Oncoplastic surgery is not only limited to breast-conserving surgery, as the techniques and principles of plastic surgery can be applied to mastectomy as well.
The evidence comparing oncoplastic breast-conserving surgery to traditional breast-conserving surgery techniques is weak. There is no strong evidence to suggest that oncoplastic breast conserving surgery results in worse outcomes compared to other breast-conserving surgical techniques.
== History ==
Prior to 1981, there existed limited evidence that breast-conserving surgery was an acceptable alternative to radical mastectomy for treatment of early stage breast cancer. Dr. Umberto Veronesi, an Italian oncologist, challenged this notion and led a clinical trial comparing the radical mastectomy with breast-conserving surgery (which was termed quadrantectomy at the time). This landmark trial showed no differences in overall survival, disease-free survival, and local recurrence for patients with breast cancer of less than 2 cm and no palpable axillary nodes. He was widely celebrated for this landmark study, so much so that some began referring to this operation as the Veronesi Quadrantectomy. The work of Bernard Fisher, who performed a randomized trial comparing lumpectomy, lumpectomy plus radiation and total mastectomy, was also pivotal in the establishment of breast-conserving surgery.
== References ==
== External links ==
American Academy of Family Physicians, Breast-Conserving Surgery, What is breast-conserving surgery?
Breast conserving surgery at National Breast and Ovarian Cancer Centre www.nbocc.org | Wikipedia/Breast-conserving_surgery |
External beam radiation therapy (EBRT) is a form of radiotherapy that utilizes a high-energy collimated beam of ionizing radiation, from a source outside the body, to target and kill cancer cells. The radiotherapy beam is composed of particles, which are focussed in a particular direction of travel using collimators. Each radiotherapy beam consists of one type of particle intended for use in treatment, though most beams contain some contamination by other particle types.
Radiotherapy beams are classified by the particle they are intended to deliver, such as photons (as x-rays or gamma rays), electrons, and heavy ions; x-rays and electron beams are by far the most widely used sources for external beam radiotherapy. Orthovoltage ("superficial") X-rays are used for treating skin cancer and superficial structures. Megavoltage X-rays are used to treat deep-seated tumors (e.g. bladder, bowel, prostate, lung, or brain), whereas megavoltage electron beams are typically used to treat superficial lesions extending to a depth of approximately 5 cm. A small number of centers operate experimental and pilot programs employing beams of heavier particles, particularly protons, owing to the rapid decrease in absorbed dose beneath the depth of the target.
Teletherapy is the most common form of radiotherapy (radiation therapy). The patient sits or lies on a couch and an external source of ionizing radiation is pointed at a particular part of the body. In contrast to brachytherapy (sealed source radiotherapy) and unsealed source radiotherapy, in which the radiation source is inside the body, external beam radiotherapy directs the radiation at the tumor from outside the body.
== X-rays and gamma rays ==
Conventionally, the energy of diagnostic and therapeutic gamma- and X-rays is on the order of kiloelectronvolts (keV) or megaelectronvolts (MeV), and the energy of therapeutic electrons is on the order of megaelectronvolts. The beam is made up of a spectrum of energies: the maximum energy is approximately equal to the beam's maximum electric potential within a linear accelerator times the electron charge. For instance, a 1 megavolt beam will produce photons with a maximum energy around 1 MeV. In practice, the mean X-ray energy is about one-third of the maximum energy. Beam quality and hardness may be improved by X-ray filters, which improves the homogeneity of the X-ray spectrum.
Medically useful X-rays are produced when electrons are accelerated to energies at which either the photoelectric effect predominates (for diagnostic use, since the photoelectric effect offers comparatively excellent contrast with effective atomic number Z) or Compton scattering and pair production predominate (at energies above approximately 200 keV for the former and 1 MeV for the latter), for therapeutic X-ray beams. Some examples of X-ray energies used in medicine are:
Very low-energy superficial X-rays – 35 to 60 keV (mammography, which prioritizes soft-tissue contrast, uses very low-energy kV X-rays)
Superficial radiotherapy X-rays – 60 to 150 keV
Diagnostic X-rays – 20 to 150 keV (mammography to CT); this is the range of photon energies at which the photoelectric effect, which gives maximal soft-tissue contrast, predominates.
Orthovoltage X-rays – 200 to 500 keV
Supervoltage X-rays – 500 to 1000 keV
Megavoltage X-rays – 1 to 25 MeV (in practice, nominal energies above 15 MeV are unusual in clinical practice).
Megavoltage X-rays are by far most common in radiotherapy for the treatment of a wide range of cancers. Superficial and orthovoltage X-rays have application for the treatment of cancers at or close to the skin surface. Typically, higher-energy megavoltage X-rays are chosen when it is desirable to maximize "skin-sparing" (since the relative dose to the skin is lower for such high-energy beams).
Medically useful photon beams can also be derived from a radioactive source such as iridium-192, caesium-137, or cobalt-60. (Radium-226 has also been used as such a source in the past, though has been replaced in this capacity by less harmful radioisotopes.) Such photon beams, derived from radioactive decay, are approximately monochromatic, in contrast to the continuous bremsstrahlung spectrum from a linac. These decays include the emission of gamma rays, whose energy is isotope-specific and ranges between 300 keV and 1.5 MeV.
Superficial radiation therapy machines produce low energy x-rays in the same energy range as diagnostic x-ray machines, 20–150 keV, to treat skin conditions. Orthovoltage X-ray machines produce higher energy x-rays in the range 200–500 keV. Radiation from orthovoltage x-ray machines has been called "deep" due to its greater penetrating ability, allowing it to treat tumors at depths unreachable by lower-energy "superficial" radiation. Orthovoltage units have essentially the same design as diagnostic X-ray machines and are generally limited to photon energies less than 600 keV. X-rays with energies on the order of 1 MeV are generated in Linear accelerators ("linacs"). The first use of a linac for medical radiotherapy was in 1953. Commercially available medical linacs produce X-rays and electrons with an energy range from 4 MeV up to around 25 MeV. The X-rays themselves are produced by the rapid deceleration of electrons in a target material, typically a tungsten alloy, which produces an X-ray spectrum via bremsstrahlung radiation. The shape and intensity of the beam produced by a linac may be modified or collimated by a variety of means. Thus, conventional, conformal, intensity-modulated, tomographic, and stereotactic radiotherapy are all provided using specially-modified linear accelerators.
Cobalt units use radiation from cobalt-60, which emits two gamma rays at energies of 1.17 and 1.33 MeV, a dichromatic beam with an average energy of 1.25 MeV. The role of the cobalt unit has largely been replaced by the linear accelerator, which can generate higher energy radiation. Nonetheless, cobalt treatment still retains some applications, such as the Gamma Knife, since the machinery is relatively reliable and simple to maintain compared to the modern linear accelerator.
=== Sources and properties of X-rays ===
Bremsstrahlung X-rays are produced by bombarding energetic cathode rays (electrons) onto a target made of a material with high atomic number, such as tungsten. The target acts as a sort of transducer, converting part of the electrons' kinetic energy into energetic photons. Kilovoltage X-rays are typically produced using an X-ray tube, in which electrons travel through a vacuum from a hot cathode to a cold anode, which also acts as the target. However, it is impractical to produce megavoltage X-rays using this method; instead, a linear accelerator is most commonly used to produce X-rays of such energy. X-ray emission is more forward-directed at megavoltage energies and more laterally-directed at kilovoltage energies. Consequently, kilovoltage X-rays tend to be produced using a reflection-type target, in which the radiation is emitted back from the target's surface, while megavoltage X-rays tend to be produced with a transmission target in which the X-rays are emitted on the side opposite that of electron incidence. Reflection type targets exhibit the heel effect and can use a rotating anode to aid in heat dissipation.
Compton scattering is the dominant interaction between a megavoltage beam and the patient, while the photoelectric effect dominates at keV energies. Additionally, Compton scattering is much less dependent on atomic number than the photoelectric effect; while kilovoltage beams enhance the distinction between muscle and bone in medical imaging, megavoltage beams suppress that distinction to the advantage of teletherapy. Pair production and photoneutron production increase at higher energies, only becoming significant at energies on the order of 1 MeV.
X-ray energy in the keV range is described by the electrical voltage used to produce it. For instance, a 100 kVp beam is produced by a 100 kV voltage applied to an X-ray tube and will have a maximum photon energy of 100 keV. However, the beam's spectrum can be affected by other factors as well, such as the voltage waveform and external X-ray filtration. These factors are reflected in the beam's half-value layer (HVL), measured in-air under conditions of "good geometry". A typical superficial X-ray energy might be 100 kVp per 3 mmAl – "100 kilovolts applied to the X-ray tube with a measured half-value layer of 3 millimeters of aluminum". The half-value layer for orthovoltage beams is more typically measured using copper; a typical orthovoltage energy is 250 kVp per 2 mmCu. For X-rays in the MeV range, an actual voltage of the same magnitude is not used in production of the beam. A 6 MV beam contains photons of no more than 1 MeV, rather than 6 MeV; the energy of such a beam is instead generally characterized by measuring the ratio of the beam's intensity at varying depths in a medium.
Kilovoltage beams do not exhibit a build-up effect and thus deposit their maximum dose at the surface, i.e. dmax = 0 or D0 = 100%. Conversely, megavoltage beams do exhibit the buildup effect deposit; they deposit their maximum dose at some depth below the surface, i.e. dmax > 0. The depth of dose maximum is governed by the range of the electrons liberated upstream during Compton scattering. At depths beyond dmax, the dose profile of all X-ray beams decreases roughly exponentially with depth. Though actual values of dmax are influenced by various factors, the following are representative benchmark values.
== Electrons ==
X-rays are generated by bombarding a high atomic number material with electrons. If the target is removed (and the beam current decreased). a high energy electron beam is obtained. Electron beams are useful for treating superficial lesions, because the maximum dose deposition occurs near the surface and thereafter decreases rapidly with depth, sparing underlying tissue. Electron beams usually have nominal energies in the range of 4–20 MeV, corresponding to a treatment range of approximately 1–5 cm (in water-equivalent tissue). Energies above 18 MeV are rarely used. Although the X-ray target is removed in electron mode, the beam must be fanned out by sets of thin scattering foils in order to achieve flat and symmetric dose profiles in the treated tissue.
Many linear accelerators can produce both electrons and x-rays.
== Hadron therapy ==
Hadron therapy involves the therapeutic use of protons, neutrons, and heavier ions (fully ionized atomic nuclei). Of these, proton therapy is by far the most common, though still rare compared to other forms of external beam radiotherapy, since it requires large and expensive equipment. The gantry (the part that rotates around the patient) is a multi-story structure, and a proton therapy system can cost (as of 2009) up to US$150 million.
== Multi-leaf collimator ==
Modern linear accelerators are equipped with multileaf collimators (MLCs), which can move within the radiation field as the linac gantry rotates, and block the field as necessary according to the gantry position. This technology allows radiotherapy treatment planners great flexibility in shielding organs-at-risk (OARSs), while ensuring that the prescribed dose is delivered to the target organs. A typical multi-leaf collimator consists of two sets of 40 to 160 leaves, each around 5–10 mm thick and several centimetres long in the other two dimensions. Each leaf in the MLC is aligned parallel to the radiation field and can be moved independently to block part of the field, adapting it to the shape of the tumor (by adjusting the position of the leaves), thus minimizing the amount of healthy tissue subject to radiation exposure. On older linacs without MLCs, this must be accomplished manually using several hand-crafted blocks.
== Intensity modulated radiation therapy ==
Intensity modulated radiation therapy (IMRT) is an advanced radiotherapy technique used to minimize the amount of normal tissue being irradiated in the treatment field. In some systems, this intensity modulation is achieved by moving the leaves in the MLC during the course of treatment, thereby delivering a radiation field with a non-uniform (i.e., modulated) intensity. Using IMRT, radiation oncologists are able to split the radiation beam into many beamlets and vary the intensity of each beamlet, and doctors are often able to further limit the amount of radiation received by healthy tissue near the tumor. Doctors have found that this sometimes allows them to safely give a higher dose of radiation to the tumor, potentially increasing the chance of successful treatment.
=== Volumetric modulated arc therapy ===
Volumetric modulated arc therapy (VMAT) is an extension of IMRT characterized by a linear accelerator rotating around the patient. This means that rather than radiation entering the patient at only a small number of fixed angles, it can enter at many angles. This can be beneficial for some treatment sites in which the target volume is surrounded by a number, allowing directed treatment without exposing nearby organs to heightened radiation levels.
=== Flattening filter free ===
The intensity of the X-rays produced in a megavoltage linac is much higher in the centre of the beam compared to the edges. To offset this central peak, a flattening filter is used. A flattening filter is cone-shaped so as to compensate for the forward bias in the momentum of incident electrons (and is typically made from a metal such as tungsten); after an X-ray beam passes through the flattening filter, it has a more uniform profile. This simplifies treatment planning, though significantly reduces the intensity of the beam. With greater computing power and more efficient treatment planning algorithms, the need for simpler treatment planning techniques – such as "forward planning", in which the planner directly instructs the linac on how to deliver the prescribed treatment – is reduced. This has led to increased interest in flattening filter free (FFF) treatments.
FFF treatments have been found to have an increased maximum dose rate, allowing reduced treatment times and a reduction in the effect of patient motion on the delivery of the treatment. This makes FFF an area of particular interest in stereotactic treatments. For instance, in treatment of breast cancer, the reduced treatment time may reduce patient movement and breast treatments where there is the potential to reduce breathing motion.
== Image-guided radiation therapy ==
Image-guided radiation therapy (IGRT) augments radiotherapy with imaging to increase the accuracy and precision of target localization, thereby reducing the amount of healthy tissue in the treatment field. To allow patients to benefit from sophisticated treatment techniques as IMRT or hadron therapy, patient alignment accuracies with an error margin of at most 0.5 mm are desirable. Therefore, methods such as stereoscopic digital kilovoltage imaging-based patient position verification (PPVS), and alignment estimation based on in-situ cone-beam computed tomography (CT), enrich the range of modern IGRT approaches.
== See also ==
Brachytherapy
Cyberknife
Gamma Knife, a type of radiosurgery
Intraoperative electron radiation therapy
Intraoperative radiation therapy
Neutron capture therapy of cancer
Radiation therapy
Tomotherapy
== References ==
== General references ==
Radiotherapy physics in practice, edited by JR Williams and DI Thwaites, Oxford University Press UK (2nd edition 2000), ISBN 0-19-262878-X
Linear Particle Accelerator (Linac) Animation by Ionactive
http://www.myradiotherapy.com
Superficial radiation therapy
National Institute of Radiological Science (Japan) | Wikipedia/External_beam_radiation_therapy |
Particle therapy is a form of external beam radiotherapy using beams of energetic neutrons, protons, or other heavier positive ions for cancer treatment. The most common type of particle therapy as of August 2021 is proton therapy.
In contrast to X-rays (photon beams) used in older radiotherapy, particle beams exhibit a Bragg peak in energy loss through the body, delivering their maximum radiation dose at or near the tumor and minimizing damage to surrounding normal tissues.
Particle therapy is also referred to more technically as hadron therapy, excluding photon and electron therapy. Neutron capture therapy, which depends on a secondary nuclear reaction, is also not considered here. Muon therapy, a rare type of particle therapy not within the categories above, has also been studied theoretically; however, muons are still most commonly used for imaging, rather than therapy.
== Method ==
Particle therapy works by aiming energetic ionizing particles at the target tumor. These particles damage the DNA of tissue cells, ultimately causing their death. Because of their reduced ability to repair DNA, cancerous cells are particularly vulnerable to such damage.
The figure shows how beams of electrons, X-rays or protons of different energies (expressed in MeV) penetrate human tissue. Electrons have a short range and are therefore only of interest close to the skin (see electron therapy). Bremsstrahlung X-rays penetrate more deeply, but the dose absorbed by the tissue then shows the typical exponential decay with increasing thickness. For protons and heavier ions, on the other hand, the dose increases while the particle penetrates the tissue and loses energy continuously. Hence the dose increases with increasing thickness up to the Bragg peak that occurs near the end of the particle's range. Beyond the Bragg peak, the dose drops to zero (for protons) or almost zero (for heavier ions).
The advantage of this energy deposition profile is that less energy is deposited into the healthy tissue surrounding the target tissue. This enables higher dose prescription to the tumor, theoretically leading to a higher local control rate, as well as achieving a low toxicity rate.
The ions are first accelerated by means of a cyclotron or synchrotron. The final energy of the emerging particle beam defines the depth of penetration, and hence, the location of the maximum energy deposition. Since it is easy to deflect the beam by means of electro-magnets in a transverse direction, it is possible to employ a raster scan method, i.e., to scan the target area quickly, as the electron beam scans a TV tube. If, in addition, the beam energy and hence the depth of penetration is varied, an entire target volume can be covered in three dimensions, providing an irradiation exactly following the shape of the tumor. This is one of the great advantages compared to conventional X-ray therapy.
At the end of 2008, 28 treatment facilities were in operation worldwide and over 70,000 patients had been treated by means of pions, protons and heavier ions. Most of this therapy has been conducted using protons.
At the end of 2013, 105,000 patients had been treated with proton beams, and approximately 13,000 patients had received carbon-ion therapy.
As of April 1, 2015, for proton beam therapy, there are 49 facilities in the world, including 14 in the US with another 29 facilities under construction. For Carbon-ion therapy, there are eight centers operating and four under construction. Carbon-ion therapy centers exist in Japan, Germany, Italy, and China. Two US federal agencies are hoping to stimulate the establishment of at least one US heavy-ion therapy center.
== Proton therapy ==
Proton therapy is a type of particle therapy that uses a beam of protons to irradiate diseased tissue, most often to treat cancer. The chief advantage of proton therapy over other types of external beam radiotherapy (e.g., radiation therapy, or photon therapy) is that the dose of protons is deposited over a narrow range of depth, which results in minimal entry, exit, or scattered radiation dose to healthy nearby tissues. High dose rates are key in cancer treatment advancements. PSI demonstrated that for cyclotron-based proton therapy facility using momentum cooling, it is possible to achieve remarkable dose rates of 952 Gy/s and 2105 Gy/s at the Bragg peak (in water) for 70 MeV and 230 MeV beams, respectively. When combined with field-specific ridge filters, Bragg peak-based FLASH proton therapy becomes feasible.
== Fast-neutron therapy ==
Fast neutron therapy utilizes high energy neutrons typically between 50 and 70 MeV to treat cancer. Most fast neutron therapy beams are produced by reactors, cyclotrons (d+Be) and linear accelerators. Neutron therapy is currently available in Germany, Russia, South Africa and the United States. In the United States, the only treatment center still operational is in Seattle, Washington. The Seattle center use a cyclotron which produces a proton beam impinging upon a beryllium target.
== Carbon ion radiotherapy ==
Carbon ion therapy (C-ion RT) was pioneered at the National Institute of Radiological Sciences (NIRS) in Chiba, Japan, which began treating patients with carbon ion beams in 1994. This facility was the first to utilize carbon ions clinically, marking a significant advancement in particle therapy for cancer treatment. The therapeutic advantages of carbon ions were recognized earlier, but NIRS was instrumental in establishing its clinical application.
C-ion RT uses particles more massive than protons or neutrons. Carbon ion radiotherapy has increasingly garnered scientific attention as technological delivery options have improved and clinical studies have demonstrated its treatment advantages for many cancers such as prostate, head and neck, lung, and liver cancers, bone and soft tissue sarcomas, locally recurrent rectal cancer, and pancreatic cancer, including locally advanced disease. It also has clear advantages to treat otherwise intractable hypoxic and radio-resistant cancers while opening the door for substantially hypo-fractionated treatment of normal and radio-sensitive disease.
By mid 2017, more than 15,000 patients have been treated worldwide in over 8 operational centers. Japan has been a conspicuous leader in this field. There are five heavy-ion radiotherapy facilities in operation and plans exist to construct several more facilities in the near future. In Germany this type of treatment is available at the Heidelberg Ion-Beam Therapy Center (HIT) and at the Marburg Ion-Beam Therapy Center (MIT). In Italy the National Centre of Oncological Hadrontherapy (CNAO) provides this treatment. Austria will open a CIRT center in 2017, with centers in South Korea, Taiwan, and China soon to open. No CIRT facility now operates in the United States but several are in various states of development.
== Biological advantages of heavy-ion radiotherapy ==
From a radiation biology standpoint, there is considerable rationale to support use of heavy-ion beams in treating cancer patients. All proton and other heavy ion beam therapies exhibit a defined Bragg peak in the body so they deliver their maximum lethal dosage at or near the tumor. This minimizes harmful radiation to the surrounding normal tissues. However, carbon-ions are heavier than protons and so provide a higher relative biological effectiveness (RBE), which increases with depth to reach the maximum at the end of the beam's range. Thus the RBE of a carbon ion beam increases as the ions advance deeper into the tumor-lying region. CIRT provides the highest linear energy transfer (LET) of any currently available form of clinical radiation. This high energy delivery to the tumor results in many double-strand DNA breaks which are very difficult for the tumor to repair. Conventional radiation produces principally single strand DNA breaks which can allow many of the tumor cells to survive. The higher outright cell mortality produced by CIRT may also provide a clearer antigen signature to stimulate the patient's immune system.
== Particle therapy of moving targets ==
The precision of particle therapy of tumors situated in thorax and abdominal region is strongly affected by the target motion. The mitigation of its negative influence requires advanced techniques of tumor position monitoring (e.g., fluoroscopic imaging of implanted radio-opaque fiducial markers or electromagnetic detection of inserted transponders) and irradiation (gating, rescanning, gated rescanning and tumor tracking).
== References ==
== External links ==
Touro University announces first combined particle therapy center in U.S.
PTCOG annual conference | Wikipedia/Carbon_ion_radiotherapy |
Neurogenic bladder dysfunction, often called by the shortened term neurogenic bladder, was technically termed neurogenic lower urinary tract dysfunction by the International Continence Society. It refers to urinary bladder problems due to disease or injury of the central nervous system or peripheral nerves involved in the control of urination. There are multiple types of neurogenic bladder depending on the underlying cause and the symptoms. Symptoms include overactive bladder, urinary urgency, frequency, incontinence or difficulty passing urine. A range of diseases or conditions can cause neurogenic bladder including spinal cord injury, multiple sclerosis, stroke, brain injury, spina bifida, peripheral nerve damage, Parkinson's disease, multiple system atrophy or other neurodegenerative diseases. Neurogenic bladder can be diagnosed through a history and physical as well as imaging and more specialized testing. In addition to symptomatic treatment, treatment depends on the nature of the underlying disease and can be managed with behavioral changes, medications, surgeries, or other procedures. The symptoms of neurogenic bladder, especially incontinence, can severely degrade a person's quality of life.
== Classification ==
There are different types of neurogenic bladder depending on the underlying cause. Many of these types may have similar symptoms.
=== Uninhibited ===
Uninhibited bladder is usually due to damage to the brain from a stroke or brain tumor. This can cause reduced sensation of bladder fullness, low capacity bladder and urinary incontinence. Unlike other forms of neurogenic bladder, it does not lead to high bladder pressures that can cause kidney damage.
=== Spastic ===
In spastic neurogenic bladder (also known as upper motor neuron or hyper-reflexive bladder), the muscle of the bladder (detrusor) and urethral sphincter do not work together and are usually tightly contracted at the same time. This phenomenon is also called detrusor external sphincter dyssynergia (DESD). This leads to urinary retention with high pressures in the bladder that can damage the kidneys. The bladder volume is usually smaller than normal due to increased muscle tone in the bladder. Spastic neurogenic bladder is usually caused by damage to the spinal cord above the level of the 10th thoracic vertebrae (T10).
=== Flaccid ===
In flaccid bladder (also known as lower motor neuron or hypotonic bladder), the muscles of the bladder lose ability to contract normally. This can cause the inability to void urine even if the bladder is full and cause a large bladder capacity. The internal urinary sphincter can contract normally, however urinary incontinence is common. This type of neurogenic bladder is caused by damage to the peripheral nerves that travel from the spinal cord to the bladder.
=== Mixed ===
Mixed type of neurogenic bladder can cause a combination of the above presentations. In mixed type A, the bladder muscle is flaccid but the sphincter is overactive. This creates a large, low pressure bladder and inability to void, but does not carry as much risk for kidney damage as a spastic bladder. Mixed type B is characterized by a flaccid external sphincter and a spastic bladder causing problems with incontinence.
== Signs and symptoms ==
Neurogenic bladder can cause a range of urinary symptoms including urinary urgency, urinary incontinence or difficulty urinating (urinary retention). The first sign of bladder dysfunction may be recurrent urinary tract infections (UTIs).
=== Complications ===
Neurogenic bladder can cause hydronephrosis (swelling of a kidney due to a build-up of urine), recurrent urinary tract infections, and recurrent kidney stones which may compromise kidney function. This is especially significant in spastic neurogenic bladder that leads to high bladder pressures. Kidney failure was previously a leading cause of mortality in patients with spinal cord injury but is now dramatically less common due to improvements in bladder management.
== Causes ==
Urine storage and elimination (urination) requires coordination between the bladder emptying muscle (detrusor) and the external sphincter of the bladder. This coordination can be disrupted by damage or diseases of the central nervous system, peripheral nerves or autonomic nervous system. Any trauma or disease impairing the voluntary micturition process' components, e.g., spinal cord, peripheral nerves, bladder sphincter or the urethral internal and external sphincters, can cause bladder dysfunction.
=== Central nervous system ===
Damage to the brain or spinal cord is the most common cause of neurogenic bladder. Damage to the brain can be caused by stroke, brain tumors, multiple sclerosis, Parkinson's disease, multiple system atrophy or other neurodegenerative conditions. Bladder involvement is more likely if the damage is in the area of the pons. Damage to the spinal cord can be caused by traumatic injury, demyelinating disease, meningitis-retention syndrome, vitamin B12 deficiency, syringomyelia, cauda equina syndrome, or spina bifida. Spinal cord compression from herniated disks, tumor, or spinal stenosis can also result in neurogenic bladder.
=== Peripheral nervous system ===
Damage to the nerves that travel from the spinal cord to the bladder (peripheral nerves) can cause neurogenic bladder, usually the flaccid type. Nerve damage can be caused by diabetes, alcoholism, vitamin B12 deficiency, or genital herpes. Peripheral nerves can also be damaged as a complication of major surgery of the pelvis, such as for removal of tumors or as collateral damage from pelvic radiation therapy or chemotherapy, e.g., cytotoxic chemotherapy involving doxorubicin.
== Diagnosis ==
The diagnosis of neurogenic bladder is made based on a complete history and physical examination and may require imaging and specialized studies. History should include information on the onset, duration, triggers, severity, other medical conditions and medications (including anticholinergics, calcium channel blockers, diuretics, sedatives, alpha-adrenergic agonist, alpha 1 antagonists). Urinary symptoms may include frequency, urgency, incontinence or recurrent urinary tract infections (UTIs). Questionnaires can be helpful in quantifying symptom burden. In children it is important to obtain a prenatal and developmental history.
Ultrasound imaging can give information on the shape of the bladder, post-void residual volume, and evidence of kidney damage such as kidney size, thickness or ureteral dilation. Trabeculated bladder on ultrasound indicates high risk of developing urinary tract abnormalities such as hydronephrosis and stones. A voiding cystourethrography study uses contrast dye to obtain images of the bladder both when it is full and after urination which can show changes in bladder shape consistent with neurogenic bladder.
Urodynamic studies are an important component of the evaluation for neurogenic bladder. Urodynamics refers to the measurement of the pressure-volume relationship in the bladder. The bladder usually stores urine at low pressure and urination can be completed without a dramatic pressure rise. Damage to the kidneys is probable if the pressure rises above 40 cm of water during filling. Bladder pressure can be measured by cystometry, during which the bladder is artificially filled with a catheter and bladder pressures and detrusor activity are monitored. Patterns of involuntary detrusor activity as well as bladder flexibility, or compliance, can be evaluated. The most valuable test to test for detrusor sphincter dyssynergia (DESD) is to perform cystometry simultaneously with external sphincter electromyography (EMG). Uroflowmetry is a less-invasive study that can measure urine flow rate and use it to estimate detrusor strength and sphincter resistance. Urethral pressure monitoring is another less-invasive approach to assessing detrusor sphincter dyssynergia. These studies can be repeated at regular intervals, especially if symptoms worsen or to measure response to therapies.
Evaluation of kidney function through blood tests such as serum creatinine should be obtained.
Sustained post-voiding high bladder pressures indicate a potential obstruction and typically recommend pelvic imaging with CT scan or cystoscopy to rule out tumor obstruction or urethral strictures. The inside of the bladder can be visualized during a cystoscopic pathological exam, but the procedure is not recommended for routine follow-up due to low observed incidence rates.
== Treatment ==
Treatment depends on the type of neurogenic bladder and other medical problems. Treatment strategies include catheterization, medications, surgeries or other procedures. The goals of treatment focus on preserving the structure and function of the upper urinary tract, and on improving the quality of life for patients with neurogenic bladder.
=== Medications ===
The first-line therapy for most patients is an anticholinergic medication. These are used for patients with over-active bladder muscles, who have lost the ability to hold their urine in. Oxybutynin is a common anti-cholinergic medication used to reduce bladder contractions by blocking M3 muscarinic receptors in the detrusor muscle. Its use is limited by side effects such as dry mouth, constipation and decreased sweating. Patients must also be monitored for newly-developed difficulty emptying the bladder, which may result from excessive effects of the drug. Tolterodine is a longer acting anticholinergic that may have fewer side effects.
For urinary retention, cholinergics (muscarinic agonists) like bethanechol can improve the squeezing ability of the bladder. Alpha blockers can also reduce outlet resistance and allow complete emptying if there is adequate bladder muscle function.
=== Catheterization ===
Use of a catheter is a standard approach for patients with difficulty voiding (emptying) the bladder. For most patients, this can be accomplished with intermittent catherization which involves no surgery or permanently attached appliances. Intermittent catheterization involves using straight catheters (which are usually disposable or single-use products) several times a day to empty the bladder. This can be done independently or with assistance. For people who are unable to use disposable straight catheters, a Foley catheter allows continuous drainage of urine into a sterile drainage bag that is worn by the patient, but such catheters are associated with higher rates of complications.
Catheters are preferred over externally-applied pressure (such as with hands) or straining of the abdomen, even when these methods succeed in completely emptying the bladder. Those techniques can elevate the pressure inside the detrusor muscle of the bladder and cause additional bladder dysfunction, or even rupture the bladder.
=== Botulinum Toxin ===
Botulinum toxin (Botox) can be used through two different approaches. For spastic neurogenic bladder, the bladder muscle (detrusor) can be injected which will cause it to be flaccid for 6–9 months. This prevents high bladder pressures and intermittent catherization must be used during this time.
Botox can also be injected into the external sphincter to paralyze a spastic sphincter in patients with detrusor sphincter dyssynergia.
=== Neuromodulation ===
There are various strategies to alter the interaction between the nerves and muscles of the bladder, including nonsurgical therapies (transurethral electrical bladder stimulation), minimally invasive procedures (sacral neuromodulation pacemaker), and operative (reconfiguration of sacral nerve root anatomy).
=== Surgery ===
Surgical interventions may be pursued if medical approaches have been maximized.
Surgical options depend on the type of dysfunction observed on urodynamic testing, and may include:
Urinary Diversion: Creation of a stoma (from the intestines, called "conduit") on the skin of the abdomen that bypasses the urethra to empty the bladder directly through the skin opening. Several techniques may be used. One technique is the Mitrofanoff stoma, where the appendix or a portion of the ileum ('Yang-Monti' conduit) are used to create the diversion. The ileum and ascending colon can also be used to create a pouch accessible for catheterization (Indiana pouch).
Urethral stents or urethral sphincterotomy are other surgical approaches that can reduce bladder pressures but require use of an external urinary collection device.
Urethral slings may be used in both adults and children
Artificial Urinary Sphincters have shown good term outcomes in adults and pediatric patients. An artificial urinary sphincter has three components: a control pump, an inflatable cuff that goes around the urethra, and a pressure regulating balloon. One study on 97 patients followed for a mean duration of 4 years found that 92% percent were continent at day and night during follow up. However, patients in this study who had intermediate-type bladders underwent adjuvant cystoplasty. Additionally, one study showed that there was no significant difference in success rates between artificial urinary sphincters and sling procedures, however patients tended to need more additional surgeries with the artificial sphincter versus a sling.
Bladder Neck Closure is a major surgical procedure which can be a last resort treatment for incontinence, a Mitrofanoff stoma is necessary to empty the bladder.
==== Pediatric Surgical Care ====
Mitrofanoff Surgery: A surgery in which a conduit, such as the small intestine or appendix, is used to divert urine from a high pressure bladder to the skin to create a stoma, where the bladder can be catheterized via the stoma. This surgery is indicated in spina bifida, urethral strictures, urogenital anomalies, and worsening bladder dysfunction that is refractory to medical treatment. Some providers have begun performing these surgery with a minimally invasive robot.
Mitrofanoff using the appendix: The appendix is mobilized from the cecum, while still being connected to its blood source (mesentery). A catheter is passed through the appendix to ensure it is patent. The appendix is then connected to the bladder on one side and to the skin of the abdomen on the other side, creating a stoma.
Yang-Monti Mitrofanoff: A 2-3 cm segment of the small intestine (ileum) is used. The ileum is then mobilized to the bladder and connected to the bladder on one side and to the skin of the abdomen on the other side, creating a stoma using the intestine.
Augmentation Cytoplasty: A class of surgery in which a segment of intestine is used to increase the capacity of the bladder. This surgery is indicated in patients who have low capacity bladders, poorly compliant bladders, and overactive bladder that is refractory to medical treatment.
Ileocystoplasty (Most common): A segment of small intestine (ileum) is isolated and disconnected from the rest of the bowel. The rest of the bowel is reconnected. The removed segment is opened up and is attached to the bladder to increase bladder capacity.
Stomach, cecum, and sigmoid colon have been used for augmentation, however it is much less commonly used.
Detrusorectomy: part of the detrusor muscle of the bladder is stripped away from the bladder to increase capacity.
Sling: A class of surgery that is often done for patients who have paralyzed pelvic floors and urinary incontinence
Sling suspension in boys: A plane is created between the bladder neck/prostate and rectum to allow a sling to be passed through in order to assist with continence.
Sling suspension in girls: A plane is created between the bladder neck and anterior vaginal wall to allow a sling to be passed in order to assist with continence.
== Epidemiology ==
The overall prevalence of neurogenic bladder is limited due to the broad range of conditions that can lead to urinary dysfunction. Neurogenic bladder is common with spinal cord injury and multiple sclerosis. Rates of some type of urinary dysfunction surpass 80% one year after spinal cord injury. Among patients with multiple sclerosis, 20–25% will develop neurogenic bladder although the type and severity bladder dysfunction is variable.
=== Incidence ===
In the United States, 40-90% of patients with multiple sclerosis, 37-72% of patients with Parkinsonism, and 15% of patients with stroke have neurogenic bladder. Dysfunction of the bladder is also frequently seen in patients with Spina Bifida, which affects 1 in 2700 births in the United States. It has been documented that about 61% of adult patients with Spina Bifida have some form of urinary incontinence. Around 70-80% of US patients with spinal cord injury have degrees of bladder dysfunction.
Worldwide annual spinal cord injuries result in neurogenic bladder dysfunction occurrences between 12 - 65+ cases/million population.
== Society and culture ==
=== Burden ===
The burden of neurogenic bladder dysfunction on individuals and health care systems is substantial, but the actual costs of care are less understood. A recent systematic review of the literature assessed the global costs associated with the current state of care for neurogenic bladder and found that the annual costs of routine care can range from $2,039.69 to $12,219.07, with lifetime costs reaching up to $112,774 when complications are considered. Catheters and absorbent aids are among the costliest categories of expenditure during routine care. More invasive and reconstructive treatments were found to be even more costly, with costs ranging from $18,057 to $55,873.
== See also ==
Bladder sphincter dyssynergia
Multiple sclerosis
Pseudodyssynergia
Spinal cord injury
Urinary retention
Neurogenic bowel dysfunction
== References ==
== External links == | Wikipedia/Neurogenic_bladder_dysfunction |
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food safety, tobacco products, caffeine products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED), cosmetics, animal foods & feed and veterinary products.
The FDA's primary focus is enforcement of the Federal Food, Drug, and Cosmetic Act (FD&C). However, the agency also enforces other laws, notably Section 361 of the Public Health Service Act as well as associated regulations. Much of this regulatory-enforcement work is not directly related to food or drugs but involves other factors like regulating lasers, cellular phones, and condoms. In addition, the FDA takes control of diseases in the contexts varying from household pets to human sperm donated for use in assisted reproduction.
The FDA is led by the commissioner of food and drugs, appointed by the president with the advice and consent of the Senate. The commissioner reports to the secretary of health and human services. Sara Brenner is the current acting commissioner as of January 24, 2025, following the resignation of Commissioner Robert Califf on January 20, 2025.
The FDA's headquarters is located in the White Oak area of Silver Spring, Maryland. The agency has 223 field offices and 13 laboratories located across the 50 states, the United States Virgin Islands, and Puerto Rico. In 2008, the FDA began to post employees to foreign countries, including China, India, Costa Rica, Chile, Belgium, and the United Kingdom.
== Organizational structure ==
== Location ==
=== Headquarters ===
FDA headquarters facilities are currently located in Montgomery County and Prince George's County, Maryland.
=== White Oak Federal Research Center ===
Since 1990, the FDA has had employees and facilities on 130 acres (53 hectares) of the White Oak Federal Research Center in the White Oak area of Silver Spring, Maryland. In 2001, the General Services Administration (GSA) began new construction on the campus to consolidate the FDA's 25 existing operations in the Washington metropolitan area, its headquarters in Rockville, and several fragmented office buildings. The first building, the Life Sciences Laboratory, was dedicated and opened with 104 employees in December 2003. As of December 2018, the FDA campus has a population of 10,987 employees housed in approximately 3,800,000 square feet (350,000 square metres) of space, divided into ten offices and four laboratory buildings. The campus houses the Office of the Commissioner (OC), the Office of Regulatory Affairs (ORA), the Center for Drug Evaluation and Research (CDER), the Center for Devices and Radiological Health (CDRH), the Center for Biologics Evaluation and Research (CBER) and offices for the Center for Veterinary Medicine (CVM).
With the passing of the FDA Reauthorization Act of 2017, the FDA projects a 64% increase in employees to 18,000 over the next 15 years and wants to add approximately 1,600,000 square feet (150,000 square metres) of office and special use space to their existing facilities. The National Capital Planning Commission approved a new master plan for this expansion in December 2018, and construction is expected to be completed by 2035, dependent on GSA appropriations.
=== Field locations ===
==== Office of Regulatory Affairs ====
The Office of Regulatory Affairs is considered the agency's "eyes and ears", conducting the vast majority of the FDA's work in the field. Its employees, known as Consumer Safety Officers, or more commonly known simply as investigators, inspect production, warehousing facilities, investigate complaints, illnesses, or outbreaks, and review documentation in the case of medical devices, drugs, biological products, and other items where it may be difficult to conduct a physical examination or take a physical sample of the product. The Office of Regulatory Affairs is divided into five regions, which are further divided into 20 districts. The districts are based roughly on the geographic divisions of the Federal court system. Each district comprises a main district office and a number of Resident Posts, which are FDA remote offices that serve a particular geographic area. ORA also includes the Agency's network of regulatory laboratories, which analyze any physical samples taken. Though samples are usually food-related, some laboratories are equipped to analyze drugs, cosmetics, and radiation-emitting devices.
==== Office of Criminal Investigations ====
The Office of Criminal Investigations was established in 1991 to investigate criminal cases. To do so, OCI employs approximately 200 Special Agents nationwide who, unlike ORA Investigators, are armed, have badges, and do not focus on technical aspects of the regulated industries. Rather, OCI agents pursue and develop cases when individuals and companies commit criminal actions, such as fraudulent claims or knowingly and willfully shipping known adulterated goods in interstate commerce. In many cases, OCI pursues cases involving violations of Title 18 of the United States Code (e.g., conspiracy, false statements, wire fraud, mail fraud), in addition to prohibited acts as defined in Chapter III of the FD&C Act. OCI Special Agents often come from other criminal investigations backgrounds, and frequently work closely with the Federal Bureau of Investigation, Assistant Attorney General, and even Interpol. OCI receives cases from a variety of sources—including ORA, local agencies, and the FBI, and works with ORA Investigators to help develop the technical and science-based aspects of a case.
==== Other locations ====
The FDA has a number of field offices across the United States, in addition to international locations in China, India, Europe, the Middle East, and Latin America.
== Scope and funding ==
As of 2021, the FDA had responsibility for overseeing $2.7 trillion in food, medical, and tobacco products. Some 54% of its budget derives from the federal government, and 46% is covered by industry user fees for FDA services. For example, pharmaceutical firms pay fees to expedite drug reviews.
According to Forbes, pharmaceutical firms provide 75% of the FDA's drug review budget.
== Regulatory programs ==
=== Emergency approvals (EUA) ===
Emergency Use Authorization (EUA) is a mechanism that was created to facilitate the availability and use of medical countermeasures, including vaccines and personal protective equipment, during public health emergencies such as the Zika virus epidemic, the Ebola virus epidemic and the COVID-19 pandemic.
=== Regulations ===
The programs for safety regulation vary widely by the type of product, its potential risks, and the regulatory powers granted to the agency. For example, the FDA regulates almost every facet of prescription drugs, including testing, manufacturing, labeling, advertising, marketing, efficacy, and safety—yet FDA regulation of cosmetics focuses primarily on labeling and safety. The FDA regulates most products with a set of published standards enforced by a modest number of facility inspections. Inspection observations are documented on Form 483.
In June 2018, the FDA released a statement regarding new guidelines to help food and drug manufacturers "implement protections against potential attacks on the U.S. food supply". One of the guidelines includes the Intentional Adulteration (IA) rule, which requires strategies and procedures by the food industry to reduce the risk of compromise in facilities and processes that are significantly vulnerable.
The FDA also uses tactics of regulatory shaming, mainly through online publication of non-compliance, warning letters, and "shaming lists." Regulation by shaming harnesses firms' sensitivity to reputational damage. For example, in 2018, the agency published an online "black list", in which it named dozens of branded drug companies that are supposedly using unlawful or unethical means to attempt to impede competition from generic drug companies.
The FDA frequently works with other federal agencies, including the Department of Agriculture, the Drug Enforcement Administration, Customs and Border Protection, and the Consumer Product Safety Commission. They also often work with local and state government agencies in performing regulatory inspections and enforcement actions.
=== Food and dietary supplements ===
The regulation of food and dietary supplements by the Food and Drug Administration is governed by various statutes enacted by the United States Congress and interpreted by the FDA. Pursuant to the Federal Food, Drug, and Cosmetic Act and accompanying legislation, the FDA has authority to oversee the quality of substances sold as food in the United States, and to monitor claims made in the labeling of both the composition and the health benefits of foods.
The FDA subdivides substances that it regulates as food into various categories—including foods, food additives, added substances (human-made substances that are not intentionally introduced into food, but nevertheless end up in it), and dietary supplements. Dietary supplements or dietary ingredients include vitamins, minerals, herbs, amino acids, and enzymes. Specific standards the FDA exercises differ from one category to the next. Furthermore, legislation had granted the FDA a variety of means to address violations of standards for a given substance category.
Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), the FDA is responsible for ensuring that manufacturers and distributors of dietary supplements and dietary ingredients meet the current requirements. These manufacturers and distributors are not allowed to advertise their products in an adulterated way, and they are responsible for evaluating the safety and labeling of their product.
The FDA has a "Dietary Supplement Ingredient Advisory List" that includes ingredients that sometimes appear on dietary supplements but need further evaluation. An ingredient is added to this list when it is excluded from use in a dietary supplement, does not appear to be an approved food additive or recognized as safe, and/or is subjected to the requirement for pre-market notification without having a satisfied requirement.
==== "FDA-Approved" vs. "FDA-Accepted in Food Processing" ====
The FDA does not approve applied coatings used in the food processing industry. There is no review process to approve the composition of nonstick coatings; nor does the FDA inspect or test these materials. Through their governing of processes, however, the FDA does have a set of regulations that cover the formulation, manufacturing, and use of nonstick coatings. Hence, materials like Polytetrafluoroethylene (Teflon) are not and cannot be considered as FDA Approved, but rather, they are a "FDA Compliant" or "FDA Acceptable".
=== Medical countermeasures (MCMs) ===
Medical countermeasures (MCMs) are products such as biologics and pharmaceutical drugs that can protect from or treat the health effects of a chemical, biological, radiological, or nuclear (CBRN) attack. MCMs can also be used for prevention and diagnosis of symptoms associated with CBRN attacks or threats. The FDA runs a program called the "FDA Medical Countermeasures Initiative" (MCMi), with programs funded by the federal government. It helps support "partner" agencies and organisations prepare for public health emergencies that could require MCMs.
=== Medications ===
The Center for Drug Evaluation and Research uses different requirements for the three main drug product types: new drugs, generic drugs, and over-the-counter drugs. A drug is considered "new" if it is made by a different manufacturer, uses different excipients or inactive ingredients, is used for a different purpose, or undergoes any substantial change. The most rigorous requirements apply to new molecular entities: drugs that are not based on existing medications.
==== New medications ====
New drugs receive extensive scrutiny before FDA approval in a process called a new drug application (NDA). Under the Presidency of Donald Trump, the agency has worked to make the drug-approval process go faster.: 10 Critics, however, argue that FDA standards are not sufficiently rigorous to prevent unsafe or ineffective drugs from getting approval. New drugs are available only by prescription by default. A change to over-the-counter (OTC) status is a separate process, and the drug must be approved through an NDA first. A drug that is approved is said to be "safe and effective when used as directed". Drugs being produced by a new manufacturer can be approved through one of two faster processes: the Abbreviated New Drug Application (ANDA) or the 505(b)(2) regulatory pathway for complex generic or biosimilar medications.
Very rare, limited exceptions to this multi-step process involving animal testing and controlled clinical trials can be granted out of compassionate use protocols. This was the case during the 2015 Ebola epidemic with the use, by prescription and authorization, of ZMapp and other experimental treatments, and for new drugs that can be used to treat debilitating and/or very rare conditions for which no existing remedies or drugs are satisfactory, or where there has not been an advance in a long period of time. The studies are progressively longer, gradually adding more individuals as they progress from stage I to stage III, normally over a period of years, and normally involve drug companies, the government and its laboratories, and often medical schools and hospitals and clinics. However, any exceptions to the aforementioned process are subject to strict review and scrutiny and conditions, and are only given if a substantial amount of research and at least some preliminary human testing has shown that they are believed to be somewhat safe and possibly effective. (See FDA Special Protocol Assessment about Phase III trials.)
===== Advertising and promotion =====
The FDA's Office of Prescription Drug Promotion (OPDP) has responsibilities that revolve around the review and regulation of prescription drug advertising and promotion. This is achieved through surveillance activities and the issuance of enforcement letters to pharmaceutical manufacturers. Advertising and promotion for over-the-counter drugs is regulated by the Federal Trade Commission. The FDA also implements regulatory oversight through engagement with third-party enforcer-firms. It expects pharmaceutical companies to ensure that third-party suppliers and labs comply with the agency's health and safety guidelines .: 4
The drug advertising regulation contains two broad requirements: (1) a company may advertise or promote a drug only for the specific indication or medical use for which it was approved by FDA. Also, an advertisement must contain a "fair balance" between the benefits and the risks (side effects) of a drug. The regulation of drug advertising in the U.S. is divided between the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC), based on whether the drug in question is a prescription drug or an over-the-counter (OTC) drug. The FDA oversees the advertising of prescription drugs, while the FTC regulates the advertising of OTC drugs.
The term off-label refers to the practice of prescribing a drug for a different purpose than what the FDA approved.
Due to this approval requirement, manufacturers were prohibited from advertising COVID-19 vaccines during the period in which they had only been approved under Emergency Use Authorization.
===== Post-market safety surveillance =====
After NDA approval, the sponsor must then review and report to the FDA every single patient adverse drug experience it learns of. They must report unexpected serious and fatal adverse drug events within 15 days, and other events on a quarterly basis. The FDA also receives directly adverse drug event reports through its MedWatch program. These reports are called "spontaneous reports" because reporting by consumers and health professionals is voluntary.
While this remains the primary tool of post-market safety surveillance, FDA requirements for post-marketing risk management are increasing. As a condition of approval, a sponsor may be required to conduct additional clinical trials, called Phase IV trials. In some cases, the FDA requires risk management plans called Risk Evaluation and Mitigation Strategies (REMS) for some drugs that require actions to be taken to ensure that the drug is used safely. For example, thalidomide can cause birth defects, but has uses that outweigh the risks if men and women taking the drugs do not conceive a child; a REMS program for thalidomide mandates an auditable process to ensure that people taking the drug take action to avoid pregnancy; many opioid drugs have REMS programs to avoid addiction and diversion of drugs. The drug isotretinoin has a REMS program called iPLEDGE.
==== Generic drugs ====
Generic drugs are chemical and therapeutic equivalents of name-brand drugs, normally whose patents have expired. Approved generic drugs should have the same dosage, safety, effectiveness, strength, stability, and quality, as well as route of administration. In general, they are less expensive than their name brand counterparts, are manufactured and marketed by rival companies and, in the 1990s, accounted for about a third of all prescriptions written in the United States. For a pharmaceutical company to gain approval to produce a generic drug, the FDA requires scientific evidence that the generic drug is interchangeable with or therapeutically equivalent to the originally approved drug. This is called an Abbreviated New Drug Application (ANDA). 80% of prescription drugs sold in the United States are generic brands.
===== Generic drug scandal =====
In 1989, a major scandal erupted involving the procedures used by the FDA to approve generic drugs for sale to the public. Charges of corruption in generic drug approval first emerged in 1988 during the course of an extensive congressional investigation into the FDA. The oversight subcommittee of the United States House Energy and Commerce Committee resulted from a complaint brought against the FDA by Mylan Laboratories Inc. of Pittsburgh. When its application to manufacture generics were subjected to repeated delays by the FDA, Mylan, convinced that it was being discriminated against, soon began its own private investigation of the agency in 1987. Mylan eventually filed suit against two former FDA employees and four drug-manufacturing companies, charging that corruption within the federal agency resulted in racketeering and in violations of antitrust law. "The order in which new generic drugs were approved was set by the FDA employees even before drug manufacturers submitted applications" and, according to Mylan, this illegal procedure was followed to give preferential treatment to certain companies. During the summer of 1989, three FDA officials (Charles Y. Chang, David J. Brancato, Walter Kletch) pleaded guilty to criminal charges of accepting bribes from generic drugs makers, and two companies (Par Pharmaceutical and its subsidiary Quad Pharmaceuticals) pleaded guilty to giving bribes.
Furthermore, it was discovered that several manufacturers had falsified data submitted in seeking FDA authorization to market certain generic drugs. Vitarine Pharmaceuticals of New York, which sought approval of a generic version of the drug Dyazide, a medication for high blood pressure, submitted Dyazide, rather than its generic version, for the FDA tests. In April 1989, the FDA investigated 11 manufacturers for irregularities; and later brought that number up to 13. Dozens of drugs were eventually suspended or recalled by manufacturers. In the early 1990s, the U.S. Securities and Exchange Commission filed securities fraud charges against the Bolar Pharmaceutical Company, a major generic manufacturer based in Long Island, New York.
==== Over-the-counter drugs ====
Over-the-counter (OTC) are drugs like aspirin that do not require a doctor's prescription. The FDA has a list of approximately 800 such approved ingredients that are combined in various ways to create more than 100,000 OTC drug products. Many OTC drug ingredients had been previously approved prescription drugs now deemed safe enough for use without a medical practitioner's supervision like ibuprofen.
==== Ebola treatment ====
In 2014, the FDA added an Ebola treatment being developed by Canadian pharmaceutical company Tekmira to the Fast Track program, but halted the phase 1 trials in July pending the receipt of more information about how the drug works. This was widely viewed as increasingly important in the face of a major outbreak of the disease in West Africa that began in late March 2014 and ended in June 2016.
==== Coronavirus (COVID-19) testing ====
During the coronavirus pandemic, FDA granted emergency use authorization for personal protective equipment (PPE), in vitro diagnostic equipment, ventilators and other medical devices.
On March 18, 2020, FDA inspectors postponed most foreign facility inspections and all domestic routine surveillance facility inspections. In contrast, the USDA's Food Safety and Inspection Service (FSIS) continued inspections of meatpacking plants, which resulted in 145 FSIS field employees who tested positive for COVID-19, and three who died.
=== Vaccines, blood and tissue products, and biotechnology ===
The Center for Biologics Evaluation and Research is the branch of the FDA responsible for ensuring the safety and efficacy of biological therapeutic agents. These include blood and blood products, vaccines, allergenics, cell and tissue-based products, and gene therapy products. New biologics are required to go through a premarket approval process called a Biologics License Application (BLA), similar to that for drugs.
The original authority for government regulation of biological products was established by the 1902 Biologics Control Act, with additional authority established by the 1944 Public Health Service Act. Along with these Acts, the Federal Food, Drug, and Cosmetic Act applies to all biologic products, as well. Originally, the entity responsible for regulation of biological products resided under the National Institutes of Health; this authority was transferred to the FDA in 1972.
=== Medical and radiation-emitting devices ===
The Center for Devices and Radiological Health (CDRH) is the branch of the FDA responsible for the premarket approval of all medical devices, as well as overseeing the manufacturing, performance and safety of these devices. The definition of a medical device is given in the FD&C Act, and it includes products from the simple toothbrush to complex devices such as implantable neurostimulators. CDRH also oversees the safety performance of non-medical devices that emit certain types of electromagnetic radiation. Examples of CDRH-regulated devices include cellular phones, airport baggage screening equipment, television receivers, microwave ovens, tanning booths, and laser products.
CDRH regulatory powers include the authority to require certain technical reports from the manufacturers or importers of regulated products, to require that radiation-emitting products meet mandatory safety performance standards, to declare regulated products defective, and to order the recall of defective or noncompliant products. CDRH also conducts limited amounts of direct product testing.
==== "FDA-Cleared" vs "FDA-Approved" ====
Clearance requests are required for medical devices that prove they are "substantially equivalent" to the predicate devices already on the market. Approved requests are for items that are new or substantially different and need to demonstrate "safety and efficacy", for example they may be inspected for safety in case of new toxic hazards. Both aspects need to be proved or provided by the submitter to ensure proper procedures are followed.
=== Cosmetics ===
Cosmetics are regulated by the Center for Food Safety and Applied Nutrition, the same branch of the FDA that regulates food. Cosmetic products are not, in general, subject to premarket approval by the FDA unless they make "structure or function claims" that make them into drugs (see Cosmeceutical). However, all color additives must be specifically FDA approved before manufacturers can include them in cosmetic products sold in the U.S. The FDA regulates cosmetics labeling, and cosmetics that have not been safety tested must bear a warning to that effect.
According to the industry advocacy group, the American Council on Science and Health, though the cosmetic industry is primarily responsible for its own product safety, the FDA can intervene when necessary to protect the public. In general, though, cosmetics do not require pre-market approval or testing. The ACSH says that companies must place a warning note on their products if they have not been tested, and that experts in cosmetic ingredient review also play a role in monitoring safety through influence on ingredients, but they lack legal authority. According to the ACSH, it has reviewed about 1,200 ingredients and has suggested that several hundred be restricted—but there is no standard or systemic method for reviewing chemicals for safety, or a clear definition of what 'safety' even means so that all chemicals get tested on the same basis.
However, on December 29, 2022, President Biden signed the '2023 Consolidated Budget Act', which includes the 'Cosmetics Regulatory Modernization Act of 2022 (MoCRA)', which is a stricter regulation that is different from the previous regulations. MoCRA requires compliance with matters such as serious adverse event reporting, safety substantiation, additional labeling, record keeping, and Good Manufacturing Practices (GMP). MoCRA also calls on the FDA to grant Mandatory Recall Authority and establish regulations for GMP rules, flavor allergen labeling rules, and testing methods for cosmetics containing talc.
=== Veterinary products ===
The Center for Veterinary Medicine (CVM) is a center of the FDA that regulates food additives and drugs that are given to animals. CVM regulates animal drugs, animal food including pet animal, and animal medical devices. The FDA's requirements to prevent the spread of bovine spongiform encephalopathy are also administered by CVM through inspections of feed manufacturers. CVM does not regulate vaccines for animals; these are handled by the United States Department of Agriculture.
=== Tobacco products ===
The FDA regulates tobacco products with authority established by the 2009 Family Smoking Prevention and Tobacco Control Act. This Act requires color warnings on cigarette packages and printed advertising, and text warnings from the U.S. Surgeon General.
The nine new graphic warning labels were announced by the FDA in June 2011 and were scheduled to be required to appear on packaging by September 2012. The implementation date is uncertain, due to ongoing proceedings in the case of R.J. Reynolds Tobacco Co. v. U.S. Food and Drug Administration. R.J. Reynolds, Lorillard, Commonwealth Brands, Liggett Group and Santa Fe Natural Tobacco Company have filed suit in Washington, D.C. federal court claiming that the graphic labels are an unconstitutional way of forcing tobacco companies to engage in anti-smoking advocacy on the government's behalf.
A First Amendment lawyer, Floyd Abrams, is representing the tobacco companies in the case, contending requiring graphic warning labels on a lawful product cannot withstand constitutional scrutiny. The Association of National Advertisers and the American Advertising Federation have also filed a brief in the suit, arguing that the labels infringe on commercial free speech and could lead to further government intrusion if left unchallenged. In November 2011, Federal judge Richard Leon of the U.S. District Court for the District of Columbia temporarily halted the new labels, likely delaying the requirement that tobacco companies display the labels. The U.S. Supreme Court ultimately could decide the matter.
In July 2017, the FDA announced a plan that would reduce the current levels of nicotine permitted in tobacco cigarettes. The proposed regulation, identified as RIN 0910-AI76, titled "Tobacco Product Standard for Nicotine Yield of Cigarettes and Certain Other Combusted Tobacco Products," seeks to reduce the nicotine content in cigarettes to approximately 0.7 milligrams per gram of tobacco.
=== Regulation of living organisms ===
With acceptance of premarket notification 510(k) k033391 in January 2004, the FDA granted Ronald Sherman permission to produce and market medical maggots for use in humans or other animals as a prescription medical device. Medical maggots represent the first living organism allowed by the Food and Drug Administration for production and marketing as a prescription medical device.
In June 2004, the FDA cleared Hirudo medicinalis (medicinal leeches) as the second living organism legal to use as a medical device.
The FDA also requires that milk be pasteurized to remove bacteria.
=== International Cooperation ===
In February 2011, President Barack Obama and Canadian Prime Minister Stephen Harper issued a "Declaration on a Shared Vision for Perimeter Security and Economic Competitiveness" and announced the creation of the Canada-United States Regulatory Cooperation Council (RCC) "to increase regulatory transparency and coordination between the two countries."
Under the RCC mandate, the FDA and Health Canada undertook a "first of its kind" initiative by selecting "as its first area of alignment common cold indications for certain over-the-counter antihistamine ingredients (GC 2013-01-10)."
A more recent example of the FDA's international work is their 2018 cooperation with regulatory and law-enforcement agencies worldwide through Interpol as part of Operation Pangea XI. The FDA targeted 465 websites that illegally sold potentially dangerous, unapproved versions of opioid, oncology, and antiviral prescription drugs to U.S. consumers. The agency focused on transaction laundering schemes in order to uncover the complex online drug network.
== Science and research programs ==
The FDA carries out research and development activities to develop technology and standards that support its regulatory role, with the objective of resolving scientific and technical challenges before they become impediments. The FDA's research efforts include the areas of biologics, medical devices, drugs, women's health, toxicology, food safety and applied nutrition, and veterinary medicine.
== Data management ==
The FDA has collected a large amount of data through the decades. The OpenFDA project was created to enable easy access of the data for the public and was officially launched in June 2014.
== History ==
Up until the 20th century, there were few federal laws regulating the contents and sale of domestically produced food and pharmaceuticals, with one exception being the Vaccine Act of 1813. The history of the FDA can be traced to the latter part of the 19th century and the Division of Chemistry of the U.S. Department of Agriculture, which itself derived from the Copyright and Patent Clause. Under Harvey Washington Wiley, appointed chief chemist in 1883, the Division began conducting research into the adulteration and misbranding of food and drugs on the American market. Wiley's advocacy came at a time when the public had become aroused to hazards in the marketplace by muckraking journalists like Upton Sinclair, and became part of a general trend for increased federal regulations in matters pertinent to public safety during the Progressive Era. The Biologics Control Act of 1902 was put in place after a diphtheria antitoxin derived from tetanus-contaminated serum caused the deaths of thirteen children in St. Louis, Missouri. The serum was originally collected from a horse named Jim who had contracted tetanus.
In June 1906, President Theodore Roosevelt signed into law the Pure Food and Drug Act of 1906, also known as the "Wiley Act" after its chief advocate. The Act prohibited, under penalty of seizure of goods, the interstate transport of food that had been "adulterated". The Act applied similar penalties to the interstate marketing of "adulterated" drugs, in which the "standard of strength, quality, or purity" of the active ingredient was not either stated clearly on the label or listed in the United States Pharmacopeia or the National Formulary.
The responsibility for examining food and drugs for such "adulteration" or "misbranding" was given to Wiley's USDA Bureau of Chemistry. Wiley used these new regulatory powers to pursue an aggressive campaign against the manufacturers of foods with chemical additives, but the Chemistry Bureau's authority was soon checked by judicial decisions, which narrowly defined the bureau's powers and set high standards for proof of fraudulent intent. In 1927, the Bureau of Chemistry's regulatory powers were reorganized under a new USDA body, the Food, Drug, and Insecticide Administration. This name was shortened to the Food and Drug Administration (FDA) three years later.
By the 1930s, muckraking journalists, consumer protection organizations, and federal regulators began mounting a campaign for stronger regulatory authority by publicizing a list of injurious products that had been ruled permissible under the 1906 law, including radioactive beverages, mascara that could cause blindness, and worthless "cures" for diabetes and tuberculosis. The resulting proposed law did not get through the Congress of the United States for five years, but was rapidly enacted into law following the public outcry over the 1937 Elixir Sulfanilamide tragedy, in which over 100 people died after using a drug formulated with a toxic, untested solvent.
President Franklin Delano Roosevelt signed the Federal Food, Drug, and Cosmetic Act into law on June 24, 1938. The new law significantly increased federal regulatory authority over drugs by mandating a pre-market review of the safety of all new drugs, as well as banning false therapeutic claims in drug labeling without requiring that the FDA prove fraudulent intent. The law also authorized the FDA to issue minimum food standards of identity for all mass-produced foods to reduce food fraud.
Soon after passage of the 1938 Act, the FDA began to designate certain drugs as safe for use only under the supervision of a medical professional, and the category of "prescription-only" drugs was securely codified into law by the Durham-Humphrey Amendment in 1951. These developments confirmed extensive powers for the FDA to enforce post-marketing recalls of ineffective drugs.
Outside of the US, the drug thalidomide was marketed for the relief of general nausea and morning sickness, but caused birth defects and even the death of thousands of babies when taken during pregnancy. American mothers were largely unaffected as Frances Oldham Kelsey of the FDA refused to authorize the medication for market. In 1962, the Kefauver-Harris Amendment to the FD&C Act was passed, which represented a "revolution" in FDA regulatory authority. The most important change was the requirement that all new drug applications demonstrate "substantial evidence" of the drug's efficacy for a marketed indication, in addition to the existing requirement for pre-marketing demonstration of safety. This marked the start of the FDA approval process in its modern form.
These reforms had the effect of increasing the time, and the difficulty, required to bring a drug to market. One of the most important statutes in establishing the modern American pharmaceutical market was the 1984 Drug Price Competition and Patent Term Restoration Act, more commonly known as the "Hatch-Waxman Act" after its chief sponsors. The act extended the patent exclusivity terms of new drugs, and tied those extensions, in part, to the length of the FDA approval process for each individual drug. For generic manufacturers, the Act created a new approval mechanism, the Abbreviated New Drug Application (ANDA), in which the generic drug manufacturer need only demonstrate that their generic formulation has the same active ingredient, route of administration, dosage form, strength, and pharmacokinetic properties ("bioequivalence") as the corresponding brand-name drug. This Act has been credited with, in essence, creating the modern generic drug industry.
Concerns about the length of the drug approval process were brought to the fore early in the AIDS epidemic. In the mid- and late 1980s, ACT-UP and other HIV activist organizations accused the FDA of unnecessarily delaying the approval of medications to fight HIV and opportunistic infections. Partly in response to these criticisms, the FDA issued new rules to expedite approval of drugs for life-threatening diseases, and expanded pre-approval access to drugs for patients with limited treatment options. All of the initial drugs approved for the treatment of HIV/AIDS were approved through these accelerated approval mechanisms. Frank Young, then commissioner of the FDA, was behind the Action Plan Phase II, established in August 1987 for quicker approval of AIDS medication.
In two instances, state governments have sought to legalize drugs that the FDA has not approved. Under the theory that federal law, passed pursuant to Constitutional authority, overrules conflicting state laws, federal authorities still claim the authority to seize, arrest, and prosecute for possession and sales of these substances, even in states where they are legal under state law. The first wave was the legalization by 27 states of laetrile in the late 1970s. This drug was used as a treatment for cancer, but scientific studies both before and after this legislative trend found it ineffective. The second wave concerned medical marijuana in the 1990s and 2000s. Though Virginia passed legislation allowing doctors to recommend cannabis for glaucoma or the side effects of chemotherapy, a more widespread trend began in California with the Compassionate Use Act of 1996.
When the FDA requested Endo Pharmaceuticals on June 8, 2017, to remove oxymorphone hydrochloride from the market, it was the first request in FDA history to recall an effective drug over its potential for misuse.
=== Trump administration ===
In February 2025, FDA food division head Jim Jones quit in protest of the "indiscriminate" layoffs of 89 staff members by the Donald Trump administration.
In May 2025, the FDA announced a ban on COVID-19 vaccine booster shots for all patients under the age of 65 or those with severe pre-existing conditions, saying that the data showing evidence of benefit for those under the age of 65 as “insufficient” and “at a high risk of bias”. Those under 65 who seek the vaccines anyway may be given a placebo to test the effects.
== 21st-century reforms ==
=== Critical Path Initiative ===
The Critical Path Initiative is the FDA's effort to stimulate and facilitate a national effort to modernize the sciences through which FDA-regulated products are developed, evaluated, and manufactured. The Initiative was launched in March 2004, with the release of a report entitled Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products.
=== Patients' rights to access unapproved drugs ===
The Compassionate Investigational New Drug program was created after Randall v. U.S. ruled in favor of Robert C. Randall in 1978, creating a program for medical marijuana.
A 2006 court case, Abigail Alliance v. von Eschenbach, would have forced radical changes in FDA regulation of unapproved drugs. The Abigail Alliance argued that the FDA must license drugs for use by terminally ill patients with "desperate diagnoses", after they have completed Phase I testing. The case won an initial appeal in May 2006, but that decision was reversed by a March 2007 rehearing. The US Supreme Court declined to hear the case, and the final decision denied the existence of a right to unapproved medications.
Critics of the FDA's regulatory power argue that the FDA takes too long to approve drugs that might ease pain and human suffering faster if brought to market sooner. The AIDS crisis created some political efforts to streamline the approval process. However, these limited reforms were targeted for AIDS drugs, not for the broader market. This has led to the call for more robust and enduring reforms that would allow patients, under the care of their doctors, access to drugs that have passed the first round of clinical trials.
=== Post-marketing drug safety monitoring ===
The widely publicized recall of Vioxx, a non-steroidal anti-inflammatory drug (NSAID) now estimated to have contributed to fatal heart attacks in thousands of Americans, played a strong role in driving a new wave of safety reforms at both the FDA rulemaking and statutory levels. The FDA approved Vioxx in 1999, and initially hoped it would be safer than previous NSAIDs due to its reduced risk of intestinal tract bleeding. However, a number of pre and post-marketing studies suggested that Vioxx might increase the risk of myocardial infarction, and results from the APPROVe trial in 2004 conclusively demonstrated this.
Faced with numerous lawsuits, the manufacturer voluntarily withdrew it from the market. The example of Vioxx has been prominent in an ongoing debate over whether new drugs should be evaluated on the basis of their absolute safety, or their safety relative to existing treatments for a given condition. In the wake of the Vioxx recall, there were widespread calls by major newspapers, medical journals, consumer advocacy organizations, lawmakers, and FDA officials for reforms in the FDA's procedures for pre- and post-market drug safety regulation.
In 2006, a Congressional committee was appointed by the Institute of Medicine to review pharmaceutical safety regulation in the U.S. and to issue recommendations for improvements. The committee was composed of 16 experts, including leaders in clinical medicine medical research, economics, biostatistics, law, public policy, public health, and the allied health professions, as well as current and former executives from the pharmaceutical, hospital, and health insurance industries. The authors found major deficiencies in the current FDA system for ensuring the safety of drugs on the American market. Overall, the authors called for an increase in the regulatory powers, funding, and independence of the FDA. Some of the committee's recommendations were incorporated into drafts of the PDUFA IV amendment, which was signed into law as the Food and Drug Administration Amendments Act of 2007.
As of 2011, Risk Minimization Action Plans (RiskMAPS) have been created to ensure risks of a drug never outweigh the benefits of that drug within the post-marketing period. This program requires that manufacturers design and implement periodic assessments of their programs' effectiveness. The Risk Minimization Action Plans are set in place depending on the overall level of risk a prescription drug is likely to pose to the public.
=== Pediatric drug testing ===
Prior to the 1990s, only 20% of all drugs prescribed for children in the United States were tested for safety or efficacy in a pediatric population. This became a major concern of pediatricians as evidence accumulated that the physiological response of children to many drugs differed significantly from those drugs' effects on adults. Children react differently to the drugs because of many reasons, including size, weight, etc. There were several reasons that few medical trials were done with children. For many drugs, children represented such a small proportion of the potential market, that drug manufacturers did not see such testing as cost-effective.
Also, the belief that children are ethically restricted in their ability to give informed consent brought increased governmental and institutional hurdles to approval of these clinical trials, and greater concerns about legal liability. Thus, for decades, most medicines prescribed to children in the U.S. were done so in a non-FDA-approved, "off-label" manner, with dosages "extrapolated" from adult data through body weight and body-surface-area calculations.
In an initial FDA attempt to address this issue they produced the 1994 FDA Final Rule on Pediatric Labeling and Extrapolation, which allowed manufacturers to add pediatric labeling information, but required drugs that had not been tested for pediatric safety and efficacy to bear a disclaimer to that effect. However, this rule failed to motivate many drug companies to conduct additional pediatric drug trials. In 1997, the FDA proposed a rule to require pediatric drug trials from the sponsors of New Drug Applications. However, this new rule was successfully preempted in federal court as exceeding the FDA's statutory authority.
While this debate was unfolding, Congress used the Food and Drug Administration Modernization Act of 1997 to pass incentives that gave pharmaceutical manufacturers a six-month patent term extension on new drugs submitted with pediatric trial data. The Best Pharmaceuticals for Children Act of 2007 reauthorized these provisions and allowed the FDA to request NIH-sponsored testing for pediatric drug testing, although these requests are subject to NIH funding constraints. In the Pediatric Research Equity Act of 2003, Congress codified the FDA's authority to mandate manufacturer-sponsored pediatric drug trials for certain drugs as a "last resort" if incentives and publicly funded mechanisms proved inadequate.
=== Priority review voucher (PRV) ===
The priority review voucher is a provision of the Food and Drug Administration Amendments Act of 2007, which awards a transferable "priority review voucher" to any company that obtains approval for a treatment for a neglected tropical diseases. The system was first proposed by Duke University faculty David Ridley, Henry Grabowski, and Jeffrey Moe in their 2006 Health Affairs paper: "Developing Drugs for Developing Countries". President Obama signed into law the Food and Drug Administration Safety and Innovation Act of 2012, which extended the authorization until 2017.
=== Rules for generic biologics ===
Since the 1990s, many successful new drugs for the treatment of cancer, autoimmune diseases, and other conditions have been protein-based biotechnology drugs, regulated by the Center for Biologics Evaluation and Research. Many of these drugs are extremely expensive; for example, the anti-cancer drug Avastin costs $55,000 for a year of treatment, while the enzyme replacement therapy drug Cerezyme costs $200,000 per year, and must be taken by Gaucher's disease patients for life.
Biotechnology drugs do not have the simple, readily verifiable chemical structures of conventional drugs, and are produced through complex, often proprietary, techniques, such as transgenic mammalian cell cultures. Because of these complexities, the 1984 Hatch-Waxman Act did not include biologics in the Abbreviated New Drug Application (ANDA) process. This precluded the possibility of generic drug competition for biotechnology drugs. In February 2007, identical bills were introduced into the House to create an ANDA process for the approval of generic biologics, but were not passed.
=== Mobile medical applications ===
In 2013, a guidance was issued to regulate mobile medical applications and protect users from their unintended use. This guidance distinguishes the apps subjected to regulation based on the marketing claims of the apps. Incorporation of the guidelines during the development phase of these apps has been proposed for expedited market entry and clearance.
=== Electronic Submissions Gateway (ESG) ===
To standardize, automate and streamline the flow of regulatory data, FDA introduced an Electronic Submissions Gateway (ESG) in 2006. This gateway allows reporting organizations to send regulatory submissions to different centers over the internet, packaged in a center-specific format and enveloped as a GNU-compatible .tar.gz file, through either a FDA-specific WebTrader application or via a more generic B2B communication protocol called AS2 (Applicability Statement 2).
For WebTrader, which is recommended for manual, small-volume submissions, users would typically install a client application on their computers and upload the package through it to FDA server. In AS2, which is recommended for automated or high-volume submissions, users can use any standard AS2 software to transmit the package to FDA by including additional routing details on top of standard AS2, in the form of custom HTTP request headers.
== Criticism ==
The FDA has regulatory oversight over a large array of products that affect the health and life of American citizens. As a result, the FDA's powers and decisions are carefully monitored by several governmental and non-governmental organizations. A $1.8 million 2006 Institute of Medicine report on pharmaceutical regulation in the U.S. found major deficiencies in the current FDA system for ensuring the safety of drugs on the American market. Overall, the authors called for an increase in the regulatory powers, funding, and independence of the FDA.
A 2022 article from Politico raised concerns that food is not a high priority at the FDA. The report explains the FDA has structural and leadership problems in the food division and is often deferential to industry. This might be attributed to lobbying and influence of big food companies in Washington, D.C.
== See also ==
Adverse reaction
Adverse event
Adverse drug reaction
Biosecurity
Biosecurity in the United States
Drug Efficacy Study Implementation
Food and Drug Administration Modernization Act of 1997
FDA Food Safety Modernization Act of 2011
FDA Fast Track Development Program (for drugs)
Food and Drug Administration Amendments Act of 2007 (e.g. drugs)
Food and Drug Administration Safety and Innovation Act of 2012 (GAIN/QIDP etc.)
Inverse benefit law
Investigational Device Exemption (for use in clinical trials)
Kefauver Harris Amendment 1962 – required "proof-of-efficacy" for drugs
International:
Food Administration
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
African Union: African Medicines Agency
Australia: Therapeutic Goods Administration
Brazil: National Health Surveillance Agency
Canada: Marketed Health Products Directorate
Canada: Health Canada
Denmark: Danish Medicines Agency
European Union: European Medicines Agency
Germany: Federal Institute for Drugs and Medical Devices
India: Food Safety and Standards Authority of India
India: Central Drugs Standard Control Organization
Japan: Ministry of Health, Labour and Welfare (MHLW)
Japan: Pharmaceuticals and Medical Devices Agency
Mexico: Federal Commission for the Protection against Sanitary Risk
Philippines: Food and Drug Administration (FDA)
Singapore: Health Sciences Authority
United Kingdom: Medicines and Healthcare products Regulatory Agency
United States: Food and Drug Administration
== Notes ==
== References ==
== Further reading ==
== External links ==
Official website
Food and Drug Administration in the Federal Register
Food and Drug Administration in the Code of Federal Regulations
Strategic Plan (archived)
Works by Food and Drug Administration at Open Library
Online books by United States Food and Drug Administration at The Online Books Page
Food and Drug Administration apportionments on OpenOMB | Wikipedia/U.S._Food_and_Drug_Administration |
The radiotherapy accident in Costa Rica occurred within the Alcyon II radiotherapy unit at San Juan de Dios Hospital in San José, Costa Rica. It was related to a cobalt-60 source that was being used for radiotherapy in 1996. An accidental overexposure of radiotherapy patients treated during August and September 1996 was detected. During the calibration process done after the change of 60Co source on 22 August 1996, a mistake was made in calculating the dose rate, leading to severe overexposure of patients. The error of calibration was detected on 27 September 1996, after which treatments ceased. In the course of the accident, 115 patients received an overdose of radiation and 13 died of radiation-related injuries.
The San Juan de Dios Hospital, located in Costa Rica, was one of the major medical facilities offering radiotherapy services in the country. In the mid-1990s, this facility introduced cobalt-60 therapy machines as a means of treating cancer. Radiotherapy is a critical component in cancer management; however, it requires careful calibration and dosimetry to ensure safety and efficacy in therapeutic procedures.
Prior to the accident in 1996, international concerns were growing over the dangers of radiation therapy errors, especially in poorly equipped facilities where outdated equipment and a lack of regulatory supervision could compromise safety. Costa Rica's health system was in the process of being upgraded at the time, and although radiotherapy was an established treatment modality, the strict application of safety measures and quality control procedures might not have been consistently practiced.
Shortly after the incident, the Ministry of Health of Costa Rica conducted an evaluation which confirmed the overexposure to patients. It was found that during the calculation for the exposure time to patients, the wrong unit of time was used. the unit that the person in charge of dosimetry thought the machine was using was 1/100th of a minute, but the actual unit being used was seconds. This resulted in the dosage received by patients being approximately 60% higher than intended. It was not until July 1997 that an official review was carried out, and by that time, only 73 of the original patients remained alive. Of the 73, only 70 were examined and evaluated, and at the time of evaluation, 4 of the patients were suffering from "catastrophic consequences," while an additional 16 were experiencing major effects of overexposure. There were 26 individuals that were identified to be suffering minor effects but that in the future there was a higher risk of suffering further complications. 22 patients that were examined had little to no identifiable effects and were told they only had a low risk for future effects. 2 of the patients evaluated were underexposed.
In 2001, the radiophysicist whose mistake caused the radiation overdoses was charged with 16 culpable homicides and sentenced to six years in prison.
== See also ==
List of civilian radiation accidents
Goiânia accident
1962 Mexico City radiation accident
Radiotherapy accident in Zaragoza
X-ray
Nuclear safety
Nuclear whistleblowers
== References == | Wikipedia/1996_San_Juan_de_Dios_radiotherapy_accident |
Atrial fibrillation (AF, AFib or A-fib) is an abnormal heart rhythm (arrhythmia) characterized by rapid and irregular beating of the atrial chambers of the heart. It often begins as short periods of abnormal beating, which become longer or continuous over time. It may also start as other forms of arrhythmia such as atrial flutter that then transform into AF.
Episodes can be asymptomatic. Symptomatic episodes may involve heart palpitations, fainting, lightheadedness, loss of consciousness, or shortness of breath. Atrial fibrillation is associated with an increased risk of heart failure, dementia, and stroke. It is a type of supraventricular tachycardia.
Atrial fibrillation frequently results from bursts of tachycardia that originate in muscle bundles extending from the atrium to the pulmonary veins. Pulmonary vein isolation by transcatheter ablation can restore sinus rhythm. The ganglionated plexi (autonomic ganglia of the heart atrium and ventricles) can also be a source of atrial fibrillation, and are sometimes also ablated for that reason. Not only the pulmonary vein, but the left atrial appendage and ligament of Marshall can be a source of atrial fibrillation and are also ablated for that reason. As atrial fibrillation becomes more persistent, the junction between the pulmonary veins and the left atrium becomes less of an initiator and the left atrium becomes an independent source of arrhythmias.
High blood pressure and valvular heart disease are the most common modifiable risk factors for AF. Other heart-related risk factors include heart failure, coronary artery disease, cardiomyopathy, and congenital heart disease. In low- and middle-income countries, valvular heart disease is often attributable to rheumatic fever. Lung-related risk factors include COPD, obesity, and sleep apnea. Cortisol and other stress biomarkers, as well as emotional stress, may play a role in the pathogenesis of atrial fibrillation.
Other risk factors include excess alcohol intake, tobacco smoking, diabetes mellitus, subclinical hypothyroidism, and thyrotoxicosis. However, about half of cases are not associated with any of these aforementioned risks. Healthcare professionals might suspect AF after feeling the pulse and confirm the diagnosis by interpreting an electrocardiogram (ECG). A typical ECG in AF shows irregularly spaced QRS complexes without P waves.
Healthy lifestyle changes, such as weight loss in people with obesity, increased physical activity, and drinking less alcohol, can lower the risk for AF and reduce its burden if it occurs. AF is often treated with medications to slow the heart rate to a near-normal range (known as rate control) or to convert the rhythm to normal sinus rhythm (known as rhythm control). Electrical cardioversion can convert AF to normal heart rhythm and is often necessary for emergency use if the person is unstable. Ablation may prevent recurrence in some people. For those at low risk of stroke, AF does not necessarily require blood-thinning though some healthcare providers may prescribe an anti-clotting medication. Most people with AF are at higher risk of stroke. For those at more than low risk, experts generally recommend an anti-clotting medication. Anti-clotting medications include warfarin and direct oral anticoagulants. While these medications reduce stroke risk, they increase rates of major bleeding.
Atrial fibrillation is the most common serious abnormal heart rhythm and, as of 2020, affects more than 33 million people worldwide. As of 2014, it affected about 2 to 3% of the population of Europe and North America. The incidence and prevalence of AF increases. In the developing world, about 0.6% of males and 0.4% of females are affected. The percentage of people with AF increases with age with 0.1% under 50 years old, 4% between 60 and 70 years old, and 14% over 80 years old being affected. The first known report of an irregular pulse was by Jean-Baptiste de Sénac in 1749. Thomas Lewis was the first doctor to document this by ECG in 1909.
== Signs and symptoms ==
Atrial fibrillation is usually accompanied by symptoms related to a rapid heart rate. Rapid and irregular heart rates may be perceived as the sensation of the heart beating too fast, irregularly, or skipping beats (palpitations) or exercise intolerance.
Other possible symptoms include congestive heart failure symptoms such as fatigue, shortness of breath, or swelling. Loss of consciousness can also occur on atrial fibrillations due to lack of oxygen and blood to the brain. The abnormal heart rhythm (arrhythmia) is sometimes only identified with the onset of a stroke or a transient ischemic attack (TIA). It is not uncommon for a person to first become aware of AF from a routine physical examination or electrocardiogram, as it often does not cause symptoms.
Since most cases of AF are secondary to other medical problems, the presence of chest pain or angina, signs and symptoms of hyperthyroidism (an overactive thyroid gland) such as weight loss and diarrhea, and symptoms suggestive of lung disease can indicate an underlying cause. A history of stroke or TIA, as well as high blood pressure, diabetes, heart failure, or rheumatic fever, may indicate whether someone with AF is at a higher risk of complications.
=== Rapid heart rate ===
Presentation is similar to other forms of rapid heart rate and may be asymptomatic. Palpitations and chest discomfort are common complaints. The rapid uncoordinated heart rate may result in reduced output of blood pumped by the heart (cardiac output), resulting in inadequate blood flow, and therefore oxygen delivery to the rest of the body. Common symptoms of uncontrolled atrial fibrillation may include shortness of breath, shortness of breath when lying flat, dizziness, and sudden onset of shortness of breath during the night. This may progress to swelling of the lower extremities, a manifestation of congestive heart failure. Due to inadequate cardiac output, individuals with AF may also complain of lightheadedness.
AF can cause respiratory distress due to congestion in the lungs. By definition, the heart rate will be greater than 100 beats per minute. Blood pressure may be variable, and often difficult to measure as the beat-by-beat variability causes problems for most digital (oscillometric) non-invasive blood pressure monitors. For this reason, when determining the heart rate in AF, direct cardiac auscultation is recommended. Low blood pressure is most concerning, and a sign that immediate treatment is required. Many of the symptoms associated with uncontrolled atrial fibrillation are a manifestation of congestive heart failure due to the reduced cardiac output. The affected person's respiratory rate often increases in the presence of respiratory distress. Pulse oximetry may confirm the presence of too little oxygen reaching the body's tissues, related to any precipitating factors such as pneumonia. Examination of the jugular veins may reveal elevated pressure (jugular venous distention). Examination of the lungs may reveal crackles, which are suggestive of pulmonary edema. Examination of the heart will reveal a rapid irregular rhythm.
== Causes ==
AF is linked to several forms of cardiovascular disease but may occur in otherwise normal hearts. Cardiovascular factors known to be associated with the development of AF include high blood pressure, coronary artery disease, mitral valve stenosis (e.g., due to rheumatic heart disease or mitral valve prolapse), mitral regurgitation, left atrial enlargement, hypertrophic cardiomyopathy, pericarditis, congenital heart disease, and previous heart surgery. People with congenital heart disease tend to develop atrial fibrillation at a younger age, that is more likely to be of right atrial origin (atypical) than of left origin, and have a greater risk of progressing to permanent atrial fibrillation.
Additionally, lung diseases (such as pneumonia, lung cancer, pulmonary embolism, and sarcoidosis) may play a role in certain people. Sepsis also increases the risk of developing new-onset atrial fibrillation. Disorders of breathing during sleep, such as obstructive sleep apnea (OSA), are also associated with AF. OSA, specifically, was found to be a very strong predictor of atrial fibrillation. Patients with OSA were shown to have an increased incidence of atrial fibrillation and a study done by Gami et al. demonstrated that increased nocturnal oxygen desaturation from OSA severity was correlated with higher incidences of atrial fibrillation. Obesity is a risk factor for AF. Hyperthyroidism and subclinical hyperthyroidism are associated with AF development.
Caffeine consumption does not appear to be associated with AF; excessive alcohol consumption ("binge drinking" or "holiday heart syndrome") is linked to AF. Low-to-moderate alcohol consumption also appears to be associated with an increased risk of developing atrial fibrillation, although the increase in risk associated with drinking less than two drinks daily appears to be small. Tobacco smoking and secondhand tobacco smoke exposure are associated with an increased risk of developing atrial fibrillation. Long-term endurance exercise that far exceeds the recommended amount of exercise (e.g., long-distance cycling or marathon running) appears to be associated with a modest increase in the risk of atrial fibrillation in middle-aged and elderly people.
Major stress biomarkers (including cortisol and heat shock proteins) indicate that stress plays a significant role in causing atrial fibrillation. There is some evidence that night shift working may be linked to a diagnosis of AF.
Atrial fibrillation is associated with elevated levels of inflammatory markers and clotting factors. Mendelian randomization indicates a causal relationship of inflammation leading to atrial fibrillation.
=== Genetics ===
Family history in a first degree relative is associated with a 40% increase in risk of AF. This finding led to the mapping of different loci such as 10q22-24, 6q14-16 and 11p15-5.3 and discover mutations associated with the loci. Mutations have been found in the genes of K+ channels and Na+ channels which affect the processes of polarization-depolarization of the myocardium, cellular hyper-excitability, shortening of effective refractory period favoring re-entries.
Using genome-wide association study (GWAS), which screen the entire genome for single nucleotide polymorphism (SNP), three susceptibility loci have been found for AF (4q25, 1q21 and 16q22). In these loci there are SNPs associated with a 30% increase in risk of recurrent atrial tachycardia after ablation. There are also SNPs associated with loss of function of the Pitx2c gene (involved in cellular development of pulmonary valves), responsible for re-entries. There are also SNPs close to ZFHX3 genes involved in the regulation of Ca2+. A 2018 meta-analysis of GWAS studies identified 97 locis associated with AF, of which 70 were newly identified associations: they are associated with genes that encode transcription factors, such as TBX3 and TBX5, NKX2-5 or PITX2, involved in the regulation of cardiac conduction, modulation of ion channels and in cardiac development.
=== Sedentary lifestyle ===
A sedentary lifestyle increases the risk factors associated with AF, such as obesity, hypertension, or diabetes mellitus. This favors remodeling processes of the atrium due to inflammation or alterations in the depolarization of cardiomyocytes by elevation of sympathetic nervous system activity. A sedentary lifestyle is associated with an increased risk of AF compared to physical activity. In both men and women, the practice of moderate exercise reduces the risk of AF progressively; intense sports may increase the risk of developing AF, as seen in athletes. It is due to a remodeling of cardiac tissue, and an increase in vagal tone, which shortens the effective refractory period (ERP) favoring re-entries from the pulmonary veins.
=== Tobacco ===
The rate of AF in smokers is 1.4 times higher than in non-smokers. Snus consumption, which delivers nicotine at a dose equivalent to that of cigarettes, is not correlated with AF.
=== Alcohol ===
Acute alcohol consumption can directly trigger an episode of atrial fibrillation. Regular alcohol consumption also increases the risk of atrial fibrillation in several ways. The long-term use of alcohol alters the physical structure and electrical properties of the atria. Alcohol consumption does this by repeatedly stimulating the sympathetic nervous system, increasing inflammation in the atria, raising blood pressure, lowering the levels of potassium and magnesium in the blood, worsening obstructive sleep apnea, and by promoting harmful structural changes (remodeling) in the atria and ventricles of the heart. This remodeling leads to abnormally increased pressure in the left atrium, inappropriately dilates it, and increases scarring (fibrosis) in the left atrium. The aforementioned structural changes increase the risk of developing atrial fibrillation when paired with the harmful changes in how the left atrium conducts electricity.
=== Hypertension ===
Hypertension is reportedly present in 49% to 90% of patients with atrial fibrillation. According to the CHARGE Consortium, both systolic and diastolic blood pressure are predictors of the risk of AF. Systolic blood pressure values close to normal limit the increase in the risk associated with AF. Diastolic dysfunction is also associated with AF, which increases left atrial pressure, left atrial volume, size, and left ventricular hypertrophy, characteristic of chronic hypertension. All atrial remodeling is related to heterogeneous conduction and the formation of re-entrant electric conduction from the pulmonary veins.
=== Other diseases ===
There is a relationship between risk factors such as obesity and hypertension, with the appearance of diseases such as diabetes mellitus and sleep apnea-hypopnea syndrome, specifically, obstructive sleep apnea (OSA). These diseases are associated with an increased risk of AF due to their remodeling effects on the left atrium.
=== Medications ===
Several medications are associated with an increased risk of developing atrial fibrillation. Few studies have examined this phenomenon, and the exact incidence of medication-induced atrial fibrillation is unknown. Medications that are commonly associated with an increased risk of developing atrial fibrillation include dobutamine and the chemotherapy agent cisplatin. Agents associated with a moderately increased risk include nonsteroidal anti-inflammatory drugs (e.g., ibuprofen), bisphosphonates, and other chemotherapeutic agents such as melphalan, interleukin 2, and anthracyclines. Other medications that rarely increase the risk of developing atrial fibrillation include adenosine, aminophylline, corticosteroids, ivabradine, ondansetron, and antipsychotics. This form of atrial fibrillation occurs in people of all ages but is most common in the elderly, in those with other atrial fibrillation risk factors, and after heart surgery.
== Pathophysiology ==
The normal electrical conduction system of the heart allows electrical impulses generated by the heart's own pacemaker (the sinoatrial node) to spread to and stimulate the muscular layer of the heart (myocardium) in both the atria and the ventricles. When the myocardium is stimulated it contracts, and if this occurs in an orderly manner allows blood to be pumped to the body. In AF, the normal regular electrical impulses generated by the sinoatrial node are overwhelmed by disorganized electrical waves, usually originating from the roots of the pulmonary veins. These disorganized waves conduct intermittently through the atrioventricular node, leading to irregular activation of the ventricles that generate the heartbeat.
=== Pathology ===
The primary pathologic change seen in atrial fibrillation is the progressive fibrosis of the atria. This fibrosis is due primarily to atrial dilation; however, genetic causes and inflammation may be factors in some individuals. Dilation of the atria can be due to almost any structural abnormality of the heart that can cause a rise in the pressure within the heart. This includes valvular heart disease (such as mitral stenosis, mitral regurgitation, and tricuspid regurgitation), hypertension, and congestive heart failure. Any inflammatory state that affects the heart can cause fibrosis of the atria.
Once dilation of the atria has occurred, this begins a chain of events that leads to the activation of the renin–angiotensin–aldosterone system (RAAS) and subsequent increase in the matrix metalloproteinases and disintegrin, which leads to atrial remodeling and fibrosis, with loss of atrial muscle mass. This process occurs gradually, and experimental studies have revealed patchy atrial fibrosis may precede the occurrence of atrial fibrillation and may progress with prolonged durations of atrial fibrillation.
Fibrosis is not limited to the muscle mass of the atria and may occur in the sinus node (SA node) and atrioventricular node (AV node), correlating with sick sinus syndrome. Prolonged episodes of atrial fibrillation have been shown to correlate with prolongation of the sinus node recovery time; this suggests that dysfunction of the SA node is progressive with prolonged episodes of atrial fibrillation.
Along with fibrosis, alterations in the atria that predispose to atrial fibrillation affect their electrical properties, as well as their responsiveness to the autonomic nervous system. The atrial remodeling that includes the pathologic changes described above has been referred to as atrial myopathy.
=== Electrophysiology ===
There are multiple theories about the cause of atrial fibrillation. An important theory is that the regular impulses produced by the sinus node for a normal heartbeat are overwhelmed by rapid electrical discharges produced in the atria and adjacent parts of the pulmonary veins. Non-pulmonary vein sources of triggers for atrial fibrillation have been identified in 10% to 33% of patients. These triggers include the coronary sinus, the posterior wall of the left atrium, the ligament of Marshall, and the left atrial appendage.
Sources of these disturbances are either automatic foci, often localized at one of the pulmonary veins, or a small number of localized sources in the form of either a re-entrant leading circle or electrical spiral waves (rotors); these localized sources may be in the left atrium near the pulmonary veins or in a variety of other locations through both the left or right atrium. Three fundamental components favor the establishment of a leading circle or a rotor: slow conduction velocity of the cardiac action potential, a short refractory period, and a small wavelength. Meanwhile, the wavelength is the product of velocity and refractory period. If the action potential has fast conduction, with a long refractory period and/or conduction pathway shorter than the wavelength, an AF focus would not be established. In multiple wavelet theory, a wavefront will break into smaller daughter wavelets when encountering an obstacle, through a process called vortex shedding. But, under the proper conditions, such wavelets can reform and spin around a center, forming an AF focus.
In a heart with AF, the increased calcium release from the sarcoplasmic reticulum and increased calcium sensitivity can lead to an accumulation of intracellular calcium and causes downregulation of L-type calcium channels. This reduces the duration of action potential and the refractory period, thus favoring the conduction of re-entrant waves. Increased expression of inward-rectifier potassium ion channels can cause a reduced atrial refractory period and wavelength. The abnormal distribution of gap junction proteins such as GJA1 (also known as connexin 43), and GJA5 (connexin 40) causes non-uniformity of electrical conduction, thus causing the arrhythmia.
AF can be distinguished from atrial flutter (AFL), which appears as an organized electrical circuit usually in the right atrium. AFL produces characteristic saw-toothed F-waves of constant amplitude and frequency on an ECG, whereas AF does not. In AFL, the discharges circulate rapidly at a rate of 300 beats per minute (bpm) around the atrium. In AF, there is no such regularity, except at the sources where the local activation rate can exceed 500 bpm. Although AF and atrial flutter are distinct arrhythmias, atrial flutter may degenerate into AF, and an individual may experience both arrhythmias at different times.
Although the electrical impulses of AF occur at a high rate, most of them do not result in a heartbeat. A heartbeat results when an electrical impulse from the atria passes through the atrioventricular (AV) node to the ventricles and causes them to contract. During AF, if all of the impulses from the atria passed through the AV node, there would be severe ventricular tachycardia, resulting in a severe reduction of cardiac output. This dangerous situation is prevented by the AV node since its limited conduction velocity reduces the rate at which impulses reach the ventricles during AF.
== Diagnosis ==
Atrial fibrillation is diagnosed on an electrocardiogram (ECG/EKG). The evaluation of atrial fibrillation involves a determination of the cause of the arrhythmia, and classification of the arrhythmia. Diagnostic investigation of AF typically includes a complete medical history and physical examination, ECG, transthoracic echocardiogram and blood tests.
=== Screening ===
Numerous guidelines recommend opportunistic screening for atrial fibrillation in those 65 years and older. These organizations include the: European Society of Cardiology,
National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand,
European Heart Rhythm Society,
AF-SCREEN International Collaboration,
Royal College of Physicians of Edinburgh
European Primary Care Cardiovascular Society, and Irish Health Information and Quality Authority.
Single timepoint screening detects undiagnosed AF, which is often asymptomatic, in approximately 1.4% of people in people aged 65 years and older. In 2022, the United States Preventive Services Task Force found insufficient evidence to determine the usefulness of routine screening.
Some smartwatches may detect AF.
==== Bloodwork ====
Blood tests such as complete blood count, kidney function, electrolytes, glucose or HbA1c, and thyroid function is often determined in new-onset atrial fibrillation, to provide risk stratification and exclude certain etiology.
==== Electrocardiogram ====
Atrial fibrillation is diagnosed on an electrocardiogram (ECG), an investigation performed routinely whenever an irregular heartbeat is suspected. Characteristic findings are the absence of P waves, with disorganized electrical activity in their place, and irregular R–R intervals due to irregular conduction of impulses to the ventricles. At very fast heart rates, atrial fibrillation may look more regular, which may make it more difficult to separate from other supraventricular tachycardias or ventricular tachycardia.
QRS complexes should be narrow, signifying that they are initiated by normal conduction of atrial electrical activity through the intraventricular conduction system. Wide QRS complexes are worrisome for ventricular tachycardia, although, in cases where there is a disease of the conduction system, wide complexes may be present in A-fib with a rapid ventricular response.
If paroxysmal AF is suspected, but an ECG during an office visit shows only a regular rhythm, AF episodes may be detected and documented with the use of ambulatory Holter monitoring (e.g., for a day). If the episodes are too infrequent to be detected by Holter monitoring with reasonable probability, then the person can be monitored for longer periods (e.g., a month) with an ambulatory event monitor.
==== Echocardiography ====
In general, a non-invasive transthoracic echocardiogram (TTE) is performed in newly diagnosed AF, as well as if there is a major change in the person's clinical state. This ultrasound-based scan of the heart may help identify valvular heart disease (which may greatly increase the risk of stroke and alter recommendations for the appropriate type of anticoagulation), left and right atrial size (which predicts the likelihood that AF may become permanent), left ventricular size and function, peak right ventricular pressure (pulmonary hypertension), presence of left atrial thrombus (low sensitivity), presence of left ventricular hypertrophy and pericardial disease.
Significant enlargement of both the left and right atria is associated with long-standing atrial fibrillation and, if noted at the initial presentation of atrial fibrillation, suggests that the atrial fibrillation is likely to be of a longer duration than the individual's symptoms.
==== Transesophageal echocardiogram ====
A regular echocardiogram (transthoracic echocardiogram; TTE) has a low sensitivity for identifying blood clots in the heart. If this is suspected (e.g. when planning urgent electrical cardioversion), a transesophageal echocardiogram (TEE, or TOE where British spelling is used) is preferred.
The TEE has much better visualization of the left atrial appendage than transthoracic echocardiography. This structure, located in the left atrium, is the place where a blood clot forms in more than 90% of cases in non-valvular (or non-rheumatic) atrial fibrillation. TEE has a high sensitivity for locating thrombi in this area and can also detect sluggish blood flow in this area that is suggestive of blood clot formation. If a blood clot is seen on TEE, then cardioversion is contraindicated due to the risk of stroke, and anticoagulation is recommended.
==== Ambulatory Holter monitoring ====
A Holter monitor is a wearable ambulatory heart monitor that continuously monitors the heart rate and heart rhythm for a short duration, typically 24 hours. In individuals with symptoms of significant shortness of breath with exertion or palpitations regularly, a Holter monitor may be of benefit to determine whether rapid heart rates (or unusually slow heart rates) during atrial fibrillation are the cause of the symptoms.
=== Classification ===
The American College of Cardiology (ACC), American Heart Association (AHA), and the European Society of Cardiology (ESC) recommend in their guidelines the following classification system based on simplicity and clinical relevance.
All people with AF are initially in the category called first detected AF. These people may or may not have had previous undetected episodes. If a first detected episode stops on its own in less than seven days and then another episode begins, later on, the category changes to paroxysmal AF. Although people in this category have episodes lasting up to seven days, in most cases of paroxysmal AF, the episodes will stop in less than 24 hours. If the episode lasts for more than seven days, it is unlikely to stop on its own and is then known as persistent AF. In this case, cardioversion can be attempted to restore a normal rhythm. If an episode continues for a year or more, the rhythm is then known as long-standing persistent AF. If a decision is made by the person and their medical team to accept persistent AF and not attempt restoration of a normal sinus rhythm but instead manage the AF by simply controlling the person's ventricular rate then the rhythm is referred to as permanent AF. As a further subtype, AF that is detected only by an implanted or wearable cardiac monitor is known as subclinical AF.
Episodes that last less than 30 seconds are not considered in this classification system. Also, this system does not apply to cases where the AF is a secondary condition that occurs in the setting of a primary condition that may be the cause of the AF.
About half of people with AF have permanent AF, while a quarter have paroxysmal AF, and a quarter have persistent AF.
In addition to the above AF categories, which are mainly defined by episode timing and termination, the ACC/AHA and ESC guidelines describe additional outdated AF categories in terms of other characteristics of the person. Valvular AF refers to AF attributable to moderate to severe mitral valve stenosis or atrial fibrillation in the presence of a mechanical artificial heart valve. This distinction may be useful as it has implications on appropriate treatment, including differing recommendations for anticoagulation, but the term is discouraged as it may be confusing. Other historically used definitions include lone AF – AF occurring in those aged under 60 in the absence of other cardiovascular or respiratory diseases. This description is also discouraged since it offers no clinical value. Secondary AF refers to AF that occurs in the setting of another condition that have caused the AF, such as acute myocardial infarction, cardiac surgery, pericarditis, myocarditis, hyperthyroidism, pulmonary embolism, pneumonia, or another acute pulmonary disease.
== Prevention ==
Prevention of atrial fibrillation focuses primarily on preventing or controlling its risk factors. Many of its risk factors, such as obesity, smoking, lack of physical activity, and excessive alcohol consumption, are modifiable and preventable with lifestyle modification or can be managed by a healthcare professional.
=== Lifestyle modification ===
Several healthy lifestyle behaviors are associated with a lower likelihood of developing atrial fibrillation. Accordingly, consensus guidelines recommend abstaining from alcohol and recreational drugs, stopping tobacco use, maintaining a healthy weight, and regularly participating in moderate-intensity physical activities. Consistent moderate-intensity aerobic exercise, defined as achieving 3.0–5.9 METs of intensity, for at least 150 minutes per week may reduce the risk of developing new-onset atrial fibrillation. Few studies have examined the role of specific dietary changes and how it relates to the prevention of atrial fibrillation.
== Management ==
The main goals of treatment are to prevent circulatory instability and stroke. Rate or rhythm control is used to achieve the former, whereas anticoagulation is used to decrease the risk of the latter. If cardiovascularly unstable due to uncontrolled tachycardia, immediate cardioversion is indicated. Many antiarrhythmics, when used long term, increase the risk of death without any meaningful benefit. An integrated management approach, which includes stroke prevention, symptoms control and management of associated comorbidities has been associated with better outcomes in patients with atrial fibrillation.
This holistic or integrated care approach is summed up as the ABC (Atrial fibrillation Better Care) pathway, as follows:
A: Avoid stroke with Anticoagulation, where the default is stroke prevention unless the patient is at low risk. Stroke prevention means use of oral anticoagulation (OAC), whether with well managed vitamin K antagonists (VKA), with time in therapeutic range >70%, or more commonly, label-adherent dosed direct oral anticoagulant (DOAC).
B: Better symptom and atrial fibrillation management with patient-centred, symptom directed decisions on rate control or rhythm control. In some selected patients, use early rhythm control may be beneficial.
C: Cardiovascular risk factor and comorbidity management, including attention to lifestyle factors and psychological morbidity.
=== Lifestyle modification ===
Regular aerobic exercise improves atrial fibrillation symptoms and AF-related quality of life. The effect of high-intensity interval training on reducing atrial fibrillation burden is unclear. Weight loss of at least 10% is associated with reduced atrial fibrillation burden in people who are overweight or obese.
=== Comorbidity treatment ===
For people who have both atrial fibrillation and obstructive sleep apnea, observational studies suggest that continuous positive airway pressure (CPAP) treatment appears to lower the risk of atrial fibrillation recurrence after undergoing ablation. Randomized controlled trials examining the role of obstructive sleep apnea treatment on atrial fibrillation incidence and burden are lacking. Guideline-recommended lifestyle and medical interventions are recommended for people with atrial fibrillation and coexisting conditions such as hyperlipidemia, diabetes mellitus, or hypertension without specific blood sugar or blood pressure targets for people with atrial fibrillation.
Bariatric surgery may reduce the risk of new-onset atrial fibrillation in people with obesity without AF and may reduce the risk of a recurrence of AF after an ablation procedure in people with coexisting obesity and atrial fibrillation. It is important for all people with atrial fibrillation to optimize the control of all coexisting medical conditions that can worsen their atrial fibrillation, such as hyperthyroidism, diabetes, congestive heart failure, high blood pressure, chronic obstructive pulmonary disease, stimulant use (e.g., methamphetamine dependence), and excessive alcohol consumption.
=== Anticoagulants ===
Anticoagulation medication can be used to reduce the risk of stroke from AF. Anticoagulation medication is recommended in most people with increased risk of stroke, which can be estimated using the CHA2DS2-VASc score.
The risk of falls and consequent bleeding in frail elderly people should not be considered a barrier to initiating or continuing anticoagulation since the risk of fall-related brain bleeding is low and the benefit of stroke prevention often outweighs the risk of bleeding. The presence or absence of AF symptoms does not determine whether a person warrants anticoagulation and is not an indicator of stroke risk.
Direct oral anticoagulant (DOAC) are recommended over warfarin in atrial fibrillation. In atrial fibrillation with presence of moderate to severe mitral stenosis or mechanical heart valve, warfarin is recommended over other therapies. DOACs carry a lower risk of bleeding in the brain compared to warfarin, although dabigatran is associated with a higher risk of intestinal bleeding.
Direct oral anticoagulant (DOAC), previously called "new", "novel", or "non-vitamin K antagonist" oral anticoagulant (NOAC), are medications taken orally that have another mechanism of action on the coagulation cascade than warfarin. DOACs recommended in atrial fibrillation include apixaban, dabigatran, edoxaban and rivaroxaban.
Antiplatelet drugs alone, such as aspirin or dual antiplatelet therapy with aspirin and clopidogrel, is not recommended as stroke prophylaxis in atrial fibrillation. In those who are also on aspirin, DOACs appear to be better than warfarin.
The optimal approach to anticoagulation in people with AF and who simultaneously have other diseases (e.g., cirrhosis and end-stage kidney disease on dialysis) that predispose a person to both bleeding and clotting complications is unclear.
For vitamin K antagonists (VKA) such as warfarin, time in therapeutic range (TTR) and INR variability are commonly used to assess the quality of VKA treatment. Patients who are unable to maintain a therapeutic INR on VKA, as indicated by low TTR and/or high INR variability, are at an increased risk of thromboembolic and bleeding events. In these patients, treatment with a DOAC is recommended. While there are no significant changes in adherence, persistence or clinical outcomes in patients switched from a VKA to a DOAC, an increase in therapy satisfaction has been reported.
=== Rate versus rhythm control ===
There are two ways to approach atrial fibrillation using medications: rate control and rhythm control. Both methods have similar outcomes. Rate control lowers the heart rate closer to normal, usually 60 to 100 bpm, without trying to convert to a regular rhythm. Rhythm control tries to restore a normal heart rhythm in a process called cardioversion and maintains the normal rhythm with medications. Studies suggest that rhythm control is more important in the acute setting AF, whereas rate control is more important in the long-term.
The risk of stroke appears to be lower with rate control versus attempted rhythm control, at least in those with heart failure. AF is associated with a reduced quality of life, and, while some studies indicate that rhythm control leads to a higher quality of life, some did not find a difference. Neither rate nor rhythm control is superior in people with heart failure when they are compared in various clinical trials. However, rate control is recommended as the first-line treatment regimen for people with heart failure. On the other hand, rhythm control is only recommended when people experience persistent symptoms despite adequate rate control therapy.
In those with a fast ventricular response, intravenous magnesium significantly increases the chances of achieving successful rate and rhythm control in the urgent setting without major side-effects. A person with poor vital signs, mental status changes, preexcitation, or chest pain often will go to immediate treatment with synchronized direct current cardioversion. Otherwise, the decision of rate control versus rhythm control using medications is made. This is based on several criteria that include whether or not symptoms persist with rate control.
=== Rate control ===
Rate control to a target heart rate of fewer than 110 beats per minute is recommended in most people. Lower heart rates may be recommended in those with left ventricular hypertrophy or reduced left ventricular function. Rate control is achieved with medications that work by increasing the degree of the block at the level of the AV node, decreasing the number of impulses that conduct into the ventricles. This can be done with:
Beta blockers (preferably the "cardioselective" beta blockers such as metoprolol, bisoprolol, or nebivolol)
Non-dihydropyridine calcium channel blockers (e.g., diltiazem or verapamil)
Cardiac glycosides (e.g., digoxin) – have less use, apart from in older people who are sedentary. They are not as effective as either beta-blockers or calcium channel blockers.
In addition to these agents, amiodarone has some AV node blocking effects (in particular when administered intravenously) and can be used in individuals when other agents are contraindicated or ineffective (particularly due to hypotension).
=== Cardioversion ===
Cardioversion is the attempt to switch an irregular heartbeat to a normal heartbeat using electrical or chemical means.
Electrical cardioversion involves the restoration of normal heart rhythm through the application of a direct current electrical shock. The exact placement of the pads does not appear to be important.
Chemical cardioversion is performed with medications, such as amiodarone, dronedarone, procainamide (especially in pre-excited atrial fibrillation), dofetilide, ibutilide, propafenone, or flecainide.
After successful cardioversion, the heart may be stunned, which means that there is a normal rhythm, but the restoration of normal atrial contraction has not yet occurred.
=== Surgery ===
==== Ablation ====
Catheter ablation (CA) is a procedure performed by an electrophysiologist, a cardiologist who specializes in heart rhythm problems, to restore the heart's normal rhythm by destroying, or electrically isolating, specific parts of the atria. A group of cardiologists led by Dr Haïssaguerre from Bordeaux University Hospital noted in 1998 that the pulmonary veins are an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation, with these foci responding to treatment with radio-frequency ablation. Most commonly, CA electrically isolates the left atrium from the pulmonary veins, where most of the abnormal electrical activity promoting atrial fibrillation originates. CA is a form of rhythm control that restores normal sinus rhythm and reduces AF-associated symptoms more reliably than antiarrhythmic medications.
Electrophysiologists generally use three forms of catheter ablation: radiofrequency (RF) ablation, cryoablation ("cryo"), or pulsed field (PF). In young people with little-to-no structural heart disease where rhythm control is desired and cannot be maintained by medication or cardioversion, ablation may be attempted and may be preferred over several years of medical therapy. Although radiofrequency ablation has become an accepted intervention in selected younger people and may be more effective than medication at improving symptoms and quality of life, there is no evidence that ablation reduces all-cause mortality, stroke, or heart failure. Some evidence indicates CA may be particularly helpful for people with AF who also have heart failure. AF may recur in people who have undergone CA and nearly half of people who undergo it will require a repeat procedure to achieve long-term control of their AF.
In general, CA is more successful at preventing AF recurrence if AF is paroxysmal as opposed to persistent. As CA does not reduce the risk of stroke, many are advised to continue their anticoagulation. Possible complications include common, minor complications such as the formation of a collection of blood at the site where the catheter goes into the vein (access site hematoma), but also more dangerous complications including bleeding around the heart (cardiac tamponade), stroke, damage to the esophagus (atrio-esophageal fistula), or even death. Use of pulsed field ablation as a non-thermal method of inducing electroporation avoids damage to the phrenic nerve, esophagus, and blood vessels, while being at least as effective as thermal ablation methods.
A hybrid convergent procedure has been developed which combines endocardial ablation with epicardial ablation, which can reduce AF recurrence to less than 5% for over one year. The epicardial ablation is performed first, with a minimally invasive surgical approach.
==== Maze procedure ====
An alternative to catheter ablation is surgical ablation. The maze procedure, first performed in 1987, is an effective invasive surgical treatment that is designed to create electrical blocks or barriers in the atria of the heart. The idea is to force abnormal electrical signals to move along one, uniform path to the lower chambers of the heart (ventricles), thus restoring the normal heart rhythm. People with AF often undergo cardiac surgery for other underlying reasons and are frequently offered concomitant AF surgery to reduce the frequency of short- and long-term AF. Concomitant AF surgery is more likely to lead to the person being free from atrial fibrillation and off medications long-term after surgery and Cox-Maze IV procedure is the gold standard treatment. There is a slightly increased risk of needing a pacemaker following the procedure. Less invasive modifications of the maze procedure have been developed, designated as minimaze procedures.
==== Left atrial appendage occlusion ====
There is growing evidence that left atrial appendage occlusion therapy may reduce the risk of stroke in people with non-valvular AF as much as warfarin. The addition of left atrial appendage isolation to catheter ablation has reduced AF recurrence by 80% in patients with persistent AF.
==== After surgery ====
After catheter ablation, people are moved to a cardiac recovery unit, intensive care unit, or cardiovascular intensive care unit where they are not allowed to move for 4–6 hours. Minimizing movement helps prevent bleeding from the site of the catheter insertion. The length of time people stay in the hospital varies from hours to days. This depends on the problem, the length of the operation, and whether or not general anesthetic was used. Additionally, people should not engage in strenuous physical activity – to maintain a low heart rate and low blood pressure – for around six weeks.
AF often occurs after cardiac surgery and is usually self-limiting. It is strongly associated with age, preoperative hypertension, and the number of vessels grafted. Measures should be taken to control hypertension preoperatively to reduce the risk of AF. Also, people with a higher risk of AF, e.g., people with pre-operative hypertension, more than three vessels grafted, or greater than 70 years of age, should be considered for prophylactic treatment. Postoperative pericardial effusion is also suspected to be the cause of atrial fibrillation. Prophylaxis may include prophylactic postoperative rate and rhythm management. Some authors perform posterior pericardiotomy to reduce the incidence of postoperative AF. When AF occurs, management should primarily be rate and rhythm control. However, cardioversion may be used if the patient is hemodynamically unstable, highly symptomatic, or AF persists for six weeks after discharge. In persistent cases, anticoagulation should be used.
== Prognosis ==
Atrial fibrillation can progress from infrequent occurrences to more frequent occurrences, ultimately becoming permanent. Some cases do not progress, especially among patients with a healthy lifestyle.
Many mechanisms contribute to cardiac remodeling leading to a worsening of atrial fibrillation, including fibrosis, fatty infiltration, amyloidosis, and ion channel modifications. Fatty infiltration helps explain why obesity is a risk factor for atrial fibrillation in one fifth of patients.
Atrial fibrillation increases the risk of heart failure by 11 per 1000, kidney problems by 6 per 1000, death by 4 per 1000, stroke by 3 per 1000, and coronary heart disease by 1 per 1000. Women have a worse outcome overall than men. Evidence increasingly suggests that atrial fibrillation is independently associated with a higher risk of developing dementia.
=== Blood clots ===
==== Prediction of embolism ====
Determining the risk of an embolism causing a stroke is important for guiding the use of anticoagulants. The most accurate clinical prediction rules is the CHA2DS2-VASc score. The addition of blood based biomarkers such as NT-proBNP and neurofilament light chain improves risk prediction significantly. A CHA2DS2-VASc score of zero is considered very low risk.
==== Mechanism of thrombus formation ====
In atrial fibrillation, the lack of an organized atrial contraction can result in some stagnant blood in the left atrium (LA) or left atrial appendage (LAA). This lack of movement of blood can lead to thrombus formation (blood clotting). If the clot becomes mobile and is carried away by the blood circulation, it is called an embolus. An embolus proceeds through smaller and smaller arteries until it plugs one of them and prevents blood from flowing through the artery. This process results in end organ damage due to the loss of nutrients, oxygen, and the removal of cellular waste products. Emboli in the brain may result in an ischemic stroke or a transient ischemic attack (TIA).
More than 90% of cases of thrombi associated with non-valvular atrial fibrillation evolve in the left atrial appendage. However, the LAA lies in close relation to the free wall of the left ventricle, and thus the LAA's emptying and filling, which determines its degree of blood stagnation, may be helped by the motion of the wall of the left ventricle if there is good ventricular function.
=== Dementia ===
Atrial fibrillation has been independently associated with a higher risk of developing cognitive impairment, vascular dementia, and Alzheimer disease and with elevated levels of neurofilament light chain in blood, a biomarker indicating neuroaxonal injury. Several mechanisms for this association have been proposed, including silent small blood clots (subclinical microthrombi) traveling to the brain resulting in small ischemic strokes without symptoms, altered blood flow to the brain, inflammation, clinically silent small bleeds in the brain, and genetic factors. Tentative evidence suggests that effective anticoagulation with direct oral anticoagulants or warfarin may be somewhat protective against AF-associated dementia and evidence of silent ischemic strokes on MRI but this remains an active area of investigation.
== Epidemiology ==
Atrial fibrillation is the most common arrhythmia and affects more than 33 million people worldwide. In Europe and North America, as of 2014, it affects about 2% to 3% of the population. In the developing world, rates are about 0.6% for males and 0.4% for females. The number of people diagnosed with AF has increased due to better detection of silent AF, increasing age and increase of conditions that predispose to it such as obesity and increasing survival from other forms of cardiovascular disease.
The rate of hospital admissions for AF has risen. AF is the cause for 20% of all ischemic strokes. After a transient ischemic attack or stroke, about 11% are found to have a new diagnosis of atrial fibrillation. 3% to 11% of patients with AF have structurally normal hearts.
The number of new cases each year of AF increases with age. In younger people the prevalence is estimated to be 0.05% and is associated with congenital heart disease or structural heart disease in this demographic. As of 2001, it was anticipated that in developed countries, the number of people with atrial fibrillation was likely to increase during the following 50 years, due to the growing proportion of elderly people.
=== Gender ===
Atrial fibrillation is more common in men than in women when reviewed in European and North American populations. In developed and developing countries, there is also a higher rate in men than in women. The risk factors associated with AF are also distributed differently according to gender. In men, coronary disease is more frequent, while in women, high systolic blood pressure and valvular heart disease are more prevalent.
=== Ethnicity ===
Rates of AF are lower in populations of African descent than in populations of European descent. African descent is associated with a protective effect for AF, due to the lower presence of SNPs with guanine alleles. European ancestry has more frequent mutations. The variant rs4611994 for the gene PITX2 is associated with risk of AF in African and European populations. Hispanic and Asian populations have a lower risk of AF than European populations. The risk of AF in non-European populations is associated with characteristic risk factors of these populations, such as hypertension.
=== Young people ===
Atrial fibrillation is an uncommon condition in children but sometimes occurs in association with certain inherited and acquired conditions. Congenital heart disease and rheumatic fever are the most common causes of atrial fibrillation in children. Other inherited heart conditions associated with the development of atrial fibrillation in children include Brugada syndrome, short QT syndrome, Wolff Parkinson White syndrome, and other forms of supraventricular tachycardia (e.g., AV nodal reentrant tachycardia). Adults who survived congenital heart disease have an increased risk of developing AF. In particular, people who had atrial septal defects, Tetralogy of Fallot, or Ebstein's anomaly, and those who underwent the Fontan procedure, are at higher risk with prevalence rates of up to 30% depending on the heart's anatomy and the person's age.
== History ==
Because the diagnosis of atrial fibrillation requires measurement of the electrical activity of the heart, atrial fibrillation was not truly described until 1874, when Edmé Félix Alfred Vulpian observed the irregular atrial electrical behavior that he termed "fremissement fibrillaire" in dog hearts. In the mid-18th century, Jean-Baptiste de Sénac made note of dilated, irritated atria in people with mitral stenosis. The irregular pulse associated with AF was first recorded in 1876 by Carl Wilhelm Hermann Nothnagel and termed "delirium cordis", stating that "[I]n this form of arrhythmia the heartbeats follow each other in complete irregularity. At the same time, the height and tension of the individual pulse waves are continuously changing". Correlation of delirium cordis with the loss of atrial contraction, as reflected in the loss of a waves in the jugular venous pulse, was made by Sir James MacKenzie in 1904. Willem Einthoven published the first ECG showing AF in 1906. The connection between the anatomic and electrical manifestations of AF and the irregular pulse of delirium cordis was made in 1909 by Carl Julius Rothberger, Heinrich Winterberg, and Sir Thomas Lewis.
== Other animals ==
Atrial fibrillation occurs in other animals, including cats, dogs, and horses. Unlike humans, dogs rarely develop the complications that stem from blood clots breaking off from inside the heart and traveling through the arteries to distant sites (thromboembolic complications). Cats rarely develop atrial fibrillation but appear to have a higher risk of thromboembolic complications than dogs.
Cats and dogs with atrial fibrillation often have underlying structural heart disease that predisposes them to the condition. The medications used in animals for atrial fibrillation are largely similar to those used in humans. Electrical cardioversion is occasionally performed in these animals, but the need for general anesthesia limits its use. Standardbred horses appear to be genetically susceptible to developing atrial fibrillation. Horses that develop atrial fibrillation often have minimal or no underlying heart disease, and the presence of atrial fibrillation in horses can adversely affect physical performance.
== References ==
== Further reading ==
Van Gelder IC, Rienstra M, Bunting KV, Casado-Arroyo R, Caso V, Crijns HJ, et al. (30 August 2024). "2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS)". European Heart Journal. 45 (36): 3314–3414. doi:10.1093/eurheartj/ehae176. hdl:11392/2573658. ISSN 0195-668X. PMID 39210723.
Joglar JA, Chung MK, Armbruster AL, Benjamin EJ, Chyou JY, Cronin EM, et al. (30 November 2023). "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines". Circulation. 149 (1): e1 – e156. doi:10.1161/CIR.0000000000001193. PMC 11095842. PMID 38033089.
== External links ==
"Atrial Fibrillation". CVD Roadmaps. World Heart Federation.
Media related to Atrial fibrillation at Wikimedia Commons | Wikipedia/Atrial_fibrillation |
A congenital heart defect (CHD), also known as a congenital heart anomaly, congenital cardiovascular malformation, and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular disease. Signs and symptoms depend on the specific type of defect. Symptoms can vary from none to life-threatening. When present, symptoms are variable and may include rapid breathing, bluish skin (cyanosis), poor weight gain, and feeling tired. CHD does not cause chest pain. Most congenital heart defects are not associated with other diseases. A complication of CHD is heart failure.
Congenital heart defects are the most common birth defect. In 2015, they were present in 48.9 million people globally. They affect between 4 and 75 per 1,000 live births, depending upon how they are diagnosed. In about 6 to 19 per 1,000 they cause a moderate to severe degree of problems. Congenital heart defects are the leading cause of birth defect-related deaths: in 2015, they resulted in 303,300 deaths, down from 366,000 deaths in 1990.
The cause of a congenital heart defect is often unknown. Risk factors include certain infections during pregnancy such as rubella, use of certain medications or drugs such as alcohol or tobacco, parents being closely related, or poor nutritional status or obesity in the mother. Having a parent with a congenital heart defect is also a risk factor. A number of genetic conditions are associated with heart defects, including Down syndrome, Turner syndrome, and Marfan syndrome. Congenital heart defects are divided into two main groups: cyanotic heart defects and non-cyanotic heart defects, depending on whether the child has the potential to turn bluish in color. The defects may involve the interior walls of the heart, the heart valves, or the large blood vessels that lead to and from the heart.
Congenital heart defects are partly preventable through rubella vaccination, the adding of iodine to salt, and the adding of folic acid to certain food products. Some defects do not need treatment. Others may be effectively treated with catheter based procedures or heart surgery. Occasionally a number of operations may be needed, or a heart transplant may be required. With appropriate treatment, outcomes are generally good, even with complex problems.
== Signs and symptoms ==
Signs and symptoms are related to type and severity of the heart defect. Symptoms frequently present early in life, but it is possible for some CHDs to go undetected throughout life. Some children have no signs while others may exhibit shortness of breath, cyanosis, fainting, heart murmur, under-development of limbs and muscles, poor feeding or growth, or respiratory infections. Congenital heart defects cause abnormal heart structure resulting in production of certain sounds called heart murmur. These can sometimes be detected by auscultation; however, not all heart murmurs are caused by congenital heart defects.
=== Associated conditions ===
Congenital heart defects are associated with an increased incidence of seven other specific medical conditions, together being called the VACTERL association:
V — Vertebral anomalies
A — Anal atresia
C — Cardiovascular anomalies
T — Tracheoesophageal fistula
E — Esophageal atresia
R — Renal (Kidney) and/or radial anomalies
L — Limb defects
Ventricular septal defect (VSD), atrial septal defect (ASD), and tetralogy of Fallot (ToF) are the most common congenital heart defects seen in the VACTERL association. Less common defects in the association are persistent truncus arteriosus and transposition of the great arteries.
== Causes ==
The cause of congenital heart disease may be genetic, environmental, or a combination of both.
=== Genetic ===
Genetic mutations, often sporadic, represent the largest known cause of congenital heart defects. They are described in the table below.
==== Molecular pathways ====
The genes regulating the complex developmental sequence have only been partly elucidated. Some genes are associated with specific defects. A number of genes have been associated with cardiac manifestations. Mutations of a heart muscle protein, α-myosin heavy chain (MYH6) are associated with atrial septal defects. Several proteins that interact with MYH6 are also associated with cardiac defects. The transcription factor GATA4 forms a complex with the TBX5 which interacts with MYH6. Another factor, the homeobox (developmental) gene, NKX2-5 also interacts with MYH6. Mutations of all these proteins are associated with both atrial and ventricular septal defects; In addition, NKX2-5 is associated with defects in the electrical conduction of the heart and TBX5 is related to the Holt–Oram syndrome which includes electrical conduction defects and abnormalities of the upper limb. The Wnt signaling co-factors BCL9, BCL9L and PYGO might be part of these molecular pathways, as when their genes are mutated, this causes phenotypes similar to the features present in Holt-Oram syndrome. Another T-box gene, TBX1, is involved in velo-cardio-facial syndrome DiGeorge syndrome, the most common deletion which has extensive symptoms including defects of the cardiac outflow tract including tetralogy of Fallot.
The notch signaling pathway, a regulatory mechanism for cell growth and differentiation, plays broad roles in several aspects of cardiac development. Notch elements are involved in determination of the right and left sides of the body plan, so the directional folding of the heart tube can be impacted. Notch signaling is involved early in the formation of the endocardial cushions and continues to be active as the develop into the septa and valves. It is also involved in the development of the ventricular wall and the connection of the outflow tract to the great vessels. Mutations in the gene for one of the notch ligands, Jagged1, are identified in the majority of examined cases of arteriohepatic dysplasia (Alagille syndrome), characterized by defects of the great vessels (pulmonary artery stenosis), heart (tetralogy of Fallot in 13% of cases), liver, eyes, face, and bones. Though less than 1% of all cases, where no defects are found in the Jagged1 gene, defects are found in Notch2 gene. In 10% of cases, no mutation is found in either gene. For another member of the gene family, mutations in the Notch1 gene are associated with bicuspid aortic valve, a valve with two leaflets instead of three. Notch1 is also associated with calcification of the aortic valve, the third most common cause of heart disease in adults.
Mutations of a cell regulatory mechanism, the Ras/MAPK pathway are responsible for a variety of syndromes, including Noonan syndrome, LEOPARD syndrome, Costello syndrome and cardiofaciocutaneous syndrome in which there is cardiac involvement. While the conditions listed are known genetic causes, there are likely many other genes which are more subtle. It is known that the risk for congenital heart defects is higher when there is a close relative with one.
=== Environmental ===
Known environmental factors include certain infections during pregnancy such as rubella, drugs (alcohol, hydantoin, lithium and thalidomide) and maternal illness (diabetes mellitus, phenylketonuria, and systemic lupus erythematosus). Alcohol exposure in the father also appears to increase the risk of congenital heart defects.
Being overweight or obese increases the risk of congenital heart disease. Additionally, as maternal obesity increases, the risk of heart defects also increases. A distinct physiological mechanism has not been identified to explain the link between maternal obesity and CHD, but both pre-pregnancy folate deficiency and diabetes have been implicated in some studies.
=== Twins and Multiple Births ===
Congenital heart defects happen more often in twins than in single babies. Monochorionic twins, who share a placenta, have a greater risk of these heart defects compared to dichorionic twins, who have their own placentas. A systematic review and meta-analysis of four studies conducted in 2007 showed a 9-fold increase in CHD risk in MC twins compared to singletons.
== Mechanism ==
There is a complex sequence of events that result in a well formed heart at birth and disruption of any portion may result in a defect. The orderly timing of cell growth, cell migration, and programmed cell death ("apoptosis") has been studied extensively and the genes that control the process are being elucidated.
Around day 15 of development, the cells that will become the heart exist in two horseshoe shaped bands of the middle tissue layer (mesoderm), and some cells migrate from a portion of the outer layer (ectoderm), the neural crest, which is the source of a variety of cells found throughout the body. On day 19 of development, a pair of vascular elements, the "endocardial tubes", form. The tubes fuse when cells between then undergo programmed death and cells from the first heart field migrate to the tube, and form a ring of heart cells (myocytes) around it by day 21. On day 22, the heart begins to beat and by day 24, blood is circulating.
At day 22, the circulatory system is bilaterally symmetrical with paired vessels on each side and the heart consisting of a simple tube located in the midline of the body layout. The portions that will become the atria and will be located closest to the head are the most distant from the head. From days 23 through 28, the heart tube folds and twists, with the future ventricles moving left of center (the ultimate location of the heart) and the atria moving towards the head.
On day 28, areas of tissue in the heart tube begin to expand inwards; after about two weeks, these expansions (the membranous "septum primum" and the muscular "endocardial cushions") fuse to form the four chambers of the heart. A failure to fuse properly will result in a defect that may allow blood to leak between chambers. After this happens, cells that have migrated from the neural crest begin to divide the bulbus cordis. The main outflow tract is divided in two by the growth of a spiraling septum, becoming the great vessels—the ascending segment of the aorta and the pulmonary trunk. If the separation is incomplete, the result is a "persistent truncus arteriosus". The vessels may be reversed ("transposition of the great vessels"). The two halves of the split tract must migrate into the correct positions over the appropriate ventricles. A failure may result in some blood flowing into the wrong vessel (e.g. overriding aorta). The four-chambered heart and the great vessels have features required for fetal growth. The lungs are unexpanded and cannot accommodate the full circulatory volume. Two structures exist to shunt blood flow away from the lungs to compensate. Cells in part of the septum primum die, creating a hole while new muscle cells (the "septum secundum") grow along the right atrial side of the septum primum except for one region, leaving a gap through which blood can pass from the right atrium to the left atrium (the foramen ovale). A small vessel called the ductus arteriosus allows blood from the pulmonary artery to pass to the aorta.
=== Changes at birth ===
The ductus arteriosus stays open because of circulating factors including prostaglandins. The foramen ovale stays open because of the flow of blood from the right atrium to the left atrium. As the lungs expand, blood flows easily through the lungs and the membranous portion of the foramen ovale (the septum primum) flops over the muscular portion (the septum secundum). If the closure is incomplete, the result is a patent foramen ovale. The two flaps may fuse, but many adults have a foramen ovale that stays closed only because of the pressure difference between the atria.
=== Theories ===
Rokitansky (1875) explained congenital heart defects as breaks in heart development at various ontogenesis stages. Spitzer (1923) treats them as returns to one of the phylogenesis stages. Krimski (1963), synthesizing two previous points of view, considered congenital heart diseases as a stop of development at the certain stage of ontogenesis, corresponding to this or that stage of the phylogenesis. Hence, these theories can explain feminine and neutral types of defects only.
== Diagnosis ==
Many congenital heart defects can be diagnosed prenatally by fetal echocardiography. This is a test which can be done during the second trimester of pregnancy, when the woman is about 18–24 weeks pregnant. It can be an abdominal ultrasound or transvaginal ultrasound.
If a baby is born with cyanotic heart disease, the diagnosis is usually made shortly after birth due to the blue colour of their skin (called cyanosis).
If a baby is born with a septal defect or an obstruction defect, often their symptoms are only noticeable after several months, or sometimes even after many years.
=== Classification ===
A number of classification systems exist for congenital heart defects. In 2000 the International Congenital Heart Surgery Nomenclature was developed to provide a generic classification system.
==== Hypoplasia ====
Hypoplasia can affect the heart, typically resulting in the underdevelopment of the right ventricle or the left ventricle. This causes only one side of the heart to be capable of pumping blood to the body and lungs effectively. Hypoplasia of the heart is rare but is the most serious form of CHD. It is called hypoplastic left heart syndrome when it affects the left side of the heart and hypoplastic right heart syndrome when it affects the right side of the heart. In both conditions, the presence of a patent ductus arteriosus (and, when hypoplasia affects the right side of the heart, a patent foramen ovale) is vital to the infant's ability to survive until emergency heart surgery can be performed, since without these pathways blood cannot circulate to the body (or lungs, depending on which side of the heart is defective). Hypoplasia of the heart is generally a cyanotic heart defect.
==== Obstructive defects ====
Obstructive defects occur when heart valves, arteries, or veins are abnormally narrow or blocked. Common defects include pulmonic stenosis, aortic stenosis, and coarctation of the aorta, with other types such as bicuspid aortic valve stenosis and subaortic stenosis being comparatively rare. Any narrowing or blockage can cause heart enlargement or hypertension.
==== Septal defects ====
The septum is a wall of tissue which separates the left heart from the right heart. Defects in the interatrial septum or the interventricular septum allow blood to flow from the left side of the heart to the right, reducing the heart's efficiency. Ventricular septal defects are collectively the most common type of CHD, although approximately 30% of adults have a type of atrial septal defect called probe patent foramen ovale. An atrioventricular septal defect is more complex involving an atrial septal defect, a ventricular septal defect, and irregularities in the heart valves.
==== Cyanotic defects ====
Cyanotic heart defects are called such because they result in cyanosis, a bluish-grey discoloration of the skin due to a lack of oxygen in the body. Such defects include persistent truncus arteriosus, total anomalous pulmonary venous connection, tetralogy of Fallot, transposition of the great vessels, and tricuspid atresia.
==== Defects ====
Aortic stenosis
Arrhythmogenic right ventricular cardiomyopathy
Atrial septal defect (ASD)
Atrioventricular septal defect (AVSD)
Bicuspid aortic valve
Cardiomyopathy
Complete heart block (CHB)
Dextrocardia
Double inlet left ventricle (DILV)
Double outlet right ventricle (DORV)
Ebstein's anomaly
Early Repolarization Syndrome
Holmes heart
Hypoplastic left heart syndrome (HLHS)
Hypoplastic right heart syndrome (HRHS)
Mitral stenosis
Myocardial bridge
Persistent truncus arteriosus
Pulmonary atresia
Pulmonary stenosis
Rhabdomyomas (Tumors of the Heart)
Transposition of the great vessels
dextro-Transposition of the great arteries (d-TGA)
levo-Transposition of the great arteries (l-TGA)
Tricuspid atresia
Ventricular septal defect (VSD)
Wolff–Parkinson–White syndrome (WPW)
Some conditions affect the great vessels or other vessels in close proximity to the heart, but not the heart itself, but are often classified as congenital heart defects.
Coarctation of the aorta (CoA)
Double aortic arch, aberrant subclavian artery, and other malformations of the great arteries
Interrupted aortic arch (IAA)
Patent ductus arteriosus (PDA)
Scimitar syndrome (SS)
Partial anomalous pulmonary venous connection (PAPVC)
Total anomalous pulmonary venous connection (TAPVC)
Some constellations of multiple defects are commonly found together.
Tetralogy of Fallot (ToF)
Pentalogy of Cantrell
Shone's syndrome/ Shone's complex / Shone's anomaly
== Treatment ==
CHD may require surgery and medications. Medications include diuretics, which aid the body in eliminating water, salts, and digoxin for strengthening the contraction of the heart. This slows the heartbeat and removes some fluid from tissues. Some defects require surgical procedures to restore circulation back to normal and in some cases, multiple surgeries are needed.
Interventional cardiology now offers minimally invasive alternatives to surgery for some patients. The Melody Transcatheter Pulmonary Valve (TPV), approved in Europe in 2006 and in the U.S. in 2010 under a Humanitarian Device Exemption (HDE), is designed to treat congenital heart disease patients with a dysfunctional conduit in their right ventricular outflow tract (RVOT). The RVOT is the connection between the heart and lungs; once blood reaches the lungs, it is enriched with oxygen before being pumped to the rest of the body. Transcatheter pulmonary valve technology provides a less-invasive means to extend the life of a failed RVOT conduit and is designed to allow physicians to deliver a replacement pulmonary valve via a catheter through the patient's blood vessels.
Many people require lifelong specialized cardiac care, first with a pediatric cardiologist and later with an adult congenital cardiologist. There are more than 1.8 million adults living with congenital heart defects.
=== Mental health ===
Supporting people with chronic diseases such as congenital heart disease with emotional problems and mental health is a treatment consideration. Since some people with congenital heart disease have a lower quality of life that is related to their condition, some people may struggle with finding a job, engaging in physical exercise, with their fertility, and clinical depression as examples. An estimated 31% of adults with congenital heart disease also have mood disorders. Psychotherapy may be helpful for treating some people who have congenital heart disease and depression, however further research is needed to determine the best way to reduce depression including the length of treatments required for an improvement, type of psychotherapy treatments, and how the psychotherapy sessions are delivered.
== Epidemiology ==
Heart defects are among the most common birth defect, occurring in 1% of live births (2–3% including bicuspid aortic valve). In 2013, 34.3 million people had CHD. In 2010, they resulted in 223,000 deaths, down from 278,000 deaths in 1990.
For congenital heart defects that arise without a family history (de novo), the recurrence risk in offspring is 3–5%. This risk is higher in left ventricular outflow tract obstructions, heterotaxy, and atrioventricular septal defects.
== Terminology ==
Congenital heart defects are known by a number of names including congenital heart anomaly, congenital heart disease, heart defects, and congenital cardiovascular malformations.
== See also ==
Congenital Heart Surgeons' Society
Congenital heart block
== References ==
== External links ==
Congenital heart disease information for parents. | Wikipedia/Congenital_heart_disease |
Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of heart disease involving the reduction of blood flow to the cardiac muscle due to a build-up of atheromatous plaque in the arteries of the heart. It is the most common of the cardiovascular diseases. CAD can cause stable angina, unstable angina, myocardial ischemia, and myocardial infarction.
A common symptom is angina, which is chest pain or discomfort that may travel into the shoulder, arm, back, neck, or jaw. Occasionally it may feel like heartburn. In stable angina, symptoms occur with exercise or emotional stress, last less than a few minutes, and improve with rest. Shortness of breath may also occur and sometimes no symptoms are present. In many cases, the first sign is a heart attack. Other complications include heart failure or an abnormal heartbeat.
Risk factors include high blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor diet, depression, and excessive alcohol consumption. A number of tests may help with diagnosis including electrocardiogram, cardiac stress testing, coronary computed tomographic angiography, biomarkers (high-sensitivity cardiac troponins) and coronary angiogram, among others.
Ways to reduce CAD risk include eating a healthy diet, regularly exercising, maintaining a healthy weight, and not smoking. Medications for diabetes, high cholesterol, or high blood pressure are sometimes used. There is limited evidence for screening people who are at low risk and do not have symptoms. Treatment involves the same measures as prevention. Additional medications such as antiplatelets (including aspirin), beta blockers, or nitroglycerin may be recommended. Procedures such as percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) may be used in severe disease. In those with stable CAD it is unclear if PCI or CABG in addition to the other treatments improves life expectancy or decreases heart attack risk.
In 2015, CAD affected 110 million people and resulted in 8.9 million deaths. It makes up 15.6% of all deaths, making it the most common cause of death globally. The risk of death from CAD for a given age decreased between 1980 and 2010, especially in developed countries. The number of cases of CAD for a given age also decreased between 1990 and 2010. In the United States in 2010, about 20% of those over 65 had CAD, while it was present in 7% of those 45 to 64, and 1.3% of those 18 to 45; rates were higher among males than females of a given age.
== Signs and symptoms ==
The most common symptom is chest pain or discomfort that occurs regularly with activity, after eating, or at other predictable times; this phenomenon is termed stable angina and is associated with narrowing of the arteries of the heart. Angina also includes chest tightness, heaviness, pressure, numbness, fullness, or squeezing. Angina that changes in intensity, character, or frequency is termed unstable. Unstable angina may precede myocardial infarction. In adults who go to the emergency department with an unclear cause of pain, about 30% have pain due to coronary artery disease. Angina, shortness of breath, sweating, nausea or vomiting, and lightheadedness are signs of a heart attack or myocardial infarction, and immediate emergency medical services are crucial.
With advanced disease, the narrowing of coronary arteries reduces the supply of oxygen-rich blood flowing to the heart, which becomes more pronounced during strenuous activities during which the heart beats faster and has an increased oxygen demand. For some, this causes severe symptoms, while others experience no symptoms at all.
=== Symptoms in females ===
Symptoms in females can differ from those in males, and the most common symptom reported by females of all races is shortness of breath. Other symptoms more commonly reported by females than males are extreme fatigue, sleep disturbances, indigestion, and anxiety. However, some females experience irregular heartbeat, dizziness, sweating, and nausea. Burning, pain, or pressure in the chest or upper abdomen that can travel to the arm or jaw can also be experienced in females, but females less commonly report it than males. Generally, females experience symptoms 10 years later than males. Females are less likely to recognize symptoms and seek treatment.
== Risk factors ==
Coronary artery disease is characterized by heart problems that result from atherosclerosis. Atherosclerosis is a type of arteriosclerosis which is the "chronic inflammation of the arteries which causes them to harden and accumulate cholesterol plaques (atheromatous plaques) on the artery walls". CAD has several well-determined risk factors contributing to atherosclerosis. These risk factors for CAD include "smoking, diabetes, high blood pressure (hypertension), abnormal (high) amounts of cholesterol and other fat in the blood (dyslipidemia), type 2 diabetes and being overweight or obese (having excess body fat)" due to lack of exercise and a poor diet. Some other risk factors include high blood pressure, smoking, diabetes, lack of exercise, obesity, high blood cholesterol, poor diet, depression, family history, psychological stress and excessive alcohol. About half of cases are linked to genetics. Apart from these classical risk factors, several unconventional risk factors have also been studied including high serum fibrinogen, high c-reactive protein (CRP), chronic inflammatory conditions, hypovitaminosis D, high lipoprotein A levels, serum homocysteine etc. Smoking and obesity are associated with about 36% and 20% of cases, respectively. Smoking just one cigarette per day about doubles the risk of CAD. Lack of exercise has been linked to 7–12% of cases. Exposure to the herbicide Agent Orange may increase risk. Rheumatologic diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and psoriatic arthritis are independent risk factors as well.
Job stress appears to play a minor role accounting for about 3% of cases. In one study, females who were free of stress from work life saw an increase in the diameter of their blood vessels, leading to decreased progression of atherosclerosis. In contrast, females who had high levels of work-related stress experienced a decrease in the diameter of their blood vessels and significantly increased disease progression.
=== Air pollution ===
Air pollution, both indoor and outdoor, is responsible for roughly 28% of deaths from CAD. This varies by region: In highly developed areas, this is approximately 10%, whereas in Southern, East and West Africa, and South Asia, approximately 40% of deaths from CAD can be attributed to unhealthy air. In particular, fine particle pollution (PM2.5), which comes mostly from the burning of fossil fuels, is a key risk factor for CAD.
=== Blood fats ===
The consumption of different types of fats including trans fat (trans unsaturated), and saturated fat, in a diet "influences the level of cholesterol that is present in the bloodstream". Unsaturated fats originate from plant sources (such as oils). There are two types of unsaturated fats, cis and trans isomers. Cis unsaturated fats are bent in molecular structure and trans are linear. Saturated fats originate from animal sources (such as animal fats) and are also molecularly linear in structure. The linear configurations of unsaturated trans and saturated fats allow them to easily accumulate and stack at the arterial walls when consumed in high amounts (and other positive measures towards physical health are not met).
Fats and cholesterol are insoluble in blood and thus are amalgamated with proteins to form lipoproteins for transport. Low-density lipoproteins (LDL) transport cholesterol from the liver to the rest of the body and raise blood cholesterol levels. The consumption of "saturated fats increases LDL levels within the body, thus raising blood cholesterol levels".
High-density lipoproteins (HDL) are considered 'good' lipoproteins as they search for excess cholesterol in the body and transport it back to the liver for disposal. Trans fats also "increase LDL levels whilst decreasing HDL levels within the body, significantly raising blood cholesterol levels".
High levels of cholesterol in the bloodstream lead to atherosclerosis. With increased levels of LDL in the bloodstream, "LDL particles will form deposits and accumulate within the arterial walls, which will lead to the development of plaques, restricting blood flow". The resultant reduction in the heart's blood supply due to atherosclerosis in coronary arteries "causes shortness of breath, angina pectoris (chest pains that are usually relieved by rest), and potentially fatal heart attacks (myocardial infarctions)".
=== Genetics ===
The heritability of coronary artery disease has been estimated between 40% and 60%. Genome-wide association studies have identified over 160 genetic susceptibility loci for coronary artery disease.
=== Transcriptome ===
Several RNA Transcripts associated with CAD - FoxP1, ICOSLG, IKZF4/Eos, SMYD3, TRIM28, and TCF3/E2A are likely markers of regulatory T cells (Tregs), consistent with known reductions in Tregs in CAD.
The RNA changes are mostly related to ciliary and endocytic transcripts, which in the circulating immune system would be related to the immune synapse. One of the most differentially expressed genes, fibromodulin (FMOD), which is increased 2.8-fold in CAD, is found mainly in connective tissue and is a modulator of the TGF-beta signaling pathway. However, not all RNA changes may be related to the immune synapse. For example, Nebulette, the most down-regulated transcript (2.4-fold), is found in cardiac muscle; it is a 'cytolinker' that connects actin and desmin to facilitate cytoskeletal function and vesicular movement. The endocytic pathway is further modulated by changes in tubulin, a key microtubule protein, and fidgetin, a tubulin-severing enzyme that is a marker for cardiovascular risk identified by genome-wide association study. Protein recycling would be modulated by changes in the proteasomal regulator SIAH3, and the ubiquitin ligase MARCHF10. On the ciliary aspect of the immune synapse, several of the modulated transcripts are related to ciliary length and function. Stereocilin is a partner to mesothelin, a related super-helical protein, whose transcript is also modulated in CAD. DCDC2, a double-cortin protein, modulates ciliary length. In the signaling pathways of the immune synapse, numerous transcripts are directly related to T-cell function and the control of differentiation. Butyrophilin is a co-regulator for T cell activation. Fibromodulin modulates the TGF-beta signaling pathway, a primary determinant of Tre differentiation. Further impact on the TGF-beta pathway is reflected in concurrent changes in the BMP receptor 1B RNA (BMPR1B), because the bone morphogenic proteins are members of the TGF-beta superfamily, and likewise impact Treg differentiation. Several of the transcripts (TMEM98, NRCAM, SFRP5, SHISA2) are elements of the Wnt signaling pathway, which is a major determinant of Treg differentiation.
=== Other ===
Endometriosis in females under the age of 40.
Depression and hostility appear to be risks.
The number of categories of adverse childhood experiences (psychological, physical, or sexual abuse; violence against mother; or living with household members who used substances, mentally ill, suicidal, or incarcerated) showed a graded correlation with the presence of adult diseases including coronary artery (ischemic heart) disease.
Hemostatic factors: High levels of fibrinogen and coagulation factor VII are associated with an increased risk of CAD.
Low hemoglobin.
In the Asian population, the b fibrinogen gene G-455A polymorphism was associated with the risk of CAD.
Patient-specific vessel ageing or remodelling determines endothelial cell behaviour and thus disease growth and progression. Such 'hemodynamic markers' are patient-specific risk surrogates.
HIV is a known risk factor for developing atherosclerosis and coronary artery disease.
== Pathophysiology ==
Limitation of blood flow to the heart causes ischemia (cell starvation secondary to a lack of oxygen) of the heart's muscle cells. The heart's muscle cells may die from lack of oxygen and this is called a myocardial infarction (commonly referred to as a heart attack). It leads to damage, death, and eventual scarring of the heart muscle without regrowth of heart muscle cells. Chronic high-grade narrowing of the coronary arteries can induce transient ischemia which leads to the induction of a ventricular arrhythmia, which may terminate into a dangerous heart rhythm known as ventricular fibrillation, which often leads to death.
Typically, coronary artery disease occurs when part of the smooth, elastic lining inside a coronary artery (the arteries that supply blood to the heart muscle) develops atherosclerosis. With atherosclerosis, the artery's lining becomes hardened, stiffened, and accumulates deposits of calcium, fatty lipids, and abnormal inflammatory cells – to form a plaque. Calcium phosphate (hydroxyapatite) deposits in the muscular layer of the blood vessels appear to play a significant role in stiffening the arteries and inducing the early phase of coronary arteriosclerosis. This can be seen in a so-called metastatic mechanism of calciphylaxis as it occurs in chronic kidney disease and hemodialysis. Although these people have kidney dysfunction, almost fifty percent of them die due to coronary artery disease. Plaques can be thought of as large "pimples" that protrude into the channel of an artery, causing partial obstruction to blood flow. People with coronary artery disease might have just one or two plaques or might have dozens distributed throughout their coronary arteries. A more severe form is chronic total occlusion (CTO) when a coronary artery is completely obstructed for more than 3 months.
Microvascular angina is a type of angina pectoris in which chest pain and chest discomfort occur without signs of blockages in the larger coronary arteries of their hearts when an angiogram (coronary angiogram) is being performed.
The exact cause of microvascular angina is unknown. Explanations include microvascular dysfunction or epicardial atherosclerosis. For reasons that are not well understood, females are more likely than males to have it; however, hormones and other risk factors unique to females may play a role.
== Diagnosis ==
The diagnosis of CAD depends largely on the nature of the symptoms and imaging. The first investigation when CAD is suspected is an electrocardiogram (ECG/EKG), both for stable angina and acute coronary syndrome. An X-ray of the chest, blood tests and resting echocardiography may be performed.
For stable symptomatic patients, several non-invasive tests can diagnose CAD depending on pre-assessment of the risk profile. Noninvasive imaging options include; Computed tomography angiography (CTA) (anatomical imaging, best test in patients with low-risk profile to "rule out" the disease), positron emission tomography (PET), single-photon emission computed tomography (SPECT)/nuclear stress test/myocardial scintigraphy and stress echocardiography (the three latter can be summarized as functional noninvasive methods and are typically better to "rule in"). Exercise ECG or stress test is inferior to non-invasive imaging methods due to the risk of false negative and false positive test results. The use of non-invasive imaging is not recommended on individuals who are exhibiting no symptoms and are otherwise at low risk for developing coronary disease. Invasive testing with coronary angiography (ICA) can be used when non-invasive testing is inconclusive or show a high event risk.
The diagnosis of microvascular angina (previously known as cardiac syndrome X – the rare coronary artery disease that is more common in females, as mentioned, is a diagnosis of exclusion. Therefore, usually, the same tests are used as in any person suspected of having coronary artery disease:
Intravascular ultrasound
Magnetic resonance imaging (MRI)
=== Stable angina ===
Stable angina is the most common manifestation of ischemic heart disease, and is associated with reduced quality of life and increased mortality. It is caused by epicardial coronary stenosis which results in reduced blood flow and oxygen supply to the myocardium.
Stable angina is short-term chest pain during physical exertion caused by an imbalance between myocardial oxygen supply and metabolic oxygen demand. Various forms of cardiac stress tests may be used to induce both symptoms and detect changes by way of electrocardiography (using an ECG), echocardiography (using ultrasound of the heart) or scintigraphy (using uptake of radionuclide by the heart muscle). If part of the heart seems to receive an insufficient blood supply, coronary angiography may be used to identify stenosis of the coronary arteries and suitability for angioplasty or bypass surgery.
In minor to moderate cases, nitroglycerine may be used to alleviate acute symptoms of stable angina or may be used immediately before exertion to prevent the onset of angina. Sublingual nitroglycerine is most commonly used to provide rapid relief for acute angina attacks and as a complement to anti-anginal treatments in patients with refractory and recurrent angina. When nitroglycerine enters the bloodstream, it forms free radical nitric oxide, or NO, which activates guanylate cyclase and in turn stimulates the release of cyclic GMP. This molecular signaling stimulates smooth muscle relaxation, resulting in vasodilation and consequently improved blood flow to heart regions affected by atherosclerotic plaque.
Stable coronary artery disease (SCAD) is also often called stable ischemic heart disease (SIHD). A 2015 monograph explains that "Regardless of the nomenclature, stable angina is the chief manifestation of SIHD or SCAD." There are U.S. and European clinical practice guidelines for SIHD/SCAD. In patients with non-severe asymptomatic aortic valve stenosis and no overt coronary artery disease, the increased troponin T (above 14 pg/mL) was found associated with an increased 5-year event rate of ischemic cardiac events (myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery).
=== Acute coronary syndrome ===
Diagnosis of acute coronary syndrome generally takes place in the emergency department, where ECGs may be performed sequentially to identify "evolving changes" (indicating ongoing damage to the heart muscle). Diagnosis is clear-cut if ECGs show elevation of the "ST segment", which in the context of severe typical chest pain is strongly indicative of an acute myocardial infarction (MI); this is termed a STEMI (ST-elevation MI) and is treated as an emergency with either urgent coronary angiography and percutaneous coronary intervention (angioplasty with or without stent insertion) or with thrombolysis ("clot buster" medication), whichever is available. In the absence of ST-segment elevation, heart damage is detected by cardiac markers (blood tests that identify heart muscle damage). If there is evidence of damage (infarction), the chest pain is attributed to a "non-ST elevation MI" (NSTEMI). If there is no evidence of damage, the term "unstable angina" is used. This process usually necessitates hospital admission and close observation on a coronary care unit for possible complications (such as cardiac arrhythmias – irregularities in the heart rate). Depending on the risk assessment, stress testing or angiography may be used to identify and treat coronary artery disease in patients who have had an NSTEMI or unstable angina.
=== Risk assessment ===
There are various risk assessment systems for determining the risk of coronary artery disease, with various emphasis on the different variables above. A notable example is Framingham Score, used in the Framingham Heart Study. It is mainly based on age, gender, diabetes, total cholesterol, HDL cholesterol, tobacco smoking, and systolic blood pressure. When predicting risk in younger adults (18–39 years old), the Framingham Risk Score remains below 10–12% for all deciles of baseline-predicted risk.
Polygenic score is another way of risk assessment. In one study the relative risk of incident coronary events was 91% higher among participants at high genetic risk than among those at low genetic risk.
== Prevention ==
Up to 90% of cardiovascular disease may be preventable if established risk factors are avoided. Prevention involves adequate physical exercise, decreasing obesity, treating high blood pressure, eating a healthy diet, decreasing cholesterol levels, and stopping smoking. Medications and exercise are roughly equally effective. High levels of physical activity reduce the risk of coronary artery disease by about 25%. Life's Essential 8 are the key measures for improving and maintaining cardiovascular health, as defined by the American Heart Association. AHA added sleep as a factor influencing heart health in 2022.
Most guidelines recommend combining these preventive strategies. A 2015 Cochrane Review found some evidence that counseling and education to bring about behavioral change might help in high-risk groups. However, there was insufficient evidence to show an effect on mortality or actual cardiovascular events.
In diabetes mellitus, there is little evidence that very tight blood sugar control improves cardiac risk although improved sugar control appears to decrease other problems such as kidney failure and blindness.
A 2024 study published in The Lancet Diabetes & Endocrinology found that the oral glucose tolerance test (OGTT) is more effective than hemoglobin A1c (HbA1c) for detecting dysglycemia in patients with coronary artery disease. The study highlighted that 2-hour post-load glucose levels of at least 9 mmol/L were strong predictors of cardiovascular outcomes, while HbA1c levels of at least 5.9% were also significant but not independently associated when combined with OGTT results.
=== Diet ===
A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death. Vegetarians have a lower risk of heart disease, possibly due to their greater consumption of fruits and vegetables. Evidence also suggests that the Mediterranean diet and a high fiber diet lower the risk.
The consumption of trans fat (commonly found in hydrogenated products such as margarine) has been shown to cause a precursor to atherosclerosis and increase the risk of coronary artery disease.
Evidence does not support a beneficial role for omega-3 fatty acid supplementation in preventing cardiovascular disease (including myocardial infarction and sudden cardiac death).
=== Secondary prevention ===
Secondary prevention is preventing further sequelae of already established disease. Effective lifestyle changes include:
Weight control
Smoking cessation
Avoiding the consumption of trans fats (in partially hydrogenated oils)
Decreasing psychosocial stress
Exercise
Aerobic exercise, like walking, jogging, or swimming, can reduce the risk of mortality from coronary artery disease. Aerobic exercise can help decrease blood pressure and the amount of blood cholesterol (LDL) over time. It also increases HDL cholesterol.
Although exercise is beneficial, it is unclear whether doctors should spend time counseling patients to exercise. The U.S. Preventive Services Task Force found "insufficient evidence" to recommend that doctors counsel patients on exercise but "it did not review the evidence for the effectiveness of physical activity to reduce chronic disease, morbidity, and mortality", only the effectiveness of counseling itself. The American Heart Association, based on a non-systematic review, recommends that doctors counsel patients on exercise.
Psychological symptoms are common in people with CHD. Many psychological treatments may be offered following cardiac events. There is no evidence that they change mortality, the risk of revascularization procedures, or the rate of non-fatal myocardial infarction.
Antibiotics for secondary prevention of coronary heart disease
Early studies suggested that antibiotics might help patients with coronary disease to reduce the risk of heart attacks and strokes. However, a 2021 Cochrane meta-analysis found that antibiotics given for secondary prevention of coronary heart disease are harmful to people with increased mortality and occurrence of stroke. So, antibiotic use is not currently supported for preventing secondary coronary heart disease.
=== Neuropsychological assessment ===
A thorough systematic review found that indeed there is a link between a CHD condition and brain dysfunction in females. Consequently, since research is showing that cardiovascular diseases, like CHD, can play a role as a precursor for dementia, like Alzheimer's disease, individuals with CHD should have a neuropsychological assessment.
== Treatment ==
There are a number of treatment options for coronary artery disease:
Lifestyle changes
Medical treatment – commonly prescribed drugs (e.g., cholesterol lowering medications, beta-blockers, nitroglycerin, calcium channel blockers, etc.);
Coronary interventions as angioplasty and coronary stent;
Coronary artery bypass grafting (CABG)
=== Medications ===
Statins, which reduce cholesterol, reduce the risk of coronary artery disease
Nitroglycerin
Calcium channel blockers and/or beta-blockers
Antiplatelet drugs such as aspirin
It is recommended that blood pressure typically be reduced to less than 140/90 mmHg. The diastolic blood pressure should not be below 60 mmHg. Beta-blockers are recommended first line for this use.
==== Aspirin ====
In those with no previous history of heart disease, aspirin decreases the risk of a myocardial infarction but does not change the overall risk of death. Aspirin therapy to prevent heart disease is thus recommended only in adults who are at increased risk for cardiovascular events, which may include postmenopausal females, males above 40, and younger people with risk factors for coronary heart disease, including high blood pressure, a family history of heart disease, or diabetes. The benefits outweigh the harms most favorably in people at high risk for a cardiovascular event, where high risk is defined as at least a 3% chance over five years, but others with lower risk may still find the potential benefits worth the associated risks.
==== Anti-platelet therapy ====
Clopidogrel plus aspirin (dual anti-platelet therapy) reduces cardiovascular events more than aspirin alone in those with a STEMI. In others at high risk but not having an acute event, the evidence is weak. Specifically, its use does not change the risk of death in this group. In those who have had a stent, more than 12 months of clopidogrel plus aspirin does not affect the risk of death.
=== Surgery ===
Revascularization for acute coronary syndrome has a mortality benefit. Percutaneous revascularization for stable ischaemic heart disease does not appear to have benefits over medical therapy alone. In those with disease in more than one artery, coronary artery bypass grafts appear better than percutaneous coronary interventions. Newer "anaortic" or no-touch off-pump coronary artery revascularization techniques have shown reduced postoperative stroke rates comparable to percutaneous coronary intervention. Hybrid coronary revascularization has also been shown to be a safe and feasible procedure that may offer some advantages over conventional CABG though it is more expensive.
== Epidemiology ==
As of 2010, CAD was the leading cause of death globally resulting in over 7 million deaths. This increased from 5.2 million deaths from CAD worldwide in 1990. It may affect individuals at any age but becomes dramatically more common at progressively older ages, with approximately a tripling with each decade of life. Males are affected more often than females.
The World Health Organization reported that: "The world's biggest killer is ischemic heart disease, responsible for 13% of the world's total deaths. Since 2000, the largest increase in deaths has been for this disease, rising by 2.7 million to 9.1 million deaths in 2021."
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.
Coronary artery disease is the leading cause of death for both males and females and accounts for approximately 600,000 deaths in the United States every year. According to present trends in the United States, half of healthy 40-year-old males will develop CAD in the future, and one in three healthy 40-year-old females. It is the most common reason for death of males and females over 20 years of age in the United States.
After analysing data from 2 111 882 patients, the recent meta-analysis revealed that the incidence of coronary artery diseases in breast cancer survivors was 4.29 (95% CI 3.09–5.94) per 1000 person-years.
== Society and culture ==
=== Names ===
Other terms sometimes used for this condition are "hardening of the arteries" and "narrowing of the arteries". In Latin it is known as morbus ischaemicus cordis (MIC).
=== Support groups ===
The Infarct Combat Project (ICP) is an international nonprofit organization founded in 1998 which tries to decrease ischemic heart diseases through education and research.
=== Industry influence on research ===
In 2016 research into the internal documents of the Sugar Research Foundation, the trade association for the sugar industry in the US, had sponsored an influential literature review published in 1965 in the New England Journal of Medicine that downplayed early findings about the role of a diet heavy in sugar in the development of CAD and emphasized the role of fat; that review influenced decades of research funding and guidance on healthy eating.
== Research ==
Research efforts are focused on new angiogenic treatment modalities and various (adult) stem-cell therapies. A region on chromosome 17 was confined to families with multiple cases of myocardial infarction. Other genome-wide studies have identified a firm risk variant on chromosome 9 (9p21.3). However, these and other loci are found in intergenic segments and need further research in understanding how the phenotype is affected.
A more controversial link is that between Chlamydophila pneumoniae infection and atherosclerosis. While this intracellular organism has been demonstrated in atherosclerotic plaques, evidence is inconclusive regarding whether it can be considered a causative factor. Treatment with antibiotics in patients with proven atherosclerosis has not demonstrated a decreased risk of heart attacks or other coronary vascular diseases.
Myeloperoxidase has been proposed as a biomarker.
Plant-based nutrition has been suggested as a way to reverse coronary artery disease, but strong evidence is still lacking for claims of potential benefits.
Several immunosuppressive drugs targeting the chronic inflammation in coronary artery disease have been tested.
== See also ==
Mental stress-induced myocardial ischemia
== References ==
== External links ==
Risk Assessment of having a heart attack or dying of coronary artery disease, from the American Heart Association.
"Coronary Artery Disease". MedlinePlus. U.S. National Library of Medicine.
Norman J (7 October 2019). "Managing Diabetes with Blood Glucose Control". Endocrineweb. | Wikipedia/Ischemic_heart_disease |
Low-level laser therapy (LLLT), cold laser therapy or photobiomodulation (PBM) is a medical treatment approach that applies low-level (low-power) lasers or light-emitting diodes (LEDs) to the surface of the body. Whereas high-power lasers are used in laser medicine to cut or destroy tissue, it is claimed that application of low-power lasers stimulates healing, relieves pain, and enhances cell function. Described sometimes as Low-level Red-light Therapy (LLRL), has effects that appear to be limited to a specified set of wavelengths. The effectiveness of red light therapy for treating various conditions is still under investigation. Repeated low level red light therapy may be effective for controlling myopia in children. Several such devices are cleared by the United States Food and Drug Administration (FDA), and low level red light therapy is being tested for treating a range of medical problems including rheumatoid arthritis and oral mucositis.
== Mechanism ==
Research is ongoing about the mechanism of LLLT. The effects of LLLT appear to be limited to a specified set of wavelengths of laser, and administering LLLT below the dose range does not appear to be effective. Photochemical reactions are well known in biological research, and LLLT make use of the first law in photochemistry (Grotthuss-Draper law): light must be absorbed by a chemical substance in order for a photochemical reaction to take place. In LLLT that chemical substance is represented by the respiratory enzyme cytochrome c oxidase which is involved in the electron transport chain in mitochondria, which is the generally accepted theory.
== Medical uses ==
Various LLLT devices have been promoted for use in treatment of several musculoskeletal conditions including carpal tunnel syndrome (CTS), fibromyalgia, osteoarthritis, and rheumatoid arthritis. They have also been promoted for temporomandibular joint disorders, wound healing, smoking cessation, and tuberculosis. LLLT appears to be effective for preventing oral mucositis in recipients of a stem cell transplant with chemotherapy. In other areas, evidence for LLLT remains conflicted. Some studies suggest that LLLT may be modestly effective in relieving short-term pain for rheumatoid arthritis, osteoarthritis, chronic low back pain, acute and chronic neck pain, tendinopathy, and chronic joint disorders. The evidence for LLLT being useful in dentistry, and in the treatment of wound healing is unclear.
Concerns have been raised in the literature about brain stimulation techniques that rely upon low-level (low-power) lasers and light-emitting diodes (LEDs). The transcranial photobiomodulation or transcranial low level light therapy is limited in neuromodulation due to several reasons:
An excessive dose of radiation can be harmful. Therefore, at adequate doses of light there may be stimulation of growth, but at high doses excessive singlet oxygen may be produced and its chemical action may be harmful to cells.
Regarding LED light therapy, this neurostimulation method based on the light-emitting diodes stimulation cannot pass through the skin, only laser can penetrate deeper tissues and stimulate brain areas accordingly. The penetration depth of white light and LED light into the skin increases with increasing wavelength from the UV to the visible light range, and then decreases again in the IR range depending on the selected optical properties. This depth further increases if the thickness of the stratum corneum decreases. Broadband polychromatic light (white light) and LED radiation can only penetrate 0.0017 mm to 5 mm of tissue. For example, research shows that at wavelengths of 450 nm and 650 nm only 1% of the light reaches approximately 1.6 mm and very little reaches 5 mm. Only laser radiation can propagate into deeper tissues.
Since the action spectrum for tissue regeneration and repair consist of more than one wavelength, laser and LED light sources may offer some disadvantages, destroying healthy cells. We still lack knowledge of mental processes at the cellular level. The link between neuronal activity and mental processes is still an intriguing research question and a problem in treatment targeting. Therefore, no one can be sure whether the laser beam only reaches the neuronal structures in the brain that need treatment. An undetermined dose of radiation and the target of radiation can destroy healthy cells during the treatment procedure.
There is not enough information from clinical trials to compare the effectiveness of different types of devices or device parameters (wavelengths, power output, session time, area of actuation).
=== Veterinary use ===
Veterinary clinics use cold laser devices to treat a wide variety of ailments, from arthritis to wounds, on dogs and cats. Very little research has been done on the effects of this treatment on animals. Brennen McKenzie, president of the Evidence-Based Veterinary Medicine Association, has stated that "research into cold laser in dogs and cats is sparse and generally low quality. Most studies are small and have minimal or uncertain controls for bias and error". While allowing that some studies show promising results, he reports that others do not. While believing that there is enough evidence to warrant further study, he concludes that there is not enough evidence to support routine clinical use of cold laser in animals.
== Contraindications ==
Based on the results of a systematic review, there is no evidence to suggest that people with cancer or people who are at risk of getting cancer should avoid photobiomodulation.
== Side effects ==
There are some reports of mild pain or skin irritation after red light therapy. The long term effects on the skin or on the hair are not known. Eye protection is suggested for some devices. For skin applications, different wavelengths of light may result in different 'biological effects' depending on the person's skin type, race, and ethnicity. Clinical guideline suggest that a dermatologist is consulted before undergoing treatment.
For safety, if a person chooses to use red light therapy, a device that has been approved for use on humans by the country the person lives in is recommended. For example, in the US, it is suggested to only use devices approved by the FDA for dermatologic application.
== Society and culture ==
=== History ===
Faroese physician Niels Finsen is believed to be the father of modern light therapy. He used red light to treat smallpox lesions. He received the Nobel Prize in Physiology or Medicine in 1903. Scientific evidence for some of his treatments is lacking, and later eradication of smallpox and development of antibiotics for tuberculosis rendered light therapy obsolete for these diseases.
Hungarian physician and surgeon Endre Mester (1903–1984) is credited with the discovery of the biological effects of low power lasers, which occurred a few years after the 1960 invention of the ruby laser and the 1961 invention of the helium–neon (HeNe) laser. Mester accidentally discovered that low-level ruby laser light could regrow hair during an attempt to replicate an experiment that showed that such lasers could reduce tumors in mice. The laser he was using was faulty and was not as powerful as he thought. It failed to affect the tumors, but he noticed that in the places where he had shaved the mice in order to do the experiments, the hair grew back more quickly on the treated mice than on those among the control group. He published those results in 1967. He went on to show that low level HeNe light could accelerate wound healing in mice.
By the 1970s, he was applying low level laser light to treat people with skin ulcers. In 1974, he founded the Laser Research Center at the Semmelweis Medical University in Budapest, and continued working there for the remainder of his life. His sons carried on his work and brought it to the United States. By 1987, companies selling lasers were claiming that they could treat pain, accelerate healing of sports injuries, and treat arthritis, but there was little evidence for this at that time. Mester originally called this approach "laser biostimulation'", but it soon became known as “low-level laser therapy" and with the adaptation of light emitting diodes by those studying this approach, it became known as "low-level light therapy", and to resolve confusion around the exact meaning of "low level", the term "photobiomodulation" arose.
=== Names ===
The following terms are accepted as alternatives of low level light therapy term: LLLT, laser biostimulation, laser phototherapy, low-level laser therapy, low-power laser irradiation, low-power laser therapy, and photobiomodulation therapy. The term photobiomodulation therapy is considered the preferred term by industry professionals. However LLLT has been marketed and researched under a number of other terms, including red light therapy, low-power laser therapy (LPLT), soft laser therapy, low-intensity laser therapy, low-energy laser therapy, cold laser therapy, bio-stimulation laser therapy, photo-biotherapy, therapeutic laser, and monochromatic infrared light energy (MIRE) therapy. More specific applications sometimes have their own terms, for example when administered to acupuncture points, the procedure is called laser acupuncture. When applied to the head, LLLT may be known as transcranial photobiomodulation, transcranial near-infrared laser therapy (NILT), or transcranial low level light therapy.
=== Government action ===
The FDA filed a complaint for injunction in 2014, alleging that company QLaser PMA were marketing their devices as being able to treat “over 200 different diseases and disorders,” including cancer, cardiac arrest, deafness, diabetes, HIV/AIDS, macular degeneration, and venereal disease. This case resulted in a permanent injunction against the manufacture, marketing, sale, and distribution of those devices in 2015.
In 2017, the owner of QLaser, Robert Lytle, and two of QLaser's distributors were charged with a criminal conspiracy to commit fraud. Lytle pleaded guilty to one count of conspiracy to introduce misbranded medical devices into interstate commerce with the intent to defraud and mislead, and one count of criminal contempt in January 2018. Lytle was sentenced to serve 12 years in prison and made an initial restitution payment of $637,000. Lytle's conspirators were sentenced to 24 months and 15 months, respectively.
=== Reimbursement ===
Blue Cross Blue Shield Association and Aetna provide coverage for the prevention of oral mucositis, but not any other reason. The Centers for Medicare and Medicaid Services does not provide coverage for LLLT. Cigna lists LLLT as "experimental, investigational, or unproven for any indication" and provides literature review summaries for a number of conditions.
== Research ==
=== Musculoskeletal ===
Evidence does not support a benefit in delayed-onset muscle soreness. It may be useful for muscle pain and injuries. A 2008 Cochrane Library review concluded that LLLT has insufficient evidence for treatment of nonspecific low back pain, a finding echoed in a 2010 review of chronic low back pain. A 2015 review found benefit in nonspecific chronic low-back pain. LLLT may be useful in the treatment of both acute and chronic neck pain. In 2013, however, a systematic review and meta-analysis of LLLT for neck pain indicated that the benefit was not of significant importance and that the evidence had a high risk of bias. In a study testing the efficacy of low-level laser therapy treating plantar fasciitis found that LLLT significantly reduces pain in lower extremity tendinopathy and plantar fasciitis in the short and medium terms. The same study also stated that while comparing the effect of LLLT to that of therapeutic ultrasound in persons with patellar tendinopathy, and they found a statistically significant effect in favour of LLLT, both on pain reduction and function.
There are tentative data that LLLT is useful in the short-term treatment of pain caused by rheumatoid arthritis, and possibly chronic joint disorders. Research that compared the effects of LLLT against other treatments, sham treatments, or no treatment at all, and randomized adult patients with rheumatoid arthritis to receive it were considered. These outcomes included pain, functional capacity, adverse events, inflammation, disease activity, range of motion, stiffness in the morning, muscle strength, and quality of life. The findings indicate that the differences between utilizing a sham and an infrared laser may be negligible or nonexistent in terms of pain, stiffness in the morning, grip strength, functional ability, inflammation, range of motion, disease activity, and side events. It was also discovered that the data about the effects of laser acupuncture against reflexology in terms of functional ability, quality of life, and inflammation is quite hazy, and about the effects of red laser versus sham in terms of pain, morning stiffness, and side events. The usefulness of red laser, laser acupuncture, and reflexology in the treatment of RA patients is not well enough demonstrated. A 2019 systematic review and meta-analysis found evidence for pain reduction in osteoarthritis. While it does not appear to improve pain in temporomandibular disorders, it may improve function.
There is tentative evidence of benefit in tendinopathy. A 2014 review found benefit in shoulder tendinopathy. A 2014 Cochrane review found tentative evidence that it may help in frozen shoulders.
=== Mouth ===
Similarly, the use of lasers to treat chronic periodontitis and to speed healing of infections around dental implants is suggested, but there is insufficient evidence to indicate a use superior to traditional practices. There is tentative evidence for dentin hypersensitivity. It does not appear to be useful for orthodontic pain LLLT might be useful for wisdom tooth extraction (complications).
=== Hair loss ===
LLLT has been studied as a treatment for hair loss; a review in 2012 found little evidence to support the use of lasers to treat hair loss. A 2014 review found tentative evidence for benefit for lasers, while another 2014 review concluded that the results were mixed, had a high risk of bias, and that its effectiveness was unclear. A 2015 review found tentative evidence of benefit. Additionally, a 2017 review of clinical trials found 10 of 11 trials reviewed "demonstrated significant improvement of androgenic alopecia in comparison to baseline or controls when treated with LLLT."
LLLT is shown to increase hair density and growth in both genders. The types of devices (hat, comb, helmet) and duration did not alter the effectiveness, with more emphasis to be placed on lasers compared to LEDs. Ultraviolet and infrared light are more effective for alopecia areata, while red light and infrared light is more effective for androgenetic alopecia.
Medical reviews suggest that LLLT is as effective or potentially more than other non invasive and traditional therapies such as minoxidil and finasteride but further studies such as RCTs, long term follow up studies, and larger double blinded trials need to be conducted to confirm the initial findings.
=== Brain injuries ===
LLLT has been studied for traumatic brain injury (TBI) and stroke among other conditions. When applied to the head it is known as transcranial photobiomodulation or transcranial low level light therapy.
=== Cancer treatment side effects ===
LLLT has been studied as a way to reduce pain and swelling in breast-cancer related lymphedema. The 2015 systematic review & meta-analysis by Smoot, Chiavola-Larson, et al found “Moderate-strength evidence supports LLLT in the management of [breast cancer related lymphoedema], with […] reductions in volume and pain immediately after conclusion of LLLT treatments. Greater reductions in volume [of lymph nodes or surrounding tissues] were found with the use of LLLT than in treatments without it.”
=== Stem cells ===
An ongoing area of research is the application of LLLT for increasing cell proliferation, including stem cells.
=== Wound healing ===
Low level laser therapy has been studied as a potential treatment for chronic wounds, and higher-power lasers have sometimes been successfully used to close acute wounds as an alternative to stitching. However, as of 2012 and due to inconsistent results and the low quality of extant research, reviews in the scientific literature have not supported its widespread application.
== See also ==
Blood irradiation therapy – Alternative medical procedure
Light therapy – Therapy involving intentional exposure to sunlight
Neurotechnology
Neurotherapy
Photomedicine – interdisciplinary field examining the effects of light on human healthPages displaying wikidata descriptions as a fallback
Photorejuvenation – Skin treatment
== References == | Wikipedia/Low_level_laser_therapy |
Androgen replacement therapy (ART), often referred to as testosterone replacement therapy (TRT), is a form of hormone therapy in which androgens, often testosterone, are supplemented or replaced. It typically involves the administration of testosterone through injections, skin creams, patches, gels, pills, or subcutaneous pellets. ART is often prescribed to counter the effects of male hypogonadism.
ART is also prescribed to lessen the effects or delay the onset of normal male aging. However, this is controversial and is the subject of ongoing clinical trials.
As men enter middle age they may notice changes caused by a relative decline in testosterone: fewer erections, fatigue, thinning skin, declining muscle mass and strength, and/or more body fat. Dissatisfaction with these changes causes some middle age men to seek ART. Androgen deficiencies in women have also, as of 2001, been recognized as a medical disorder that can be treated with ART. As with men, symptoms associated with androgen deficiency are most prevalent with age, and androgen replacement therapy has been shown to help with symptoms of menopause.
== Medical uses ==
=== Males ===
Androgen replacement is the classic treatment of hypogonadism. It is also used in men who have lost the ability to produce androgens due to disease or its treatment.
==== Diabetes ====
The risks of diabetes and of testosterone deficiency in men over 45 (i.e., hypogonadism, specifically hypoandrogenism) are strongly correlated. Testosterone replacement therapies have been shown to improve blood glucose management. Still, "it is prudent not to start testosterone therapy in men with diabetes solely for the purpose of improving metabolic control if they show no signs and symptoms of hypogonadism."
=== Females ===
Androgen replacement is used in postmenopausal women: the indications are to increase sexual desire; and to prevent or treat osteoporosis. Other symptoms of androgen deficiency are similar in both sexes, such as muscle loss and physical fatigue. The androgens used for androgen replacement in women include testosterone (and esters), prasterone (dehydroepiandrosterone; DHEA) (and the ester prasterone enanthate), methyltestosterone, nandrolone decanoate, and tibolone, among others.
== Adverse effects ==
The Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone have been established for low testosterone levels due to aging. The FDA has required that testosterone labels include warning information about the possibility of an increased risk of heart attacks and stroke.
=== Heart disease ===
On January 31, 2014, reports of strokes, heart attacks, and deaths in men taking testosterone-replacement led the FDA to announce that it would be investigating this issue. The FDA's action followed three peer-reviewed studies of increased cardiovascular events and deaths. Due to an increased rate of adverse cardiovascular events compared to a placebo group, a randomized trial stopped early. Also, in November 2013, a study reported an increase in deaths and heart attacks in older men. Concerns have been raised that testosterone was being widely marketed without the benefit of data on efficacy and safety from large randomized controlled trials. As a result of the "potential for adverse cardiovascular outcomes", the FDA announced, in September 2014, a review of the appropriateness and safety of testosterone replacement therapy. However, when given to men with hypogonadism in the short- and medium-term, testosterone replacement therapy does not increase the risk of cardiovascular events (including strokes and heart attacks and other heart diseases). The long-term safety of the therapy is not known yet.
=== Other ===
Other significant adverse effects of testosterone supplementation include acceleration of pre-existing prostate cancer growth in individuals who have undergone androgen deprivation; increased hematocrit, which can require venipuncture in order to treat; and, exacerbation of sleep apnea. A 2014 review said there was some evidence men with certain comorbidities may be at risk of adverse effects including sleep apnoea, metabolic syndrome and cardiovascular disease. Exogenous testosterone may also cause suppression of spermatogenesis, leading to, in some cases, infertility. It is recommended that physicians screen for prostate cancer with a digital rectal exam and prostate-specific antigen (PSA) level before starting therapy, and monitor PSA and hematocrit levels closely during therapy.
Some studies argue that ART increases the risk of prostate cancer, although the results are not conclusive.
== Methods of administration ==
There are several artificial androgens, many of which are manipulations of the testosterone molecule referred to as anabolic-androgenic steroids. Androgen replacement is administered by patch, tablet, capsule, cream or gel; or depot injections given into fat or muscle.
== Society and culture ==
=== MMA ===
Some UFC fighters used TRT until 2014 when the Nevada State Athletic Commission banned its use.
=== Regulation ===
As of September 2014, testosterone replacement therapy has been under review for appropriateness and safety by the Food and Drug Administration due to the "potential for adverse cardiovascular outcomes".
=== Frequency of use ===
In the United States usage increased from 0.5% in 2002 to 3.2% in 2013 and have since decreased to 1.7% in 2016.
A UK study in 2013 showed that prescriptions for testosterone replacement, particularly transdermal products, almost doubled between 2000 and 2010.
== Research ==
Testosterone is being investigated as therapy for the following conditions:
Erectile dysfunction
Osteoporosis
Diabetes mellitus
Chronic heart failure
Dementia, but the evidence base is small and the balance of benefit needs to be clarified
== See also ==
List of androgens/anabolic steroids available in the United States
Androgen deficiency
Masculinizing hormone therapy
Hormone replacement therapy
Feminizing hormone therapy
== References == | Wikipedia/Androgen_replacement_therapy |
An infrared sauna uses infrared heaters to emit infrared light experienced as radiant heat which is absorbed by the surface of the skin. Infrared saunas are popular in alternative therapies, where they are claimed to help with a number of medical issues including autism, cancer, and COVID-19, but these claims are entirely pseudoscientific. Traditional saunas differ from infrared saunas in that they heat the body primarily by conduction and convection from the heated air and by radiation of the heated surfaces in the sauna room whereas infrared saunas primarily use just radiation.
Infrared saunas are also used in Infrared Therapy and Waon Therapy; while there is a small amount of preliminary evidence that these therapies correlate with a number of benefits, including reduced blood pressure, increased heart rate and increased left ventricular function, there are several problems with linking this evidence to alleged health benefits.
== History ==
John Harvey Kellogg invented the use of radiant heat saunas with his incandescent electric light bath in 1891. He claimed that it stimulated healing in the body and in 1893 displayed his invention at the Chicago World's Fair. In 1896 the Radiant Heat Bath was patented by Kellogg and described in the patent as not depending on the heat in the air to heat the body but able to more quickly produce a sweat than traditional Turkish or Russian baths at a lower ambient temperature. The idea became popular, particularly in Germany where "Light Institutes" were set up. King Edward VII of England and Kaiser Wilhelm II of Germany both had radiant heat baths set up in their various palaces. The modern concept of the infrared sauna was revived in the 1970s in Japan as Waon (Japanese: "soothing warmth") Therapy and neonatal beds for newborns use infrared elements to keep the baby warm without being stifled.
== Description ==
Infrared saunas can be designed to look like traditional saunas but cheaper models can be in the form of a tent with an infrared element inside. Infrared saunas differ from other types of sauna such as traditional Finnish saunas mainly in the method of heat delivery. Far infrared light, which is emitted in an infrared sauna at a wavelength of around 10 μm, is felt directly by the body in the form of radiated heat without the need to heat the air around the body first. This results in a lower ambient air temperature allowing for longer sustained stays in the sauna. Infrared light also penetrates the body deeply resulting in a fast and vigorous sweat being produced. The average ambient temperature in an infrared sauna is usually 40–60 °C (104–140 °F) compared to 70–90 °C (158–194 °F) in traditional saunas.
== Effects ==
A 2009 literature review of research on far-infrared saunas (FIRS) concluded that there was limited moderate evidence supporting their efficacy in normalizing blood pressure and treating congestive heart failure. The review found fair evidence from a single study supporting FIRS therapy for chronic pain. They found fair evidence against claims that FIRS reduces cholesterol levels. They found weak evidence, from a single study, supporting FIRS therapy as treatment for obesity. All of the studies in the review were limited: they were small sample sizes, short duration, unvalidated symptom scales, and were conducted by the same core research group.
In February 2021 Steven Novella of Science-Based Medicine commented on the quality of studies in an article entitled "Infrared Saunas for 'Detoxification'" he stated that: Most of the mainstream attention is on the cardiovascular effects. Using a sauna does correlate with reduced blood pressure (in some, BP may also increase), increased heart rate, increased dermal perfusion with a reduction in organ perfusion, and increased left ventricular function and arterial flexibility. There are several problems with linking this evidence to alleged health benefits. First – these effects are all short term, during the sauna and for 30 minutes following. We don't know if there is any sustained change in cardiovascular function. Second, we don't know that these changes are improvements. This relates to the third issue, it is possible that at least most of these changes may simply be due to dehydration. Reduced blood volume from water loss (similar to a diuretic effect) will reduce the blood pressure and increase the heart rate, relaxing blood vessels to increase perfusion. So perhaps all we are seeing is a transient effect of the dehydration that accompanies using a sauna.
A 2018 systematic review and meta-analysis of nine clinical trials found that five weekly conventional sauna sessions for 2 to 4 weeks was associated with a significant reduction in brain natriuretic peptide (BNP; a marker of heart failure progression) and cardiothoracic ratio (an indicator of heart enlargement), and improved left-ventricular ejection fraction, but no significant effect on left-ventricular end-diastolic diameter, left atrial diameter, systolic blood pressure, or diastolic blood pressure. The review also rated the quality of evidence for these findings as moderate to insufficient, citing a risk of bias and imprecision as the reason for the low evidence rating. The evidence presented by the review supported a therapeutic effect of sauna bathing for heart failure patients but recommended that further studies were needed to be able to draw definitive conclusions.
A 2019 scientific survey found that most people use both infrared and traditional saunas for relaxation and that its use, 5 to 15 times per month, was associated with higher mental well-being.
== Use in alternative therapies ==
There are a number of claims made about the health effects of infrared saunas that are entirely based in pseudoscience and have no evidence to support them.
=== Claims of detoxification ===
Proponents of infrared saunas may, without evidence, advertise benefits of detoxification, or that infrared saunas detoxify to a greater extent than traditional saunas. Proponents of infrared saunas will often claim that because infrared light penetrates the body so deeply, it must detoxify better than other means of sweat induction. Infrared saunas do induce body warmth and sweat much more vigorously and at lower ambient temperatures than traditional saunas or exercise; this does not mean that they detoxify more efficiently, or at all. Sweating removes an insignificant amount of toxins from the body and can be counterproductive to the function of the body's actual detoxification system, the liver and kidneys. Producing more sweat reduces the amount of urine produced by the body, which may actually reduce toxin excretion.
=== Applications ===
Fire departments in Texas and Indiana have purchased infrared saunas under the premise that they will prevent cancer and that the firefighters will be able to sweat out inhaled pollutants. Alternative therapists such as naturopaths have advised the use of infrared saunas for the treatment of cancer and autism. Wellness clinics have recommended it to remove radiation and heavy metals from the body, as well as a preventative treatment for COVID-19. Gwyneth Paltrow has also been criticised by experts for recommending infrared saunas as a post COVID-19 treatment.
== See also ==
== References ==
== External links ==
Light therapeutics; a practical manual of phototherapy for the student and the practitioner, with special reference to the incandescent electric-light bath by Kellogg, John Harvey,1852-1943 | Wikipedia/Waon_therapy |
Urine therapy or urotherapy, (also urinotherapy, Shivambu, uropathy, or auto-urine therapy) in alternative medicine, and Amaroli in medieval hatha yoga, is the application of human urine for medicinal or cosmetic purposes, including drinking of one's own urine and massaging one's skin, or gums, with one's own urine. No scientific evidence exists to support any beneficial health claims of urine therapy.
== History ==
Though urine has been believed useful for diagnostic and therapeutic purposes in several traditional systems, and mentioned in some medical texts, auto-urine therapy as a system of alternative medicine was popularized by British naturopath John W. Armstrong in the early 20th century. Armstrong was inspired by his family's practice of using urine to treat minor stings and toothaches, by a metaphorical misreading of the Hebrew Biblical Proverb 5:15 "Drink waters out of thine own cistern, and running waters out of thine own well", and his own experience with ill-health that he treated with a 45-day fast "on nothing but urine and tap water". Starting in 1918, Armstrong prescribed urine therapy regimens that he devised for thousands of patients, and in 1944 he published The Water of Life: A Treatise on Urine Therapy, which became a founding document of the field.
Armstrong's book sold widely, and in India inspired the writing of Manav mootra (Gujarati: Urine therapy; 1959) by Gandhian social reformer Raojibhai Manibhai Patel, and many later works. These works often reference Shivambu Kalpa, a treatise on the pharmaceutical value of urine, as a source of the practice in the East. They also cite passing references to properties and uses of urine in Yogic-texts such as Vayavaharasutra by Bhadrabahu and Hatha Yoga Pradapika by Svatmarama; and Ayurvedic texts such as Sushruta Samhita, Bhava Prakasha and Harit. However, according to medical anthropologist Joseph Alter, the practices of sivambu (drinking one's own urine) and amaroli recommended by modern Indian practitioners of urine therapy are closer to the ones propounded by Armstrong than traditional ayurveda or yoga, or even the practices described in Shivambu Kalpa.
Urine therapy has also been combined with other forms of alternative medicine.
It was used by ancient Roman dentists to whiten teeth.
== Modern claims and findings ==
An exhaustive description of the composition of human urine was prepared for NASA in 1971. Urine is an aqueous solution of greater than 95% water. The remaining constituents are, in order of decreasing concentration: urea 9.3 g/L, chloride 1.87 g/L, sodium 1.17 g/L, potassium 0.750 g/L, creatinine 0.670 g/L and other dissolved ions, inorganic and organic compounds.
In China there is a Urine Therapy Association which claims thousand of members.
According to a BBC report, a Thai doctor promoting urine therapy said that Thai people had been practicing urophagia for a long time, but according to the Department of Thai Traditional and Alternative Medicine, there was no record of the practice. In 2022, Thawee Nanra, a self-proclaimed holy man from Thailand, was arrested by police; his followers were observed consuming his urine and feces which they believed to have healing properties.
Urinating on jellyfish stings is a common "folk remedy". This does not help with jellyfish stings, and can be counterproductive, activating nematocysts remaining at the site of the sting, making the pain worse. This is because nematocysts are triggered by the change in the concentration of solutes (e.g. salt), such as when freshwater or similarly-composed urine is applied to the site. The myth originated from the false idea that ammonia, urea, and other compounds in urine could break down the nematocysts: however, urine is much too low in concentration to have those effects.
Urine and urea have been claimed by some practitioners to have an anti-cancer effect, and urotherapy has been offered along with other forms of alternative therapy in some cancer clinics in Mexico. No well-controlled studies support this, and available scientific evidence does not support this theory.
In the Arabian Peninsula, bottled camel urine is sold by vendors as prophetic medicine. In 2015, Saudi police arrested a man for selling supposed "camel urine" that was actually his own.
In January 2022, Christopher Key, a spreader of COVID-19 misinformation, claimed that urine therapy is the antidote to the COVID-19 pandemic. Key also falsely claims that a 9-month research trial on urine therapy has been conducted. There is no scientific evidence supporting urine therapy as a cure for COVID-19.
Urea-containing creams are sold commercially for topical use, and contain synthetically produced urea rather than being derived from urine. Urea in very high concentrations is effective as a humectant and a keratolytic. Actual urine is too dilute to work well for this purpose.
== Health concerns ==
There is no scientific evidence of therapeutic use for untreated urine.
According to the American Cancer Society, "available scientific evidence does not support claims that urine or urea given in any form is helpful for cancer patients".
In 2016, the Chinese Urine Therapy Association was included on a list of illegal organizations by the Ministry of Civil Affairs. However, the Municipal Bureau of Civil Affairs in Wuhan said they had no jurisdiction over the association.
== See also ==
Conjugated estrogens, a hormone therapy medication manufactured by purification from horse urine
Fecal microbiota transplant
List of topics characterized as pseudoscience
List of unproven and disproven cancer treatments
Panchgavya, one of several uses of cow urine in Ayurveda
Urea-containing cream
Urinalysis, tests performed on urine for diagnostic purposes
Virgin boy egg, a traditional dish of Dongyang, Zhejiang, China in which eggs are boiled in the urine of young boys
== Notes ==
== References ==
== Further reading ==
"Urine therapy", Martin Gardner, Skeptical Inquirer, May–June 1999. | Wikipedia/Urine_therapy |
Speech–language pathology, also known as speech and language pathology or logopedics, is a healthcare and academic discipline concerning the evaluation, treatment, and prevention of communication disorders, including expressive and mixed receptive-expressive language disorders, voice disorders, speech sound disorders, speech disfluency, pragmatic language impairments, and social communication difficulties, as well as swallowing disorders across the lifespan. It is an allied health profession regulated by professional bodies including the American Speech-Language-Hearing Association (ASHA) and Speech Pathology Australia. The field of speech-language pathology is practiced by a clinician known as a speech–language pathologist (SLP) or a speech and language therapist (SLT). SLPs also play an important role in the screening, diagnosis, and treatment of autism spectrum disorder (ASD), often in collaboration with pediatricians and psychologists.
== History ==
The development of speech-language pathology into a profession took different paths in the various regions of the world. Three identifiable trends influenced the evolution of speech-language pathology in the United States during the late 19th century to early 20th century: the elocution movement, scientific revolution, and the rise of professionalism. Groups of "speech correctionists" formed in the early 1900s. The American Academy of Speech Correction was founded in 1925, which became ASHA in 1978.
== Profession ==
Speech–language pathologists (SLPs) provide a wide range of services, mainly on an individual basis, but also as support for families, support groups, and providing information for the general public. SLPs work to assess levels of communication needs, make diagnoses based on the assessments, and then treat the diagnoses or address the needs. Speech/language services begin with initial screening for communication or swallowing disorders and continue with assessment and diagnosis, consultation for the provision of advice regarding management, intervention, and treatment, and providing counseling and other followup services for these disorders. Services are provided in the following areas:
Developmental language and early feeding neurodevelopment and prevention;
Cognitive aspects of communication (e.g., attention, memory, problem-solving, executive functions);
Speech (phonation, articulation, fluency, resonance, and voice including aeromechanical components of respiration);
Language (phonology, morphology, syntax, semantics, and pragmatic/social aspects of communication) including comprehension and expression in oral, written, graphic, and manual modalities; language processing; preliteracy and language-based literacy skills, phonological awareness;
Augmentative and alternative communication (AAC) for individuals with severe language and communication impairments;
Swallowing or other upper aerodigestive functions such as infant feeding and aeromechanical events (evaluation of esophageal function is for the purpose of referral to medical professionals);
Voice (hoarseness, dysphonia), poor vocal volume (hypophonia), abnormal (e.g., rough, breathy, strained) vocal quality. Research demonstrates voice therapy to be especially helpful with certain patient populations; individuals with Parkinson's Disease often develop voice issues as a result of their disease.
Sensory awareness related to communication, swallowing, or other upper aerodigestive functions.
Speech, language, and swallowing disorders result from a variety of causes, such as a stroke, brain injury, hearing loss, developmental delay, a cleft palate, cerebral palsy, or emotional issues.
A common misconception is that speech–language pathology is restricted to the treatment of articulation disorders (e.g., helping English-speaking individuals enunciate the traditionally difficult r) or the treatment of individuals who stutter but, in fact, speech–language pathology is concerned with a broad scope of speech, language, literacy, swallowing, and voice issues involved in communication, some of which include:
Word-finding and other semantic issues, either as a result of a specific language impairment (SLI) such as a language delay or as a secondary characteristic of a more general issue such as dementia.
Social communication difficulties involving how people communicate or interact with others (pragmatics).
Language impairments, including difficulties creating sentences that are grammatical (syntax) and modifying word meaning (morphology).
Literacy impairments (reading and writing) related to the letter-to-sound relationship (phonics), the word-to-meaning relationship (semantics), and understanding the ideas presented in a text (reading comprehension).
Voice difficulties, such as a raspy voice, a voice that is too soft, or other voice difficulties that negatively impact a person's social or professional performance.
Cognitive impairments (e.g. attention, memory, executive function) to the extent that they interfere with communication.
Parent, caregiver, and other communication partner coaching.
Primary pediatric speech and language disorders include: receptive and expressive language disorders, speech sound disorders, childhood apraxia of speech (CAS), stuttering, and language-based learning disabilities. Speech-language pathologists (SLPs) work with people of all ages.
Swallowing disorders include difficulties in any phase of the swallowing process (i.e., oral, pharyngeal, esophageal), as well as functional dysphagia and feeding disorders. Swallowing disorders can occur at any age and can stem from multiple causes.
=== Multi-discipline collaboration ===
SLPs collaborate with other health care professionals, often working as part of a multidisciplinary team. They can provide information and referrals to audiologists, physicians, dentists, nurses, nurse practitioners, occupational therapists, rehabilitation psychologists, dietitians, educators, behavior consultants (applied behavior analysis), and parents as dictated by the individual client's needs. For example, the treatment for patients with cleft lip and palate often requires multidisciplinary collaboration. Speech–language pathologists can be very beneficial in helping resolve speech problems associated with cleft lip and palate. Research has indicated that children who receive early language intervention are less likely to develop compensatory error patterns later in life, although speech therapy outcomes are usually better when surgical treatment is performed earlier. Another area of collaboration relates to auditory processing disorders, where SLPs can collaborate in assessments and provide intervention where there is evidence of speech, language, and/or other cognitive-communication disorders.
=== Working environments ===
SLPs work in a variety of clinical and educational settings. SLPs work in public and private hospitals, private practices, skilled nursing facilities (SNFs), long-term acute care (LTAC) facilities, hospice, and home healthcare. SLPs may also work as part of the support structure in the education system, working in both public and private schools, colleges, and universities. Some SLPs also work in community health, providing services at prisons and young offenders' institutions or providing expert testimony in applicable court cases.
Following ASHA's 2005 approval of the delivery of speech/language services via video conference or telepractice, SLPs in the United States have begun to use this service model.
Children with speech, language, and communication needs (SLCN) are particularly at risk of not being heard because of communication challenges. Speech-language pathologists (SLPs) can explain the significance of supporting communication as a tool for the child to shape and influence choices available to them in their lives, even though it is advised that children with SLCN can and should be actively involved as equal partners in decision-making about their communication needs. Building these skills is especially crucial for SLPs working in settings related to traditional education.
=== Research ===
SLPs conduct research related to communication sciences and disorders, swallowing disorders, or other upper aerodigestive functions.
Experimental, empirical, and scientific methodologies that build on hypothesis testing and logical, deductive reasoning have dominated research in speech-language pathology. Other types of research in the field are complemented by qualitative research.
=== Education and training ===
==== United States ====
In the United States, speech–language pathologists must hold a master's degree from an ASHA-accredited program. Following graduation and passing a nation-wide board exam, SLPs typically begin their Clinical Fellowship Year, during which they are granted a provisional license and receive guidance from their supervisor. At the end of this process, SLPs may choose to apply for ASHA's Certificate of Clinical Competence and apply for full state licensure. SLPs may additionally choose to earn advanced degrees such as a clinical doctorate in speech–language pathology, PhD, or EdD.
== Methods of assessment ==
Many approaches exist to assess language, communication, speech and swallowing. Two main aspects of assessment can be to determine the extent of breakdown (impairment-level), or how communication can be supported (functional level). When evaluating impairment-based level of breakdown, therapists are trained to use a cognitive neuropsychological approach to assessment, to precisely determine what aspect of communication is impaired. Some therapists use assessments that are based on historic anatomical models of language, that have since been shown to be unreliable. These tools are often preferred by therapists working within a medical model, where medics request a 'type' of impairment, and a 'severity' rating. The broad tools available allow clinicians to precisely select the aspect of communication that they wish to assess.
Because school-based speech therapy is run under state guidelines and funds, the process of assessment and qualification is more strict. To qualify for in-school speech therapy, students must meet the state's criteria on language testing and speech standardization. Due to such requirements, some students may not be assessed in an efficient time frame or their needs may be undermined by criteria. For a private clinic, students are more likely to qualify for therapy because it is a paid service with more availability.
== Clients and patients ==
Speech–language pathologists work with clients and patients who may present with a wide range of issues.
=== Infants and children ===
Premature infants are at higher risk of feeding and later language needs and SLTS work with this cohort to prevent developmental difficulties and support neonatal care
Infants with injuries due to complications at birth, feeding and swallowing difficulties, including dysphagia
Children with mild, moderate or severe:
Genetic disorders that adversely affect speech, language or cognitive development including cleft palate, Down syndrome, DiGeorge syndrome
Attention deficit hyperactivity disorder
Autism spectrum disorders, including Asperger syndrome
Developmental delay
Feeding disorders, including oral motor deficits
Cranial nerve damage
Hearing loss
Craniofacial anomalies that adversely affect speech, language or cognitive development
Language delay
Specific language impairment
Specific difficulties in producing sounds, called articulation disorders, (including vocalic /r/ and lisps)
Pediatric traumatic brain injury
Developmental verbal dyspraxia
Cleft palate
==== United States ====
In the US, some children are eligible to receive speech therapy services, including assessment and lessons through the public school system. If not, private therapy is readily available through personal lessons with a qualified speech–language pathologist or the growing field of telepractice. Teleconferencing tools such as Skype are being used more commonly as a means to access remote locations in private therapy practice, such as in the geographically diverse south island of New Zealand. More at-home or combination treatments have become readily available to address specific types of articulation disorders. The use of mobile applications in speech therapy is also growing as an avenue to bring treatment into the home.
==== United Kingdom ====
In the UK, children are entitled to an assessment by local NHS speech- and language-therapy teams, usually after referral by health visitors or education settings, but parents are also entitled to request an assessment directly. If treatment is appropriate, an educational plan will be drawn up. Speech therapists often play a role in multi-disciplinary teams when a child has speech delay or disorder as part of a wider health condition. The Children's Commissioner for England reported in June 2019 that there was a postcode lottery; £291.65 a year per head was spent on services in some areas, while the budget in some areas was £30.94 or less. In 2018, 193,971 children in English primary schools were on the special educational needs register needing speech-therapy services.
Speech and language therapists work in acute settings and are often
integrated into the MDT in multiple areas of speciality for neonatal, children and adult services. Areas include but not limited to; neonatal care, respiratory, ENT, gastrointestinal, stroke, Neurology,ICU, oncology and geriatric care
=== Children and adults ===
=== Adults ===
Adults with aphasia
Adults with mild, moderate, or severe eating, feeding and swallowing difficulties, including dysphagia
Adults recovering from significant tumors in the bronchus, lung, oropharynx, breast, and brain
Adults with mild, moderate, or severe language difficulties as a result of:
Motor neuron diseases,
Alzheimer's disease,
Dementia,
Huntington's disease,
Hearing loss
Multiple sclerosis,
Parkinson's disease,
Traumatic brain injury,
Mental health issues
Stroke
Progressive neurological conditions such as cancer of the head, neck and throat (including laryngectomy)
Aphasic
Adults seeking transgender-specific voice training, including voice feminization and voice masculinization
== See also ==
== References ==
== Further reading ==
Fisher, S. E.; Scharff, C. (April 2009). "FOXP2 as a molecular window into speech and language". Trends in Genetics. 25 (4): 166–77. doi:10.1016/j.tig.2009.03.002. hdl:11858/00-001M-0000-0012-CA31-7. PMID 19304338.
"Discussion Meeting Issue 'Language in developmental and acquired disorders: converging evidence for models of language representation in the brain' - Table of Contents". Royal Society Publishing. 2014. Retrieved 31 December 2013.
Nelson, H. D. (1 February 2006). "Screening for Speech and Language Delay in Preschool Children: Systematic Evidence Review for the US Preventive Services Task Force". Pediatrics. 117 (2): e298 – e319. doi:10.1542/peds.2005-1467. PMID 16452337.
Howell, Peter (2011). Recovery from stuttering. New York: Psychology Press / Taylor Francis Group. ISBN 978-1-84872-916-2. OCLC 814245820.
Janes, Tina Leann; Zupan, Barbra; Signal, Tania (February 2021). "Community awareness of speech pathology: A regional perspective". Australian Journal of Rural Health. 29 (1): 61–70. doi:10.1111/ajr.12680. ISSN 1038-5282. PMID 33274537.
== External links ==
American Speech–Language–Hearing Association (ASHA) – Communication for a Lifetime
National Institutes of Health – Voice, Speech, and Language
The Royal College of Speech and Language Therapists
Speech-Language Pathologists – O*Net Online | Wikipedia/Speech_therapy |
Step therapy, also called step protocol or a fail first requirement, is a managed care approach to prescription. It is a type of prior authorization requirement that is intended increase insurance company profits at the expense of patient health by forcing patients onto lower cost prescription drugs. The practice begins medication for a medical condition with the most cost-effective drug therapy and progresses to other more costly or risky therapies only if necessary.
The increase in prescription drug prices in the United States has increased the pressure on health care providers to keep down the cost of prescription medication while maintaining high levels of availability to the patient. The use of generic drugs whenever possible allows health care plans to pursue both goals effectively.
Physicians and managed care providers may disagree on the proper step therapy, and patients are encouraged to become knowledgeable in managing their own care.
== Opponents ==
Opponents of step therapy, such as Fail First Hurts, have detailed the pitfalls of step therapy. "Fail First is used by health insurers to control costs. It is time-consuming from a physician and patient standpoint, is more expensive from a direct and indirect out-of-pocket cost perspective, denies patients the drugs they need when they need them, and allows payers to practice medicine without a license." They claim that it also has the following disadvantages:
Creating additional barriers, leading people to forgo needed medications
Possibly causing patients' medical conditions to deteriorate, increasing the need for later medical intervention in the future, thus making patients require increasingly-costly medical care
Increasing frustration and incidents of depression
Increasing the risk of non-compliance and self-medication
== See also ==
Health care in the United States
Prescription drug
Prescription drug prices in the United States
== References ==
== Further reading ==
The Academy of Managed Care Pharmacy - Hosting the Journal of Managed Care & Specialty Pharmacy
The Academy of Managed Care Pharmacy's Concepts in Managed Care Pharmacy: Prior Authorization | Wikipedia/Step_therapy |
Human interaction with cats relates to the hundreds of millions of cats that are kept as pets around the world. The inter-relationship involves companionship, communication and caregiving. Dating back thousands of years, cats were originally domesticated for their ability to control pests and later became valued companions. Cats communicate through vocalizations, body language and behaviors, forming strong bonds with their human owners. Owners provide the food, shelter, and medical care, while play and enrichment activities stimulate their physical and mental well-being. Despite their independent nature, cats enjoy human company and require understanding of their unique behaviours. Positive reinforcement training can shape desired behaviours, fostering a harmonious relationship between humans and their feline companions, built on mutual respect and affection.
== Pets ==
Cats are common pets in all continents of the world permanently inhabited by humans, and their global population is difficult to ascertain, with estimates ranging from anywhere between 200 million to 600 million.
In 1998 there were around 76 million cats in Europe, 7 million in Japan and 3 million in Australia.: 4 A 2007 report stated that about 37 million US households owned cats, with an average of 2.2 cats per household giving a total population of around 82 million; in contrast, there are about 72 million pet dogs in that country. Cats exceeded dogs in number as pets in the United States in 1985 for the first time, in part because the development of cat litter in the mid-20th century eliminated the unpleasantly powerful smell of cat urine.
A 2007 Gallup poll reported that men and women in the United States of America were equally likely to own a cat. The ratio of pedigree/purebred cats to random-bred cats varies from country to country. However, generally speaking, purebreds are less than 10% of the total population.
As of 2021 in the United States, human owners of cats typically keep cats indoors at all times. In typically rural settings, cats oftentimes live outside and are used as a deterrent to rodents, snakes, and other pests. In the United Kingdom most cats go outdoors from time to time, with 26% being indoors at all times.
The compulsive hoarding of cats, a symptom of obsessive compulsive disorder (OCD), has long been associated with "cat ladies" although there is no evidence that older women are more likely than other people to hoard cats.
== Fur ==
According to the Humane Society of the United States, as well as being kept as pets, cats are also used in the international fur trade. Cat fur is used in coats, gloves, hats, shoes, blankets and stuffed toys. About 24 cats are needed to make a cat fur coat. This use has now been outlawed in several countries, including the United States, Australia and the European Union countries. However, despite being outlawed, some cat furs are still made into blankets in Switzerland as folk remedies that are believed to help rheumatism.
== Pest control ==
Cats, as with the traditional farm cat and ship's cat, are also used for pest control, particularly in the case of rat or mouse infestation. As such, they are sometimes referred to as a "mouser", and in the United Kingdom there has been one at Number 10 since the 1500s (officially titled 'Chief Mouser to the Cabinet Office' since 2011; additional duties include "greeting guests to the house, inspecting security defences, and testing antique furniture for napping quality").
== Domesticated varieties ==
The current list of cat breeds is quite large, with the US Cat Fanciers' Association recognizing 41 breeds, of which 16 are "natural breeds" that probably emerged before humans began breeding pedigree cats, while the others were developed over the latter half of the 20th century. Because of common crossbreeding, many cats are simply identified as belonging to the homogeneous breeds of domestic longhair and domestic shorthair, depending on their type of fur.
== Effects on human health ==
Because of their small size, domesticated house cats pose little physical danger to adult humans. However, in the US cats inflict about 400,000 bites per year that result in emergency room visits, at least 10% of which are bites from cats that were unprovoked. This number represents about one in ten of all animal bites. Cat bites may become infected, sometimes with serious consequences such as cat-scratch disease, or, very rarely, rabies. Cats may also pose a danger to pregnant women and immunosuppressed individuals, since their feces, in rare cases, can transmit toxoplasmosis. A large percentage of cats are infected with this parasite, with infection rates ranging from around 40 to 60% in both domestic and stray cats worldwide. Research indicates a correlation between the parasite Toxoplasma gondii, which sexually reproduces exclusively in cats, and numerous human psychiatric conditions, including OCD.
Allergic reactions to cats are relatively common, happening in as many as every 3 in 10 Americans. The major allergen, Fel d 1, is found in the saliva and/or dander of all cat breeds. There have been attempts to breed hypoallergenic cats, which would be less likely to provoke an allergic reaction. Some humans who are allergic to cats—typically manifested by hay fever, asthma, or a skin rash—quickly acclimate themselves to a particular animal and live comfortably in the same house with it, while retaining an allergy to cats in general. Whether the risk of developing allergic diseases such as asthma is increased or decreased by cat ownership is uncertain. Some owners cope with this problem by taking allergy medicine, along with bathing their cats frequently, since weekly bathing will reduce the amount of dander shed by a cat.
As well as posing health risks, interactions with cats may improve health and reduce physical responses to stress: for example the presence of cats may moderately decrease blood pressure. Cat ownership may also improve psychological health by providing emotional support and dispelling feelings of depression, anxiety and loneliness.: 23–56 Their ability to provide companionship and friendship are common reasons given for owning a cat.
From another point of view, cats are thought to be able to improve the general mood of their owners by alleviating negative attitudes. According to a Swiss study carried out in 2003, cats may change the overall psychological state of their owner as their company's effect appears to be comparable to that of a human partner. The researchers concluded that, while cats were not shown to promote positive moods, they do alleviate negative ones.
One study found that cat ownership is associated with a reduced risk of heart attacks and strokes at the 95% confidence interval.
Several studies have shown that cats develop affection towards their owners. However, the effect of these pets on human health is closely related to the time and effort the cat owner is able to invest in it, in terms of bonding and playing.
Ailurophobia is a rare animal phobia affecting humans characterized by the persistent and excessive fear or hate of cats. The exact cause of ailurophobia is unknown and potential treatment usually involves therapy. The case of Stephen Bouquet is a classic example of ailurophobia.
=== Therapy cats ===
Some cats, called "therapy cats" are trained to help ailing humans in a medically beneficial way to take advantage of the human-animal interaction for purposes of relaxation and healing. Certain breeds are desirable when looking into therapy cats due to their personality and temperament. Some examples of preferred breeds are Ragdolls, Maine Coons, American Shorthairs, Siamese, and Persians. The important traits to look for in a cat include a steady demeanor with tolerance to sights and sounds that are unfamiliar or sudden, petting that could be awkward or rough, and the ability to stay calm when being poked or pulled in unusual manners. Therapy cats must also be acclimated to humans of all ages and enjoy engaging with strangers daily. Some therapy cats are used as alternatives to therapy dogs due to the cats' size and nature, allowing them to work with patients/people who might otherwise be scared of dogs. Therapy cats should still be accustomed to dogs since most visits happen in conjunction with one another.
The presence of cats in addition to their purring as well as petting them can deliver both psychological and physical benefits. Therapy cats are being used as companions to help the recovery and well-being of people who have had strokes, high blood pressure, anxiety, and/or depression to name a few.
Therapy cats are utilized as companions at juvenile detention centers; for children with developmental disabilities; and for children with language, speech and hearing difficulties. Therapy cats are also sometimes used in hospitals to relax children who are staying there, as well as helping those in hospice care cope with their terminal illness.
== Indoor scratching ==
A natural behavior in cats is to hook their front claws periodically into suitable surfaces and pull backwards. Cats, like humans, keep their muscles trim and their body flexible by stretching. Additionally, such periodic scratching serves to clean and sharpen their claws. Indoor cats may benefit from being provided with a scratching post so that they are less likely to use carpet or furniture, which they can easily ruin. However, some cats may simply ignore such a device. Commercial scratching posts typically are covered in carpeting or upholstery. Using a plain wooden surface, or reversing the carpeting on the posts so that the rougher texture of the carpet backing faces outward, may be a more attractive alternative to the cat than the floor covering. Scratching posts made of sisal rope or corrugated cardboard are also common.
Although scratching can serve cats to keep their claws from growing excessively long, their nails can be trimmed if necessary. Another response to indoor scratching is onychectomy, commonly known as declawing. This is a surgical procedure to remove the claw and first bone of each digit of a cat's paws. Declawing is most commonly only performed on the front feet. A related procedure is tendonectomy, which involves cutting a tendon needed for cats to extend their claws. Declawing is a major surgical procedure and can produce pain and infections.
Since this surgery is almost always performed for the benefit of owners, it is controversial and remains uncommon outside of North America. In many countries, declawing is prohibited by animal welfare laws and it is ethically controversial within the veterinary community. While both the Humane Society of the United States and the American Society for the Prevention of Cruelty to Animals strongly discourage or condemn the procedure, the American Veterinary Medical Association supports the procedure under certain guidelines and finds "no scientific evidence that declawing leads to behavioral abnormalities when the behavior of declawed cats is compared with that of cats in control groups." They further argue that many cats would be given up and euthanized were declawing not performed.
== Waste ==
Being fastidious self-cleaners, cats detest their own waste and instinctually bury their urine and feces. House cats are usually provided with a box containing litter, generally consisting of bentonite, but sometimes other absorbent material such as shredded paper or wood chips, or sometimes sand or similar material can be used. It should be cleaned daily and changed often, depending on the number of cats using it and the type of litter; if it is not kept clean, a cat may be fastidious enough to find other locations for urination or defecation. This may also happen for other reasons; for instance, if a cat becomes constipated and defecation is uncomfortable, it may associate the discomfort with the litter box and avoid it in favor of another location.
Daily attention to the litter box also serves as a monitor of the cat's health. Bentonite or clumping litter is a variation which absorbs urine into clumps which can be sifted out along with feces, and thus stays cleaner longer with regular sifting, but has sometimes been reported to cause health problems in some cats.
Some cats can be trained to use the human toilet, eliminating the litter box and its attendant expense, unpleasant odor, and the need to use landfill space for disposal.
An exhibit at the San Diego Natural History Museum states that cat feces from urban runoff carry Toxoplasma gondii parasites to the ocean and kill sea otters.
== Pet humanization ==
Pet humanization is a form of anthropomorphism in which cats are kept for companionship and treated more like human family members than traditional pets. This trend of pet culture involves providing cats with a higher level of care, attention and often even luxury, similar to the way humans are treated. It involves attributing human-like qualities, emotions and needs to cats and providing them with care, attention and comforts similar to those given to human family members. In a pet-humanized context, cats kept as pets are often regarded as beloved members of the family, rather than just animals or possessions.
== Genetic similarities with humans ==
Cats and humans evolutionarily diverged from a common ancestor (boreoeutherian ancestor) approximately 80 million years ago, accumulating only 10–12 chromosomal translocations. The order of eight genes on the cats' Y chromosome closely resembles that in humans. Genes on X chromosomes of cats and humans are arranged in a similar way.
Domestic cats are affected by over 250 naturally occurring hereditary disorders, many of which are similar to those in humans, such as diabetes, hemophilia and Tay–Sachs disease. For example, Abyssinian cat's pedigree contains a genetic mutation that causes retinitis pigmentosa, which also affects humans. The domestic cat is also an excellent model for human infectious diseases, including HIV/AIDS. Feline immunodeficiency virus (FIV) is a genetic relative of HIV.
== See also ==
== References == | Wikipedia/Therapy_cat |
Extracorporeal shockwave therapy (ESWT) is a treatment using powerful acoustic pulses which is mostly used to treat kidney stones and in physical therapy and orthopedics.
== Medical uses ==
The most common use of extracorporeal shockwave therapy (ESWT) is for lithotripsy to treat kidney stones (urinary calculosis) and biliary calculi (stones in the gallbladder or in the liver) using an acoustic pulse. It is also reported to be used for salivary stones and pancreatic stones.
In the UK, the National Institute for Health and Care Excellence (NICE) found that the evidence for ESWT in the majority of indications is conflicting, and therefore ESWT should only be used where there are special arrangements for clinical governance and audit. Two 2017 reviews had similar findings, with moderate level evidence at best.
Extracorporeal shockwave therapy is used as a second line measure to treat tennis elbow, shoulder rotator cuff pain, Achilles tendinitis, plantar fasciitis, and greater trochanteric pain syndrome.
ESWT is also used to promote bone healing and treat bone necrosis. It is an effective alternative to surgical treatment of non-healing fractures.
ESWT is used for wound healing and has shown positive results in short-term and long-term outcomes in diabetic patients with foot ulcers. Randomised controlled trials into the use of ESWT for healing venous leg ulcers are needed as there is a lack of evidence in this area.
Low-intensity extracorporeal shock wave therapy has been used as a treatment for erectile dysfunction. It differs from palliative options by aiming to restore natural erectile function by inducing cellular microtrauma, triggering the release of angiogenic factors and promoting neovascularization in treated tissue. This mechanism is distinct from the high-intensity shock waves used in lithotripsy and medium-intensity shock waves used for anti-inflammatory purposes in orthopedics. Clinical studies, including double-blind randomized trials, have demonstrated LI-ESWT's ability to significantly improve erectile function and penile hemodynamics in men with vasculogenic ED.
== Procedure ==
The lithotripter attempts to break up the stone with minimal collateral damage by using an externally applied, focused, high-intensity acoustic pulse. The patient is usually sedated or anesthetized for the procedure in order to help them remain still and reduce possible discomfort. Sedation is not required in its application for soft tissue injuries.
== History ==
Beginning in 1969 and funded by the German Ministry of Defense, Dornier began a study of the effects of shock waves on tissue. In 1972, on the basis of preliminary studies performed by Dornier Medical Systems, an agreement was reached with Egbert Schmiedt, director of the urologic clinic at the University of Munich. The development of the Dornier lithotripter progressed through several prototypes, ultimately culminating in February 1980 with the first treatment of a human by shockwave lithotripsy (SWL). The production and distribution of the Dornier HM3 lithotripter began in late 1983, and SWL was approved by the U.S. Food and Drug Administration in 1984.
In the 1980s people using ESWT for kidney stones noticed that it appeared to increase bone density in nearby bones, leading them to explore it for orthopedic purposes.
== Research ==
In response to concerns raised by NICE, in 2012 a study called the Assessment of the Effectiveness of ESWT for Soft Tissue Injuries was launched (ASSERT).
As of 2018 use of ESWT had been studied as a potential treatment for chronic prostatitis/chronic pelvic pain syndrome in three small studies; there were short-term improvements in symptoms and few adverse effects, but the medium-term results are unknown, and the results are difficult to generalize due to the low quality of the studies.
== Veterinary use ==
ESWT is commonly used for treating orthopedic problems in horses, including tendon and ligament injuries, kissing spine, navicular syndrome, and arthritis. The evidence for these uses is weak.
== Physiotherapy use ==
ESWT is used in physical therapy for pain reduction, increase in metabolism at the cellular level, revascularisation, and recovering normal muscle tone following various disorders. The use of ESWT was demonstrated in patients with frozen shoulders compared to therapeutic ultrasound with exercises.
Research suggests that ESWT can accelerate the blood flow, facilitating the healing of the inflamed Achilles tendon. In one study involving 23 patients with chronic Achilles tendinopathy, 20 reported improvement in their condition and pain scores after ESWT; three saw no change, and none reported any worsening.
== See also ==
Laser lithotripsy
== References == | Wikipedia/Extracorporeal_shockwave_therapy |
Hirudo medicinalis, or the European medicinal leech, is one of several species of leeches used as medicinal leeches.
Other species of Hirudo sometimes also used as medicinal leeches include H. orientalis, H. troctina, and H. verbana. The Asian medicinal leech includes Hirudinaria manillensis, and the North American medicinal leech is Macrobdella decora.
Medicinal leech populations were reduced significantly in many countries during the 19th century due to the high demand in medical contexts, and remain endangered in many countries today.
== Morphology ==
The general morphology of medicinal leeches follows that of most other leeches. Fully mature adults can be up to 20 centimeters in length, and are green, brown, or greenish-brown with a darker tone on the dorsal side and a lighter ventral side. The dorsal side also has a thin red stripe. These organisms have two suckers, one at each end, called the anterior and posterior suckers. The posterior is used mainly for leverage, whereas the anterior sucker, consisting of the jaw and teeth, is where the feeding takes place. Medicinal leeches have three jaws (tripartite) that resemble saws, on which are approximately 100 sharp edges used to incise the host. The incision leaves a mark that is an inverted Y inside of a circle. After piercing the skin, they suck out blood while injecting blood thinners similar to Anophelins; anticoagulants (hirudin). Large adults can consume up to ten times their body weight in a single meal, with 5–15 mL being the average volume taken. These leeches can live for up to a year between feedings.
Medicinal leeches are hermaphrodites that reproduce by sexual mating, laying eggs in clutches of up to 50 near (but not under) water, and in shaded, humid places. A study done in Poland found that medicinal leeches sometimes breed inside the nests of large aquatic birds, noting that conservation efforts directed at bird habitats may also indirectly help preserve dwindling leech populations.
== Range and ecology ==
Their range extends over almost the whole of Europe and into Asia as far as Kazakhstan and Uzbekistan. The preferred habitat for this species is muddy freshwater pools and ditches with plentiful weed growth in temperate climates.
Over-exploitation by leech collectors in the 19th century has left only scattered populations, and reduction in natural habitat through drainage has also contributed to their decline. Another factor includes the replacement of horses - medicinal leeches' preferred host species - by motor vehicles and mechanical farming equipment, and the provision of artificial water supplies for cattle. As a result, this species is now considered near threatened by the IUCN, and European medicinal leeches are legally protected through nearly all of their natural range. They are particularly sparsely distributed in France and Belgium, and in the UK there may be as few as 20 remaining isolated populations (all widely scattered). The largest, located at Lydd, England, is estimated to contain several thousand individuals; 12 of these areas have been designated Sites of Special Scientific Interest. There are small, transplanted populations in several countries outside their natural range, including the USA. The species is protected under Appendix II of CITES meaning international trade (including in parts and derivatives) is regulated by the CITES permitting system.
== Medical use ==
=== Beneficial secretions ===
Medicinal leeches have been found to secrete saliva containing about 60 different proteins. These achieve a wide variety of goals useful to the leech as it feeds, helping to keep the blood in liquid form and increasing blood flow in the affected area. Several of these secreted proteins serve as anticoagulants (such as hirudin), platelet aggregation inhibitors (most notably apyrase, collagenase, and calin), vasodilators, and proteinase inhibitors. It is also thought that the saliva contains an anesthetic, as leech bites are generally not painful.
=== Historically ===
The first recorded use of leech therapy was 3,500 years ago in Ancient Egypt. The next recorded uses of leeches in medicine come in the last few centuries BCE, by the Greek physician Nicander in Colophon and in the ancient Sanskrit text Sushruta Samhita. Leech therapy is mentioned a few hundred years later in Shennong Bencaojing, a 3rd-century CE book of traditional Chinese medicine.
Medical use of leeches was discussed by Avicenna in The Canon of Medicine (1020s), and by Abd al-Latif al-Baghdadi in the 12th century.
These sources indicated leech therapy for a wide variety of ailments, including edema, "blood stasis", and skin diseases.
In medieval and early modern European medicine, the medicinal leech (Hirudo medicinalis and its congeners H. verbana, H. troctina, and H. orientalis) was used to remove blood from a patient as part of a process to balance the humors that, according to Galen, must be kept in balance for the human body to function properly. (The four humors of ancient medical philosophy were blood, phlegm, black bile, and yellow bile.) Any sickness that caused the subject's skin to become red (e.g. fever and inflammation), so the theory went, must have arisen from too much blood in the body. Similarly, any person whose behavior was strident and sanguine was thought to be suffering from an excess of blood. Leeches, by removing blood, were thought to help with these kinds of conditions — a wide range which included illnesses like polio and laryngitis. Leeches were often gathered by leech collectors and were eventually farmed in large numbers. A unique 19th-century "Leech House" survives in Bedale, North Yorkshire on the bank of the Bedale Beck, used to store medicinal leeches until the early 20th century.
Manchester Royal Infirmary used 50,000 leeches a year in 1831. The price of leeches varied between one penny and threepence halfpenny each. In 1832 leeches accounted for 4.4% of the total hospital expenditure. The hospital maintained an aquarium for leeches until the 1930s. The use of leeches began to become less widespread towards the end of the 19th century.
=== Current ===
Medicinal leech therapy (also referred to as Hirudotherapy or Hirudin therapy) made an international comeback in the 1970s in microsurgery, used to stimulate circulation in tissues threatened by postoperative venous congestion, particularly in finger reattachment and reconstructive surgery of the ear, nose, lip, and eyelid. Other clinical applications of medicinal leech therapy include varicose veins, muscle cramps, thrombophlebitis, and osteoarthritis, among many varied conditions. The therapeutic effect is not from the small amount of blood taken in the meal, but from the continued and steady bleeding from the wound left after the leech has detached, as well as the anesthetizing, anti-inflammatory, and vasodilating properties of the secreted leech saliva. The most common complication from leech treatment is prolonged bleeding, which can easily be treated, but more serious allergic reactions and bacterial infections may also occur. Leech therapy was classified by the US Food and Drug Administration as a medical device in 2004.
Because of the minuscule amounts of hirudin present in leeches, it is impractical to harvest the substance for widespread medical use. Hirudin (and related substances) are synthesized using recombinant techniques. Devices called "mechanical leeches" that dispense heparin and perform the same function as medicinal leeches have been developed, but they are not yet commercially available.
== See also ==
Helminthic therapy – other medical use of parasites
Ichthyotherapy – medical use of fish
== References ==
== External links ==
Media related to Hirudo medicinalis at Wikimedia Commons
Early Practices: A Brief History of Bloodletting | Wikipedia/Leech_therapy |
Herbal medicine (also called herbalism, phytomedicine or phytotherapy) is the study of pharmacognosy and the use of medicinal plants, which are a basis of traditional medicine. Scientific evidence for the effectiveness of many herbal treatments remains limited, prompting ongoing regulatory evaluation and research into their safety and efficacy. Standards for purity or dosage are generally not provided. The scope of herbal medicine sometimes includes fungal and bee products, as well as minerals, shells and certain animal parts.
Paraherbalism is the pseudoscientific use of plant or animal extracts as medicine, relying on unproven beliefs about the safety and effectiveness of minimally processed natural substances.
Herbal medicine has been used since at least the Paleolithic era, with written records from ancient Sumer, Egypt, Greece, China, and India documenting its development and application over millennia. Modern herbal medicine is widely used globally—especially in Asia and Africa. Traditional medicine systems involve long-standing, culturally-embedded practices using local herbs, animal products, and spiritual elements. These systems have influenced and contributed to modern pharmacology. Herbalists believe that plants, having evolved defenses against environmental stressors, produce beneficial phytochemicals, often extracted from roots or leaves, that can be used in medicine.
Sick often seek out and eat plants containing compounds like tannins and alkaloids to help purge parasites—a behavior observed by scientists and sometimes cited by indigenous healers as the source of their knowledge.
== History ==
Archaeological evidence indicates that the use of medicinal plants dates back to the Paleolithic age, approximately 60,000 years ago. Written evidence of herbal remedies dates back over 5,000 years to the Sumerians, who compiled lists of plants. Some ancient cultures wrote about plants and their medical uses in books called herbals. In ancient Egypt, herbs were mentioned in Egyptian medical papyri, depicted in tomb illustrations, or on rare occasions found in medical jars containing trace amounts of herbs. In ancient Egypt, the Ebers papyrus dates from about 1550 BCE, and covers more than 700 compounds, mainly of plant origin. The earliest known Greek herbals came from Theophrastus of Eresos who, in the 4th century BCE, wrote in Greek Historia Plantarum, from Diocles of Carystus who wrote during the 3rd century BCE, and from Krateuas who wrote in the 1st century BCE. Only a few fragments of these works have survived intact, but from what remains, scholars have noted overlap with the Egyptian herbals.
Seeds likely used for herbalism were found in archaeological sites of Bronze Age China dating from the Shang dynasty (c. 1600 – c. 1046 BCE). Over a hundred of the 224 compounds mentioned in the Huangdi Neijing, an early Chinese medical text, are herbs. Herbs were also commonly used in the traditional medicine of ancient India, where the principal treatment for diseases was diet. De Materia Medica, originally written in Greek by Pedanius Dioscorides (c. 40 – c. 90 CE) of Anazarbus, Cilicia, a physician and botanist, is one example of herbal writing used over centuries until the 1600s.
== Modern herbal medicine ==
The World Health Organization (WHO) estimates that 80 percent of the population of some Asian and African countries presently uses herbal medicine for some aspect of primary health care.
Some prescription drugs have a basis as herbal remedies, including artemisinin, digitalis, quinine and taxanes.
=== Regulatory review ===
In 2015, the Australian Government's Department of Health published the results of a review of alternative therapies that sought to determine if any were suitable for being covered by health insurance; herbalism was one of 17 topics evaluated for which no clear evidence of effectiveness was found. Establishing guidelines to assess the safety and efficacy of herbal products, the European Medicines Agency provided criteria in 2017 for evaluating and grading the quality of clinical research in preparing monographs about herbal products. In the United States, the National Center for Complementary and Integrative Health of the National Institutes of Health funds clinical trials on herbal compounds, provides fact sheets evaluating the safety, potential effectiveness and side effects of many plant sources, and maintains a registry of clinical research conducted on herbal products.
According to Cancer Research UK as of 2015, "there is currently no strong evidence from studies in people that herbal remedies can treat, prevent or cure cancer".
=== Prevalence of use ===
The use of herbal remedies is more prevalent in people with chronic diseases, such as cancer, diabetes, asthma, and end-stage kidney disease. Multiple factors such as gender, age, ethnicity, education and social class are also shown to have associations with the prevalence of herbal remedy use.
=== Herbal preparations ===
There are many forms in which herbs can be administered, the most common of which is a liquid consumed as a herbal tea or a (possibly diluted) plant extract.
Herbal teas, or tisanes, are the resultant liquid of extracting herbs into water, though they are made in a few different ways. Infusions are hot water extracts of herbs, such as chamomile or mint, through steeping. Decoctions are the long-term boiled extracts, usually of harder substances like roots or bark. Maceration is the cold infusion of plants with high mucilage-content, such as sage or thyme. To make macerates, plants are chopped and added to cold water. They are then left to stand for 7 to 12 hours (depending on the herb used). For most macerates, 10 hours is used.
Tinctures are alcoholic extracts of herbs, which are generally stronger than herbal teas. Tinctures are usually obtained by combining pure ethanol (or a mixture of pure ethanol with water) with the herb. A completed tincture has an ethanol percentage of at least 25% (sometimes up to 90%). Non-alcoholic tinctures can be made with glycerin but it is believed to be less absorbed by the body than alcohol based tinctures and has a shorter shelf life. Herbal wine and elixirs are alcoholic extracts of herbs, usually with an ethanol percentage of 12–38%. Extracts include liquid extracts, dry extracts, and nebulisates. Liquid extracts are liquids with a lower ethanol percentage than tinctures. They are usually made by vacuum distilling tinctures. Dry extracts are extracts of plant material that are evaporated into a dry mass. They can then be further refined to a capsule or tablet.
The exact composition of a herbal product is influenced by the method of extraction. A tea will be rich in polar components because water is a polar solvent. Oil, on the other hand, is a non-polar solvent and it will absorb non-polar compounds. Alcohol lies somewhere in-between.
Many herbs are applied topically to the skin in a variety of forms. Essential oil extracts can be applied to the skin, usually diluted in a carrier oil. Many essential oils can burn the skin or are simply too high dose used straight; diluting them in olive oil or another food grade oil such as almond oil can allow these to be used safely as a topical. Salves, oils, balms, creams, and lotions are other forms of topical delivery mechanisms. Most topical applications are oil extractions of herbs. Taking a food grade oil and soaking herbs in it for anywhere from weeks to months allows certain phytochemicals to be extracted into the oil. This oil can then be made into salves, creams, lotions, or simply used as an oil for topical application. Many massage oils, antibacterial salves, and wound healing compounds are made this way.
Inhalation, as in aromatherapy, can be used as a treatment.
=== Safety ===
It is a popular misconception that herbal medicines are safe and side-effect free. Consumption of herbs may cause adverse effects. Furthermore, "adulteration, inappropriate formulation, or lack of understanding of plant and drug interactions have led to adverse reactions that are sometimes life threatening or lethal." Proper double-blind clinical trials are needed to determine the safety and efficacy of each plant before medical use.
Although many consumers believe that herbal medicines are safe because they are natural, herbal medicines and synthetic drugs may interact, causing toxicity to the consumer. Herbal remedies can also be dangerously contaminated, and herbal medicines without established efficacy, may unknowingly be used to replace prescription medicines.
Standardization of purity and dosage is not mandated in the United States, but even products made to the same specification may differ as a result of biochemical variations within a species of plant. Plants have chemical defense mechanisms against predators that can have adverse or lethal effects on humans. Examples of highly toxic herbs include poison hemlock and nightshade. They are not marketed to the public as herbs, because the risks are well known, partly due to a long and colorful history in Europe, associated with "sorcery", "magic" and intrigue.
Although not frequent, adverse reactions have been reported for herbs in widespread use. On occasion serious untoward outcomes have been linked to herb consumption. A case of major potassium depletion has been attributed to chronic licorice ingestion, and consequently professional herbalists avoid the use of licorice where they recognize that this may be a risk. Black cohosh has been implicated in a case of liver failure.
Few studies are available on the safety of herbs for pregnant women, and one study found that use of complementary and alternative medicines is associated with a 30% lower ongoing pregnancy and live birth rate during fertility treatment.
Examples of herbal treatments with likely cause-effect relationships with adverse events include aconite (which is often a legally restricted herb), Ayurvedic remedies, broom, chaparral, Chinese herb mixtures, comfrey, herbs containing certain flavonoids, germander, guar gum, liquorice root, and pennyroyal. Examples of herbs that may have long-term adverse effects include ginseng, the endangered herb goldenseal, milk thistle, senna, aloe vera juice, buckthorn bark and berry, cascara sagrada bark, saw palmetto, valerian, kava (which is banned in the European Union), St. John's wort, khat, betel nut, the restricted herb ephedra, and guarana.
There is also concern with respect to the numerous well-established interactions of herbs and drugs. In consultation with a physician, usage of herbal remedies should be clarified, as some herbal remedies have the potential to cause adverse drug interactions when used in combination with various prescription and over-the-counter pharmaceuticals, just as a customer should inform a herbalist of their consumption of actual prescription and other medication.
For example, dangerously low blood pressure may result from the combination of a herbal remedy that lowers blood pressure together with prescription medicine that has the same effect. Some herbs may amplify the effects of anticoagulants.
Certain herbs as well as common fruit interfere with cytochrome P450, an enzyme critical to much drug metabolism.
In a 2018 study, the FDA identified active pharmaceutical additives in over 700 analyzed dietary supplements sold as "herbal", "natural" or "traditional". The undisclosed additives included "unapproved antidepressants and designer steroids", as well as prescription drugs, such as sildenafil or sibutramine.
=== Labeling accuracy ===
Researchers at the University of Adelaide found in 2014 that almost 20 percent of herbal remedies surveyed were not registered with the Therapeutic Goods Administration, despite this being a condition for their sale. They also found that nearly 60 percent of products surveyed had ingredients that did not match what was on the label. Out of 121 products, only 15 had ingredients that matched their TGA listing and packaging.
In 2015, the New York Attorney General issued cease and desist letters to four major U.S. retailers (GNC, Target, Walgreens, and Walmart) who were accused of selling herbal supplements that were mislabeled and potentially dangerous. Twenty-four products were tested by DNA barcoding as part of the investigation, with all but five containing DNA that did not match the product labels.
=== Practitioners of herbalism ===
In some countries, formalized training and minimum education standards exist for herbalists, although these are not necessarily uniform within or between countries. In Australia, for example, the self-regulated status of the profession (as of 2009) resulted in variable standards of training, and numerous loosely formed associations setting different educational standards. One 2009 review concluded that regulation of herbalists in Australia was needed to reduce the risk of interaction of herbal medicines with prescription drugs, to implement clinical guidelines and prescription of herbal products, and to assure self-regulation for protection of public health and safety. In the United Kingdom, the training of herbalists is done by state-funded universities offering Bachelor of Science degrees in herbal medicine. In the United States, according to the American Herbalist Guild, "there is currently no licensing or certification for herbalists in any state that precludes the rights of anyone to use, dispense, or recommend herbs." However, there are U.S. federal restrictions for marketing herbs as cures for medical conditions, or essentially practicing as an unlicensed physician.
=== United States herbalism fraud ===
Over the years 2017–2021, the U.S. Food and Drug Administration (FDA) issued warning letters to numerous herbalism companies for illegally marketing products under "conditions that cause them to be drugs under section 201(g)(1) of the Act [21 U.S.C. § 321(g)(1)], because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and/or intended to affect the structure or any function of the body" when no such evidence existed. During the COVID-19 pandemic, the FDA and U.S. Federal Trade Commission issued warnings to several hundred American companies for promoting false claims that herbal products could prevent or treat COVID-19 disease.
=== Government regulations ===
The World Health Organization (WHO), the specialized agency of the United Nations (UN) that is concerned with international public health, published Quality control methods for medicinal plant materials in 1998 to support WHO Member States in establishing quality standards and specifications for herbal materials, within the overall context of quality assurance and control of herbal medicines.
In the European Union (EU), herbal medicines are regulated under the Committee on Herbal Medicinal Products.
In the United States, herbal remedies are regulated dietary supplements by the Food and Drug Administration (FDA) under current good manufacturing practice (cGMP) policy for dietary supplements. Manufacturers of products falling into this category are not required to prove the safety or efficacy of their product so long as they do not make 'medical' claims or imply uses other than as a 'dietary supplement', though the FDA may withdraw a product from sale should it prove harmful.
Canadian regulations are described by the Natural and Non-prescription Health Products Directorate which requires an eight-digit Natural Product Number or Homeopathic Medicine Number on the label of licensed herbal medicines or dietary supplements.
Some herbs, such as cannabis and coca, are outright banned in most countries though coca is legal in most of the South American countries where it is grown. The Cannabis plant is used as a herbal medicine, and as such is legal in some parts of the world. Since 2004, the sales of ephedra as a dietary supplement is prohibited in the United States by the FDA, and subject to Schedule III restrictions in the United Kingdom.
=== Scientific criticism ===
Herbalism has been criticized as a potential "minefield" of unreliable product quality, safety hazards, and the potential for misleading health advice. Globally, there are no standards across various herbal products to authenticate their contents, safety or efficacy, and there is generally an absence of high-quality scientific research on product composition or effectiveness for anti-disease activity. Presumed claims of therapeutic benefit from herbal products, without rigorous evidence of efficacy and safety, receive skeptical views by scientists.
Unethical practices by some herbalists and manufacturers, which may include false advertising about health benefits on product labels or literature, and contamination or use of fillers during product preparation, may erode consumer confidence about services and products.
== Paraherbalism ==
Paraherbalism is the pseudoscientific use of extracts of plant or animal origin as supposed medicines or health-promoting agents. Phytotherapy differs from plant-derived medicines in standard pharmacology because it does not isolate and standardize the compounds from a given plant believed to be biologically active. It relies on the false belief that preserving the complexity of substances from a given plant with less processing is safer and potentially more effective, for which there is no evidence either condition applies.
Phytochemical researcher Varro Eugene Tyler described paraherbalism as "faulty or inferior herbalism based on pseudoscience", using scientific terminology but lacking scientific evidence for safety and efficacy. Tyler listed ten fallacies that distinguished herbalism from paraherbalism, including claims that there is a conspiracy to suppress safe and effective herbs, herbs cannot cause harm, whole herbs are more effective than molecules isolated from the plants, herbs are superior to drugs, the doctrine of signatures (the belief that the shape of the plant indicates its function) is valid, dilution of substances increases their potency (a doctrine of the pseudoscience of homeopathy), astrological alignments are significant, animal testing is not appropriate to indicate human effects, anecdotal evidence is an effective means of proving a substance works and herbs were created by God to cure disease. Tyler suggests that none of these beliefs have any basis in fact.
== Traditional systems ==
=== Africa ===
Up to 80% of the population in Africa uses traditional medicine as primary health care.
=== Americas ===
Native Americans used about 2,500 of the approximately 20,000 plant species that are native to North America.
In Andean healing practices, the use of entheogens, in particular the San Pedro cactus (Echinopsis pachanoi) is still a vital component, and has been around for millennia.
=== Asia ===
==== China ====
Some researchers trained in both Western and traditional Chinese medicine have attempted to deconstruct ancient medical texts in the light of modern science. In 1972, Tu Youyou, a pharmaceutical chemist and Nobel Prize winner, extracted the anti-malarial drug artemisinin from sweet wormwood, a traditional Chinese treatment for intermittent fevers.
==== India ====
In India, Ayurvedic medicine has quite complex formulas with 30 or more ingredients, including a sizable number of ingredients that have undergone "alchemical processing", chosen to balance dosha. In Ladakh, Lahul-Spiti, and Tibet, the Tibetan Medical System is prevalent, also called the "Amichi Medical System". Over 337 species of medicinal plants have been documented by C.P. Kala. Those are used by Amchis, the practitioners of this medical system. The Indian book, Vedas, mentions treatment of diseases with plants.
==== Indonesia ====
In Indonesia, especially among the Javanese, the jamu traditional herbal medicine may have originated in the Mataram Kingdom era, some 1300 years ago. The bas-reliefs on Borobudur depict the image of people grinding herbs with stone mortar and pestle, a drink seller, a herbalist, and masseuse treating people. The Madhawapura inscription from Majapahit period mentioned a specific profession of herb mixer and combiner (herbalist), called Acaraki. The book from Mataram dated from circa 1700 contains 3,000 entries of jamu herbal recipes, while Javanese classical literature Serat Centhini (1814) describes some jamu herbal concoction recipes.
Though possibly influenced by Indian Ayurveda systems, the Indonesia archipelago holds numerous indigenous plants not found in India, including plants similar to those in Australia beyond the Wallace Line. Jamu practices may vary from region to region, and are often not recorded, especially in remote areas of the country. Although primarily herbal, some Jamu materials are acquired from animals, such as honey, royal jelly, milk, and Ayam Kampung eggs.
== Beliefs ==
Herbalists tend to use extracts from parts of plants, such as the roots or leaves, believing that plants are subject to environmental pressures and therefore develop resistance to threats such as radiation, reactive oxygen species and microbial attack to survive, providing defensive phytochemicals of use in herbalism.
== Use of plants by animals ==
Indigenous healers often claim to have learned by observing that sick animals change their food preferences to nibble at bitter herbs they would normally reject. Field biologists have provided corroborating evidence based on observation of diverse species, such as chickens, sheep, butterflies, and chimpanzees. The habit of changing diet has been shown to be a physical means of purging intestinal parasites. Sick animals tend to forage plants rich in secondary metabolites, such as tannins and alkaloids.
== See also ==
Chinese herbology
Ethnobotany
Ethnomedicine
Herbal
Medicinal fungi
List of plants used in herbalism
Thomsonianism, a popular 19th century movement
Traditional medicine
Traditional Knowledge Digital Library
== References ==
== Further reading ==
Aronson JK (2008). Meyler's Side Effects of Herbal Medicines. Elsevier. ISBN 9780080932903.
Braun L, Cohen M (2007). Herbs and Natural Supplements: An Evidence-Based Guide. Elsevier. ISBN 9780729537964. | Wikipedia/Phytotherapy |
Cold compression therapy, also known as hilotherapy, combines two of the principles of rest, ice, compression, elevation to reduce pain and swelling from a sports or activity injury to soft tissues and is recommended by orthopedic surgeons following surgery. The therapy is especially useful for sprains, strains, pulled muscles and pulled ligaments.
== Cold compression ==
Cold compression is a combination of cryotherapy and static compression, commonly used for the treatment of pain and inflammation after acute injury or surgical procedures.
Cryotherapy, the use of ice or cold in a therapeutic setting, has become one of the most common treatments in orthopedic medicine. The primary reason for using cryotherapy in acute injury management is to lower the temperature of the injured tissue, which reduces the tissue's metabolic rate and helps the tissue to survive the period following the injury. It is well documented that metabolic rate decreases by application of cryotherapy.
A study done found that current literature on the use of cryotherapy on acute ankle sprains has insufficient evidence for the efficacy.
Static compression is often used in conjunction with cryotherapy for the care of acute injuries. To date, the primary reason for using compression is to increase external pressure on the tissue to prevent edema formation (swelling). This occurs by hindering fluid loss from the vessels in the injured area, making it more difficult for fluids to accumulate. Ice with compression is significantly colder than ice alone due to improved skin contact and increased tissue density caused by extended static compression. Tissue reaches its lowest temperature faster and the tissue maintains its cool even after treatment ends.
Compression therapy has been used in deep venous thrombosis prevention, wound care, as well as managing edema. Literature suggests that compression therapy use for perioperative ankle fractures will be beneficial for edema reduction and therefore, will probably be beneficial for pain and ankle joint mobility as well. Post operative arthroscopic surgeries also shows significant recovery with cold compression.
It has been studied following facial surgery where it has been found to decrease pain and swelling on day two or three. In athletes, cryotherapy has its greatest effect on recovery by using it within the first 24 hours of exercise or injury. Cryotherapy has also been shown that it can increase joint flexibility. It is unclear if it affects the risk of bruising.
== Devices ==
Continuous cold therapy devices (also called ice machines) which circulate ice water through a pad are currently the subject of class action lawsuits for skin and tissue damage caused by excessive cooling or icing time and lack of temperature control. Reported injuries range from frostbite to severe tissue damage resulting in amputation.
Studies have shown that the body activates the hunting reaction after only 10 minutes of cryotherapy, at temperatures less than 9.5 °C (49 °F). The hunting response is a cycle of vasoconstriction (decreased blood flow), then vasodilation (increased blood flow) that increases the delivery of oxygen and nutrient rich blood to the tissue. Studies show a debate whether cold should be used or not for faster recovery. Increased blood flow can slow cell death, limit tissue damage and aid in the removal of cellular debris and waste products. Under normal circumstances the hunting reaction would be essential to tissue health but only serves to increase pain, inflammation and cell death as excess blood is forced into the area.
== Wraps ==
Cold compression wraps using either re-freezable ice or gel are a much safer product, as such products do not exceed the cooling or icing time recommended by the established medical community.
Many of the ice wraps available use adjustable elastic straps to aid in compression over the injured areas. More advanced single-use wraps have guidelines to indicate how the bandage should be applied in order to achieve optimum compression required for an acute injury.
Most ice wraps that use ice, have a built-in protective layer, so ice is not applied directly to the skin, which can result in a burn to the area, sometimes known as a "cryoburn".
== See also ==
Achilles tendinitis
Dermatitis
Plantar fasciitis
Repetitive strain injury
Rotator cuff
Sprain
Strain (injury)
Tennis elbow
Torn rotator cuff
== References ==
Works cited | Wikipedia/Cold_compression_therapy |
Vision therapy (VT), or behavioral optometry, is an umbrella term for alternative medicine treatments using eye exercises, based around the pseudoscientific claim that vision problems are the true underlying cause of learning difficulties, particularly in children. Vision therapy has not been shown to be effective using scientific studies, except for helping with convergence insufficiency. Most claims—for example that the therapy can address neurological, educational, and spatial difficulties—lack supporting evidence. Neither the American Academy of Pediatrics nor the American Academy of Ophthalmology support the use of vision therapy.
== Definition and conceptual basis ==
Vision therapy is based on the proposition that many learning disabilities in children are based on vision problems, and that these can be cured by performing eye exercises. Vision therapy lacks sound evidence, has been characterized as a pseudoscience and its practice as quackery.
Vision therapy is a broad concept that encompasses a wide range of treatment types. These include those aimed at convergence insufficiency – where it is often termed "vergence therapy" or "orthoptic therapy" – and at a variety of neurological, educational and spatial difficulties.
== Efficacy ==
There is no good evidence that vision therapy of any benefit in treating learning disabilities, reading, dyslexia, or ADHD, although there is some evidence that it may help treat convergence insufficiency in healthy people. As of 2020 the consensus among ophthalmologists, orthoptists and pediatricians is that non-strabismic visual therapy lacks documented evidence of effectiveness.
A review in 2000 concluded that there were insufficient controlled studies of the approach. A 2008 review of the literature also noted that there were insufficient controlled studies, and concluded that the approaches "are not evidence-based, and thus cannot be advocated."
There is no good evidence supporting the use of vision therapy in the rehabilitation of patients with mild traumatic brain injury, although it may be useful for the treatment of post-traumatic convergence insufficiency and accommodative insufficiency.
== Treatment types ==
There exist a few different broad classifications of vision treatment philosophies, which have been traditionally divided between optometrists, ophthalmologists, and practitioners of alternative medicine.
Orthoptic vision therapy, also known as orthoptics, is a field pertaining to the evaluation and treatment of patients with disorders of the visual system with an emphasis on binocular vision and eye movements. Commonly practiced by orthoptists, optometrists, behavioral optometrists, pediatric ophthalmologists, and general ophthalmologists, traditional orthoptics addresses problems of eye strain, visually induced headaches, strabismus, diplopia and visual-related skills required for reading.
Behavioral vision therapy, or visual integration vision therapy (also known as behavioral optometry).
There have been a number of alternative vision therapy approaches which have not been studied in traditional or evidence-based medicine. They are commonly provided by unlicensed professionals, although a minority of optometrists also provide them. These methods are commonly under scrutiny by ophthalmological and optometric journals for lack of proven effectiveness.
=== Orthoptic vision therapy ===
Orthoptics emphasises the diagnosis and non-surgical management of strabismus (wandering eye), amblyopia (lazy eye), and eye movement disorders. Evidence to support its use in amblyopia is unclear as of 2011.
Much of the practice of orthoptists concerns refraction and muscular eye control. Orthoptists are trained professionals who specialize in orthoptic treatment. With specific training, in some countries orthoptists may be involved in monitoring some forms of eye disease, such as glaucoma, cataract screening, and diabetic retinopathy.
=== Behavioral vision therapy ===
Behavioral vision therapy (BVT) aims to treat problems including difficulties of visual attention and concentration, which behavioral optometrists classify as visual information processing weaknesses. These manifest themselves as an inability to sustain focus or to shift focus from one area of space to another. Some practitioners assert that poor eye tracking may impact reading skills, and suggest that vision training may improve some of the visual skills helpful for reading.
Behavioral vision therapy is practiced primarily by optometrists who specialize in the area. Historically, there has been some difference in philosophy among optometry and medicine regarding the efficacy and relevance of vision therapy, although none support its use in treating learning disorders. Major organizations, including the International Orthoptic Association and the American Academy of Ophthalmology, have concluded that there is no validity for clinically significant improvements in vision with BVT, and therefore do not practice it. However, major optometric organizations, including the American Optometric Association, the American Academy of Optometry, the College of Optometrists in Vision Development, and the Optometric Extension Program, support the assertion that non-strabismic visual therapy does address underlying visual problems which are claimed to affect learning potential. These optometric organizations are careful to distinguish, though, that vision therapy does not directly treat learning disorders.
==== Behavioral optometry ====
Behavioral optometry is a scientifically unproven branch of optometry that explores how visual function influences a patient's day-to-day activities. Vision therapy is a subset of behavioral optometry. In general, vision therapists attempt to improve the vision, and therefore day-to-day well-being, of patients using "eye exercises," prism, and lenses, with more emphasis on the patient's visual function.
Among schools of medicine, ophthalmology does not see merit in the procedures surrounding many of behavioral optometry's practices, as there have not been enough studies of high enough rigor to warrant practicing vision therapy. According to the American Association for Pediatric Ophthalmology and Strabismus, the behavioral aspects of vision therapy are considered scientifically unproven.
===== Techniques =====
In 2008, vision scientist Brendan Barrett published a review of behavioral optometry at the invitation of the UK College of Optometrists. He wrote that behavioral optometry was not a well-defined field but that proponents believed it could go beyond standard programmes, like an extension to optometry, taking a holistic approach. Barrett enumerated the therapies:
Vision therapy for accommodation/vergence disorders – eye exercises and training to try and alleviate these disorders. There is evidence that convergence disorders may be helped by eye exercises, but no good evidence exists that exercises help with accommodation disorders.
The underachieving child – therapies claimed to help children with dyslexia, dyspraxia and attention deficit disorder – a "vulnerable" target market. There is no evidence that behavioral optometry is of any benefit in relation to these conditions.
Prisms for near binocular disorders and for producing postural change – the use of "yoked" prisms to redirect a person's gaze and bring about a range of claimed benefits including postural improvements and increased wellbeing. There is a lack of evidence for the effect this approach may have.
Near point stress and low-plus – the use of special lenses to adjust near-field vision, even for people who would not normally need glasses. This is claimed to bring about postural benefits and relieve visual stress. Some research has been carried out in this area and its effectiveness remains "unproven".
Use of low-plus lenses at near to slow the progression of myopia.
Therapy to reduce myopia.
Behavioural approaches to the treatment of strabismus and amblyopia.
Training central and peripheral awareness and syntonic.
Sports vision therapy.
Neurological disorders and neurorehabilitation after trauma/stroke.
Barrett noted the lack of published controlled trials of the techniques. He found that there are a few areas where the available evidence suggest that the approach might have some value, namely in the treatment of convergence insufficiency, the use of yoked prisms in neurological patients, and in vision rehabilitation after brain disease or injury—but he found that in the other areas where the techniques have been used, i.e., the majority of situations, there is no evidence of their value. In contrast, Steven Novella points out that the only condition for which there is good quality scientific evidence is convergence disorders. This points out a problem that is common with Complementary or integrative medicine, a type of Alternative medicine, is that a promising use for treating a single disorder is applied to a wide range of disorders for which there is no evidence.
===== Eye exercises =====
The eye exercises used in vision therapy can generally be divided into two groups: those employed for "strabismic" outcomes and those employed for "non-strabismic" outcomes, to improve eye health.
Ophthalmologists and orthoptists do not endorse these exercises as having clinically significant validity for improvements in vision. Usually, they see these perceptual-motor activities being in the sphere of either speech therapy or occupational therapy.
Some of the exercises used are:
Near the point of convergence training, or the ability for both eyes to focus on a single point in space.
Base-out prism reading, stereogram cards, computerized training programs are used to improve fusional vergence.
The wearing of convex lenses.
The wearing of concave lenses.
"Cawthorne Cooksey Exercises" also employ various eye exercises, however, these are designed to alleviate vestibular disorders, such as dizziness, rather than eye problems.
Antisuppression exercises for amblyopia - this is no longer commonly practiced, although occasionally it may be used.
Eye exercises used in behavioural vision therapy, also known as developmental optometry, aim to treat problems, including difficulties of visual attention and concentration, which may manifest themselves as an inability to sustain focus or to shift focus from one area of space to another.
Some of the exercises use:
Marsden balls
Rotation trainers
Syntonics
Balance board or beams
Saccadic fixators
Directional sequencers
Fusional amplitude and relative fusional amplitude training are designed to alleviate convergence insufficiency. The CITT study (Convergence Insufficiency Treatment Trial) was a randomized, double-blind multi-center trial (high level of reliability) indicating that orthoptic vision therapy is an effective method of treatment of convergence insufficiency (CI). Both optometrists and ophthalmologists were coauthors of this study. Fusional amplitude training is also designed to alleviate intermittent exotropia and other less common forms of strabismus.
Certain do-it-yourself eye exercises are claimed by some to improve visual acuity by reducing or eliminating refractive errors. Such claims rely mainly on anecdotal evidence, and are not generally endorsed by orthoptists, ophthalmologists or optometrists.
The German optician Hans-Joachim Haase developed a method to correct an alleged misalignment. His method, called the MKH method, is not recognized as an evidence-based approach.
Beginning in the early 1960s, the Chinese government, concerned about the high incidence of nearsightedness among the Chinese population, undertook a programme to combat this problem. In 1963, the government began requiring schoolchildren between the ages of 6 and 17 to perform eye exercises at school. Ever since, this has been a common practice at schools in the People's Republic. The actual method used by the schoolchildren to exercise their eyes is based on traditional Chinese massage therapy, involving self-massage of acupoints around the eyes. The programme's effectiveness, however, is very much in question, given that over the same time as that in which there have been regular school eye exercises, the prevalence of nearsightedness among Chinese children, quite contrarily to the government's intended goal, has risen significantly.
===== Conceptual basis and effectiveness =====
Behavioral optometry is largely based on concepts that lack plausibility or which contradict mainstream neurology, and most of the research done has been of poor quality. As with chiropractic, there seems to be a spectrum of scientific legitimacy among practitioners: at one extreme there is some weak evidence in support of the idea that myopia may be affected by eye training; at the other extreme are concepts such as "syntonic phototherapy" which proposes that differently colored lights can be used to treat a variety of medical conditions.
A review in 2000 concluded that there were insufficient controlled studies of the approach. In 2008 Barrett concluded that "the continued absence of rigorous scientific evidence to support behavioural management approaches, and the paucity of controlled trials, in particular, represents a major challenge to the credibility of the theory and practice of behavioural optometry."
Behavioral optometry has been proposed as being of benefit for children with attention deficit hyperactivity disorder and autism – this proposal is based on the idea that since people with these conditions often have abnormal eye movement, correcting this may address the underlying condition. Evidence supporting this approach is, however, weak; the American Academy of Pediatrics, the American Academy of Ophthalmology and the American Association for Pediatric Ophthalmology and Strabismus have said that learning disabilities are neither caused nor treatable by visual methods.
=== Sports vision training ===
Practitioners of sports vision training claim to be able to enhance the function of an athlete's vision beyond what is expected in individuals with already healthy visual systems.
== History ==
Various forms of eye exercises have been used for centuries. The concept of orthoptics was introduced in the late nineteenth century for the non-surgical treatment of strabismus. This early and traditional form of vision therapy was the foundation of what is now known as orthoptics and was based on observation not research or evidence.
In the first half of the twentieth century, orthoptists, working with ophthalmologists, introduced a variety of training techniques mainly designed to improve ocular alignment. In the second half of the twentieth century, vision therapy began to be used by specially trained optometrists to treat conditions ranging from uncomfortable vision (asthenopia), ocular motor skills, focusing control, binocular vision, depth perception, eye-hand coordination and visual processing. These treatments have been demonstrated to help many patients with poor reading and academic performance caused by their vision. There are many unscientific techniques promoted commercially and claimed specifically to improve eyesight and even to improve athletic performance.
=== Behavioral optometry ===
Behavioral optometry is considered by some optometrists to have its origins in the teachings of Skeffington and Alexander. They promoted continuing education for optometrists to further their knowledge of how vision impacts performance. Vision therapy is differentiated between strabismic/orthoptic vision therapy (which many optometrists, orthoptists and ophthalmologists practice) and non-strabismic vision therapy. A.M. Skeffington was an American optometrist known to some as "the father of behavioral optometry". Skeffington has been credited as co-founding the Optometric Extension Program with E.B. Alexander in 1928.
== See also ==
Bates method
Irlen syndrome
Journal of Behavioral Optometry
Reichian therapy
Visual Snow
== References ==
== Further reading ==
Handler SM, Fierson WM (March 2011). "Learning Disabilities, Dyslexia, and Vision". Pediatrics (Review). 127 (3): e818–56. doi:10.1542/peds.2010-3670. PMID 21357342.
Worrall RS, Nevyas J, Barrett S (6 July 2018). "Eye-Related Quackery". Quackwatch. Retrieved 20 March 2021. | Wikipedia/Vision_therapy |
Cell therapy (also called cellular therapy, cell transplantation, or cytotherapy) is a therapy in which viable cells are injected, grafted or implanted into a patient in order to effectuate a medicinal effect, for example, by transplanting T-cells capable of fighting cancer cells via cell-mediated immunity in the course of immunotherapy, or grafting stem cells to regenerate diseased tissues.
Cell therapy originated in the nineteenth century when scientists experimented by injecting animal material in an attempt to prevent and treat illness. Although such attempts produced no positive benefit, further research found in the mid twentieth century that human cells could be used to help prevent the human body rejecting transplanted organs, leading in time to successful bone marrow transplantation as has become common practice in treatment for patients that have compromised bone marrow after disease, infection, radiation or chemotherapy. In recent decades, however, stem cell and cell transplantation has gained significant interest by researchers as a potential new therapeutic strategy for a wide range of diseases, in particular for degenerative and immunogenic pathologies.
== Background ==
Cell therapy can be defined as therapy in which cellular material is injected or otherwise transplanted into a patient. The origins of cell therapy can perhaps be traced to the nineteenth century, when Charles-Édouard Brown-Séquard (1817–1894) injected animal testicle extracts in an attempt to stop the effects of aging. In 1931 Paul Niehans (1882–1971) – who has been called the inventor of cell therapy – attempted to cure a patient by injecting material from calf embryos. Niehans claimed to have treated many people for cancer using this technique, though his claims have never been validated by research.
In 1953 researchers found that laboratory animals could be helped not to reject organ transplants by pre-inoculating them with cells from donor animals; in 1968, in Minnesota, the first successful human bone marrow transplantation took place. In more recent work, cell encapsulation is pursued as a means to shield therapeutic cells from the host immune response. Recent work includes micro-encapsulating cells in a gel core surrounded by a solid, but permeable, shell.
Bone marrow transplants are the most common and well established cell transplantation therapies. The first recording of a successful bone marrow transplant, dates back to 1956 by dr. E Donnall Thomas, who treated a leukemia patient with their twin-siblings bone marrow. In general, for patients presenting damaged or destroyed bone marrow, for example after chemotherapy and/or radiation for acute myeloid leukemia (AML), bone marrow derived cells can be infused into the patients blood stream. Here the injected cells are able to home into the affected bone marrow, integrate, proliferate and recover or re-establish its biological function e.g. the haematopoiesis. Annually an estimated 18,000 patients require potentially life-saving bone marrow transplants in the US. For a long time, bone marrow transplantation was the only clinically applicable method of cell transplantation, however, since the 1990s, cell therapy has been investigated for a wide scale of pathologies and disorders. Cell therapy provided a novel approach to effectuate therapeutic efficacy. Previously, medical agents could only be effective by directing and inducing the patients own cells. However, in many diseases and disorders, cell are compromised by e.g. senescence, limited blood supply (ischemia), inflammation, or simply a reduction in the number of cells. Cell therapy offers a new strategy that supports the introduction of new and active cells to restore previously compromised or deteriorated tissue- and organ structures. As such, in recent times, cell therapy has been recognized as an important field in the treatment of human disease, and investigations are ongoing in articular cartilage, brain tissue, spine, heart, cancers, etc. As a consequence cell therapy as a strategy has been attracting significant investments by commercial entities which suggest strong prospects for future growth.
In 2021 Atara biotherapeutics became the first ever allogeneic T cell therapy company to be reviewed by any regulatory agency in the world (EMA)
== Mechanisms of action ==
Cell therapy is targeted at many clinical indications in multiple organs and by several modes of cell delivery. Accordingly, the specific mechanisms of action involved in the therapies are wide-ranging. However, there are two main principles by which cells facilitate therapeutic action:
Stem, progenitor, or mature cell engraftment, differentiation, and long-term replacement of damaged tissue. In this paradigm multipotent or unipotent cells differentiate into a specific cell type in the lab or after reaching the site of injury (via local or systemic administration). These cells then integrate into the site of injury, replacing damaged tissue, and thus facilitate improved function of the organ or tissue. An example of this is the use of cells to replace cardiomyocytes after myocardial infarction, to facilitate angiogenesis in ischemic limb disease, or the production of cartilage matrix in intervertebral disc degeneration.
Cells that have the capacity to release soluble factors such as cytokines, chemokines, and growth factors which act in a paracrine or endocrine manner. These factors facilitate self-healing of the organ or region by inducing local (stem) cells or attracting cells to migrate towards the transplantation site. Early cell passages have been shown to be more efficient paracrine activity than later passages. The delivered cells (via local or systemic administration) remain viable for a relatively short period (days-weeks) and then die. This includes cells that naturally secrete the relevant therapeutic factors, or which undergo epigenetic changes or genetic engineering that causes the cells to release large quantities of a specific molecule. Examples of this include cells that secrete factors which facilitate angiogenesis, anti-inflammation, and anti-apoptosis. This mode of action is proposed by companies such as Pluristem and Pervasis that use adherent stromal cells or mature endothelial cells to treat peripheral artery disease and arteriovenous access complications.
== Cell therapy strategies ==
=== Allogeneic ===
In allogeneic cell therapy the donor is a different person to the recipient of the cells. In pharmaceutical manufacturing, the allogenic methodology is promising because unmatched allogenic therapies can form the basis of "off the shelf" products. There is research interest in attempting to develop such products to treat conditions including Crohn's disease and a variety of vascular conditions.
=== Autologous ===
In autologous cell therapy, cells are transplanted that are derived from the patients own tissues. Multiple clinical studies are ongoing that obtain stromal cells from bone-marrow, adipose tissue, or peripheral blood to be transplanted at sites of injury or stress; which is being actively explored for e.g. cartilage and muscle repair. It could also involve the isolation of matured cells from diseased tissues, to be later re-implanted at the same or neighboring tissues; a strategy being assessed in clinical trials for e.g. the spine in preventing disc reherniation or adjacent disc disease. The benefit of an autologous strategy is that there is limited concern for immunogenic responses or transplant rejection. Nevertheless, an autologous strategy is often costly due to patient-by-patient processing, thus preventing the option to create large quality-controlled batches. Moreover, autologous strategies generally do not allow for product quality and effectiveness testing prior to transplantation, as it is highly donor (thus patient) dependent. This is a particular concern as often the patient functioning as donor is diseased, and this can impact cell potency and quality.
=== Xenogeneic ===
In xenogeneic cell therapies, the recipient will receive cells from another species. For example, the transplantation of pig derived cells to humans. Currently, xenogeneic cell therapies primarily involve human cell transplantation into experimental animal models for assessment of efficacy and safety, however future advances could potentially enable xenogeneic strategies to humans as well.
== Types of cells ==
=== Human embryonic stem cells ===
Research into human embryonic stem cells is controversial, and regulation varies from country to country, with some countries banning it outright. Nevertheless, these cells are being investigated as the basis for a number of therapeutic applications, including possible treatments for diabetes and Parkinson's disease.
=== Neural stem cell therapy ===
Neural stem cells (NSCs) are the subject of ongoing research for possible therapeutic applications, for example for treating a number of neurological disorders such as Parkinson's disease and Huntington's disease.
=== Mesenchymal stem cell therapy ===
MSCs are immunomodulatory, multipotent and fast proliferating and these unique capabilities mean they can be used for a wide range of treatments including immune-modulatory therapy, bone and cartilage regeneration, myocardium regeneration and the treatment of Hurler syndrome, a skeletal and neurological disorder.
Researchers have demonstrated the use of MSCs for the treatment of osteogenesis imperfecta (OI). Horwitz et al. transplanted bone marrow (BM) cells from human leukocyte antigen (HLA)-identical siblings to patients with OI. Results show that MSCs can develop into normal osteoblasts, leading to fast bone development and reduced fracture frequencies. A more recent clinical trial showed that allogeneic fetal MSCs transplanted in utero in patients with severe OI can engraft and differentiate into bone in a human fetus.
Besides bone and cartilage regeneration, cardiomyocyte regeneration with autologous BM MSCs has also been reported recently. Introduction of BM MSCs following myocardial infarction (MI) resulted in significant reduction of damaged regions and improvement in heart function. Clinical trials for treatment of acute MI with Prochymal by Osiris Therapeutics are underway. Also, a clinical trial revealed huge improvements in nerve conduction velocities in Hurler's Syndrome patients infused with BM MSCs from HLA-identical siblings.
=== Hematopoietic stem cell transplantation ===
Hematopoietic stem cells (HSCs), derived from bone marrow or blood, are cells with the abilities to self-renew and to differentiate into all types of blood cells, especially those involved in the human immune system. Thus, they can be used to treat blood and immune disorders. Since human bone marrow grafting was first published in 1957, there have been significant advancements in HSCs therapy. Following that, syngeneic marrow infusion and allogeneic marrow grafting were performed successfully. HSCs therapy can also render its cure by reconstituting damaged blood-forming cells and restoring the immune system after high-dose chemotherapy to eliminate disease.
There are three types of HSC transplantation: syngeneic, autologous, and allogeneic transplants. Syngeneic transplantations occur between identical twins. Autologous transplantations use the HSCs obtained directly from the patient and hence avoid complications of tissue incompatibility; whereas allogeneic transplantations involve the use of donor HSCs, either genetically related or unrelated to the recipient. To lower the risks of transplant, which include graft rejection and graft-versus-host disease (GVHD), allogeneic HSCT must satisfy compatibility at the HLA loci (i.e. genetic matching to reduce the immunogenicity of the transplant).
In addition to bone marrow-derived HSCs, the use of alternative sources such as umbilical cord blood (UCB) and peripheral blood stem cells (PBSCs) has been increasing. In comparison with bone marrow-derived HSC recipients, PBSC recipients who had myeloid malignancies reported a faster engraftment and better overall survival. The use of UCB requires less stringent HLA loci matching, although the time of engraftment is longer and graft failure rate is higher.
=== Differentiated or mature cell transplantation ===
Alternative to stem- or progenitor cells, investigations are exploring the transplantation of differentiated cells that only possess low or no proliferation ability. This tends to involve specialized cells able to facilitate specific function in the patients body (for example, transplantation of cardiomyocytes to repair heart function or islet cell transplantation for establishing insulin homeostasis in diabetes patients) or support/regenerate the extracellular matrix production of specific tissues (for example intervertebral disc repair by transplanting chondrocytes).
== Alternative medicine ==
In alternative medicine, cell therapy is defined as the injection of non-human cellular animal material in an attempt to treat illness. Quackwatch labels this as "senseless", since "cells from the organs of one species cannot replace the cells from the organs of other species" and because a number of serious adverse effects have been reported. Of this alternative, animal-based form of cell therapy, the American Cancer Society say: "Available scientific evidence does not support claims that cell therapy is effective in treating cancer or any other disease. It may in fact be lethal ...".
== Manufacturing ==
Despite being one of the fast growing areas within Life Sciences, the manufacturing of cell therapy products is largely hindered by small scale batches and labour-intensive processes.
A number of manufacturers are turning to automated methods of production, eliminating human involvement and risk of human error. Automated methods of cell therapy manufacturing have opened up larger scale production of higher quality products at lower cost.
== Supply chain ==
Logistics departments of biopharma companies experience new obstacles because of the introduction of new cell and gene therapy products, such as CAR T-cell therapies and allogeneic therapies. Cell and gene therapies require manufacturer and distributors alike to implement new systems and processes in order to ensure safe handling and delivery. Additionally, on-demand inventory therefore becomes more and more important, especially with regard to unforeseeable events like the COVID-19 pandemic, so that supply chain interruptions can be prevented. Furthermore, recent changes as a result of the COVID-19 pandemic and political instability in Europe, secondary to Brexit, have further impacted the logistics chain for cellular therapies.
== See also ==
Stem cell
Stem cell therapy
Allotransplantation
Autotransplantation
Xenotransplantation
Regenerative medicine
Mesenchymal stem cell
Hematopoietic stem cell transplantation
Stem cell therapy for macular degeneration
== References ==
== External links ==
International Society for Cellular Therapy Archived 2016-01-12 at the Wayback Machine
International Society for Stem Cell Research | Wikipedia/Cell_therapy |
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/Electromagnetic_therapy_(alternative_medicine) |
Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body. Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme.
ERT is available for some lysosomal storage diseases: Gaucher disease, Fabry disease, MPS I, MPS II (Hunter syndrome), MPS VI and Pompe disease. ERT does not correct the underlying genetic defect, but it increases the concentration of the enzyme that the patient is lacking. ERT has also been used to treat patients with severe combined immunodeficiency (SCID) resulting from an adenosine deaminase deficiency (ADA-SCID).
Other treatment options for patients with enzyme or protein deficiencies include substrate reduction therapy, gene therapy, and bone-marrow derived stem cell transplantation.
== History ==
ERT was developed in 1964 by Christian de Duve and Roscoe Brady. Leading work was done on this subject at the Department of Physiology at the University of Alberta by Mark J. Poznansky and Damyanti Bhardwaj, where a model for enzyme therapy was developed using rats. ERT was not used in clinical practice until 1991, after the FDA gave orphan drug approval for the treatment of Gaucher disease with Alglucerase. ERTs were initially manufactured by isolating the therapeutic enzyme from human placenta. The FDA has approved ERTs that are derived from other human cells, animal cells (i.e. Chinese hamster ovary cells, or CHO cells), and plant cells.
== Medical uses ==
Lysosomal storage diseases are a group of diseases and a main application of ERT. Lysosomes are cellular organelles that are responsible for the metabolism of many different macromolecules and proteins. They use enzymes to break down macromolecules, which are recycled or disposed. As of 2012, there are 50 lysosomal storage diseases, and more are still being discovered. These disorders arise because of genetic mutations that prevent the production of certain enzymes used in the lysosomes. The missing enzyme often leads to a build-up of the substrate within the body. This can result in a variety of symptoms, many of which are severe and can affect the skeleton, brain, skin, heart, and the central nervous system. Increasing the concentration of the missing enzyme within the body has been shown to improve the body's normal cellular metabolic processes and reduce substrate concentration in the body.
ERT has also been successful in treating severe combined immunodeficiency caused by an adenosine deaminase deficiency (ADA-SCID). This is a fatal childhood disease that requires early medical intervention. When the enzyme adenosine deaminase is deficient in the body, the result is a toxic build-up of metabolites that impair lymphocyte development and function. Many ADA deficient children with SCID have been treated with the polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) enzyme. This is a form of ERT that has resulted in healthier, longer lives for patients with ADA-SCID.
== Administration ==
ERT is administered by IV infusion. Typically, infusions occur every week or every two weeks. For some types of ERT, these infusions can occur as infrequently as every four weeks.
== Complications ==
ERT is not a cure for lysosomal storage diseases, and it requires lifelong IV infusions of the therapeutic enzyme. This procedure is expensive; in the United States, it may cost over $200,000 annually. The distribution of the therapeutic enzyme in the body (biodistribution) after these IV infusions is not uniform. The enzyme in less available to certain areas in the body, like the bones, lungs, brain. For this reason, many symptoms of lysosomal storage diseases remain untreated by ERT, especially neurological symptoms. Additionally, the efficacy of ERT is often reduced due to an unwanted immune response against the enzyme, which prevents metabolic function.
== Other treatments for enzyme deficiencies ==
Substrate reduction therapy is another method for treating lysosomal storage diseases. In this treatment, the accumulated compounds are inhibited from forming in the body of a patient with a lysosomal storage disease. The accumulated compounds are responsible for the symptoms of these disorders, and they form via a multi-step biological pathway. Substrate reduction therapy uses a small molecule to interrupt this multi-step pathway and inhibit the biosynthesis of these compounds. This type of treatment is taken orally. It does not induce an unwanted immune response, and a single type of small molecule could be used to treat many lysosomal storage diseases. Substrate reduction therapy is FDA approved and there is at least one treatment available on the market.
Gene therapy aims to replace a missing protein in the body through the use of vectors, usually viral vectors. In gene therapy, a gene encoding for a certain protein is inserted into a vector. The vector containing the therapeutic gene is then injected into the patient. Once inside the body the vector introduces the therapeutic gene into host cells, and the protein encoded by the newly inserted gene is then produced by the body's own cells. This type of therapy can correct for the missing protein/enzyme in patients with lysosomal storage diseases.
Hematopoietic stem cell (HSC) transplantation is another treatment for lysosomal storage diseases. HSCs are derived from bone-marrow. These cells have the ability to mature into the many cell types that comprise blood, including red blood cells, platelets, and white blood cells. Patients with enzyme deficiencies often undergo HSC transplantations in which HSCs from a healthy donor are injected. This treatment introduces HSCs that regularly produce the deficient enzyme since they have normal metabolic function. This treatment is often used to treat the central nervous system of patients with some lysosomal storage diseases.
== See also ==
Protein replacement therapy
== References ==
== Further reading ==
"GAA: glucosidase alpha, acid". NIH Genetics Home Reference. US Government. | Wikipedia/Enzyme_replacement_therapy |
A pharmacological chaperone or pharmacoperone is a drug that acts as a protein chaperone. That is, it contains small molecules that enter cells and serve as a molecular scaffolding in order to cause otherwise-misfolded mutant proteins to fold and route correctly within the cell.
Mutation of proteins often causes molecular misfolding, which results in protein misrouting within the cell. Accordingly, mutant molecules may retain proper function but end up in parts of the cell where the function is inappropriate, or even deleterious, to cell function. Misfolded proteins are usually recognized by the quality-control system of the cell and retained (and often destroyed or recycled) in the endoplasmic reticulum.
Pharmacoperones correct the folding of misfolded proteins, allowing them to pass through the cell's quality-control system and become correctly routed. Since mutations often cause disease by causing misfolding and misrouting, pharmacoperones are potentially therapeutic agents, since they are able to correct this defect.
Diseases that may be susceptible to such treatments include diabetes, inherited cataracts and cystic fibrosis.
== Examples ==
Migalastat is a pharmacological chaperone for the treatment of Fabry disease.
Tafamidis is a pharmacological chaperone for the treatment of transthyretin amyloidosis (ATTR).
In 2013, mice with a disease that makes the males unable to father offspring were cured by use of pharmacoperones.
== See also ==
Autochaperone
Enzyme replacement therapy
== References ==
== Sources ==
Conn, P.M. and Janovick, J.A., A New Understanding of Protein Mutation Unfolds, American Scientist 93:314-321, 2005. | Wikipedia/Molecular_chaperone_therapy |
Aromatherapy is a practice based on the use of aromatic materials, including essential oils and other aroma compounds, with claims for improving psychological well-being. It is used as a complementary therapy or as a form of alternative medicine, and typically is used via inhalation and not by ingestion.
Fragrances used in aromatherapy are not approved as prescription drugs in the United States. Although there is insufficient medical evidence that aromatherapy can prevent, treat or cure any disease, aromatherapy is used by some people with diseases, such as cancer, to provide general well-being and relief from pain, nausea or stress.
People may use blends of essential oils as a topical application, massage, inhalation, or water immersion. Due to the low quality of research evidence, it is uncertain if aromatherapy provides any benefit to people experiencing nausea after surgery.
Essential oils comprise hundreds to thousands of aromatic constituents, like terpinoids and phenylpropanoids, and to sufficiently research the pharmacological effects of essential oil constituents, each isolated constituent in the selected essential oil would have to be studied.
== History ==
Oils and the belief that they had healing properties, along with other beliefs of the time, are described by Dioscorides in his De Materia Medica, written in the 1st century A.D. Distilled cedarwood oil was used by the ancient Egyptians, and the process of distilling essential oils like rose essence was refined by the 11th century Persian scholar Ibn Sina. Hildegard of Bingen used distilled lavender oil for medicinal treatments in the 12th century, and by the 15th century, oils were commonly distilled from various plant sources.
In the era of modern medicine, the name "aromatherapy" first appeared in print in 1937 in a French book on the subject: Aromathérapie: Les Huiles Essentielles, Hormones Végétales by René-Maurice Gattefossé, a chemist. An English version was published in 1993.
Jean Valnet, a French surgeon, pioneered the supposed medicinal uses of essential oils, which he used as antiseptics in the treatment of wounded soldiers during World War II.
== Choice and purchase ==
Aromatherapy products, and essential oils in particular, may be regulated differently depending on their intended use. Products that are marketed with a therapeutic use in the US are regulated by the US Food and Drug Administration (FDA); products with a cosmetic use must meet safety requirements, regardless of their source. The US Federal Trade Commission (FTC) regulates any aromatherapy advertising claims.
There are no standards for determining the quality of essential oils in the United States; while the term "therapeutic grade" is in use, it does not have a regulatory meaning.
Analysis using gas chromatography and mass spectrometry has been used to identify bioactive compounds in essential oils. These techniques are able to measure the levels of components to a few parts per billion. This does not make it possible to determine whether each component is natural or whether a poor oil has been "improved" by the addition of synthetic aromachemicals, but the latter is often signalled by the minor impurities present.
== Effectiveness ==
There is no clinical evidence that aromatherapy can prevent or cure any disease, although it may be useful for managing symptoms.
Evidence for the efficacy of aromatherapy in treating medical conditions is poor, with a particular lack of studies employing rigorous methodology. In 2015, the Australian Government's Department of Health published the results of a review of alternative therapies that sought to determine if any were suitable for being covered by health insurance; aromatherapy was one of 17 therapies evaluated for which no clear evidence of effectiveness was found.
Several systematic reviews have studied the clinical effectiveness of aromatherapy in respect to pain management in labor, the treatment of post-operative nausea and vomiting, managing challenging behaviors in people suffering from dementia, and symptom relief in cancer.
According to the US National Cancer Institute, no studies of aromatherapy in cancer treatment have been published in a peer-reviewed scientific journal. Results are mixed for other studies. Some showed improved sleep, anxiety, mood, nausea, and pain, while others showed no change in symptoms.
== Safety concerns ==
Aromatherapy carries several risks of adverse effects; combined with the lack of evidence of its therapeutic benefit, the practice is of questionable worth.
Many studies have explored the concerns that essential oils are highly concentrated and can irritate the skin when used in undiluted form, often referred to as neat application. Therefore, they are normally diluted with a carrier oil for topical application such as jojoba oil, olive oil, sweet almond oil or coconut oil. Phototoxic reactions may occur with many cold-pressed citrus peel oils such as lemon or lime.
Many essential oils have chemical components that are sensitisers (meaning that they will, after several uses, cause reactions on the skin and more so in the rest of the body). All cosmetic products and ingredients must meet the same safety requirements, regardless of their source. Chemical composition of essential oils could be affected by herbicides if the original plants are cultivated versus wild-harvested. Some oils can be toxic to some domestic animals, with cats being particularly prone.
Most oils can be toxic to humans as well. A report on three different cases documented gynecomastia in prepubertal boys who were exposed to topical lavender and tea tree oils. The Aromatherapy Trade Council of the UK issued a rebuttal.
Another article published by a different research group also documented three cases of gynecomastia in prepubertal boys who were exposed to topical lavender oil. Persistent exposure to lavender products may be associated with premature breast development in girls and "that chemicals in lavender oil and tea tree oil are potential endocrine disruptors with varying effects on receptors for two hormones – estrogen and androgen".
Essential oils can be toxic when ingested or absorbed internally. Doses as low as 2 ml have been reported to cause clinically significant symptoms and severe poisoning can occur after ingestion of as little as 4 ml. A few reported cases of toxic reactions like liver damage and seizures have occurred after ingestion of sage, hyssop, thuja and cedar oils. Accidental ingestion may happen when oils are not kept out of reach of children. As with any bioactive substance, an essential oil that may be safe for the general public could still pose hazards for pregnant and lactating people.
Oils both ingested and applied to the skin can potentially have negative interactions with conventional medicine. For example, the topical use of methyl salicylate–heavy oils like wintergreen may cause bleeding in users taking the anticoagulant warfarin.
In late 2021, an aromatherapy spray was recalled after it was found to be contaminated with Burkholderia pseudomallei, the bacterial agent that causes melioidosis, which led to four cases of the disease and two deaths.
== See also ==
Aromachologist
List of unproven and disproven cancer treatments
== References == | Wikipedia/Aromatherapy |
Treatment as prevention (TasP) is a concept in public health that promotes treatment as a way to prevent and reduce the likelihood of HIV illness, death and transmission from an infected individual to others. Expanding access to earlier HIV diagnosis and treatment as a means to address the global epidemic by preventing illness, death and transmission was first proposed in 2000 by Garnett et al. The term is often used to talk about treating people that are currently living with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) to prevent illness, death and transmission. Although some experts narrow this to only include preventing infections, treatment prevents illnesses such as tuberculosis and has been shown to prevent death. In relation to HIV, antiretroviral therapy (ART) is a three or more drug combination therapy that is used to decrease the viral load, or the measured amount of virus, in an infected individual. Such medications are used as a preventative for infected individuals to not only spread the HIV virus to their negative partners but also improve their current health to increase their lifespans. When taken correctly, ART is able to diminish the presence of the HIV virus in the bodily fluids of an infected person to a level of undetectability. Consistent adherence to an ARV regimen, monitoring, and testing are essential for continued confirmed viral suppression. Treatment as prevention rose to great prominence in 2011, as part of the HPTN 052 study, which shed light on the benefits of early treatment for HIV positive individuals.
Evidence through observational, ecological and clinical trials reveal positive results in regards to the implementation of antiretroviral drugs as preventative measures against HIV transmission. Progress in scaling up access to treatment is brisk, and as of 2023 there are over 29 million people receiving antiretroviral therapy. Challenges to scaling access to treatment include cost and drug resistance.
TasP's legitimacy has influenced the World Health Organization's (WHO) 2015 shift from "test and wait" to "test and treat" recommendation, focusing on alerting as many people as possible of their HIV status through testing and starting them on ART treatment, regardless of their viral load or CD4 count. The diminished rate of new HIV infections brought about by these strategies are marked progress towards UNAIDS' 90-90-90 and 95-95-95 target to eliminate HIV/AIDS as a public health crisis by 2030. However, key populations in countries in Africa, Asia, and the Middle East may still have lower access to treatment. Understanding whether marginalized groups have access to testing and treatment are often hampered by harsh laws that do not allow for the accurate collection of data regarding these communities. Estimates of the number of people who are men who have sex with men, female sex workers, and/or drug users are very difficult to ascertain, rendering understanding diagnosis and access to treatment levels also difficult to determine.
TasP and test and treat to maximize access to early treatment is now the global standard for HIV prevention.
== HIV Prevention Trials Network clinical trial 052 ==
Early work by Quinn in Uganda demonstrated that transmission was reduced by over 90% when people living with HIV were on treatment and virally suppressed. Observational evidence accumulated and the Attia meta analysis supported the 2008 Swiss Statement that said that those suppressed on treatment had little or no chance of transmission. Many experts, citing the Bradford Hill criteria, accepted this observational data. However, others called for randomized control trials.
The HIV Prevention Trials Network conducted a clinical trial, HPTN 052, that analyzed the effectiveness of antiretroviral drugs on the HIV-1 virus. 1,783 HIV sero-discordant couples, or couples that consist of an HIV-positive individual and an HIV-negative partner, from nine different countries were a part of the study, 97% of the couples being heterosexual. In August 2011, the HIV Prevention Trials Network concluded that the likelihood of transmission between the couples who were provided early antiretroviral therapy reduced by 96%. When the trial completed, the overall reduction percentage of HIV-1 transmission between couples who were treated early with ART or received the delay-ART treatment was 93%. The study's purpose was to reveal that HIV-1 viral transmission can be prevented through treatment, leading many regions to incorporate a treatment as prevention plan into their public health policy for responding to HIV.
== Implementation ==
Treatment as prevention has been used as a form of controlling the spread of HIV since the mid-1990s, initially in the context of preventing the transmission of the virus from mothers to their children. Research in 1994 revealed how the drug zidovudine can reduce vertical transmission. The testing and treatment of HIV-positive mothers during pregnancy, childbirth, and breastfeeding has since led to the reduction of the risk of transmission by up to 95%. A program for offering ARVs for life to any HIV-positive pregnant woman called "Option B+" served as a precursor to the "test and treat" strategy that is now being rolled out in various countries. Assessments of the Option B+ program are able to aid in the improvement and further establishment of "test and treat".
From 2013 to 2018, the global number of people receiving ARV treatment rose by a third, and now is at 23 million people. This is a result of increased use of "test and treat". In 2015, about one fourth of the 148 countries informed about national treatment plans had initiated the WHO's "test and treat" approaches, and 44 more countries pledged to implement them by the end of 2016. The five-year HPTN 071 "PopART" study is currently examining the efficacy of TasP in 21 communities throughout South Africa and Zambia. PopART is focused on the advantages and downfalls of providing free voluntary HIV testing in combination with instant treatment for those who test positive. This study has a scope of about 1 million residents, making it the largest executed test of "test and treat".
== Challenges and risks associated with Treatment as Prevention ==
While TasP has a huge potential to prevent the further spread of HIV worldwide, the major barrier to implementing TasP is lack of political will. Specifically, estimates suggest that only around 60% of all resources for HIV go towards ensuring diagnosis and treatment while the rest is spent on other priorities. In some African countries multiple billions of dollars have been allocated with some only achieving 60-70% ART coverage. Global HIV control priorities often include 90-90-90 and 95-95-95 (proxies for TasP coverage), however, TasP is often not included when calling for increased efforts in preventing and ending the epidemic. Many of the most vulnerable populations may not be seeing these benefits as a result of a social and political climate that is deterrent to seeking testing and treatment, in addition to making it difficult to stick with the ARV regimen. With this, antiretroviral therapy should be implemented within every country's public health policy, yet challenges and risks are faced when such implementation is put into action. While vulnerable populations often have difficulty accessing services, it is unknown what proportion of MSM, FSW and DUs are on ART due to uncertainties in determining estimating the numbers of people and the understandable reluctance for many people to disclose whether they are in these groups when accessing services.
=== Overall cost of treatment ===
For many countries, especially low- and middle-income countries, the overall cost of treatment in the 1990s and early 2000s was too expensive for infected patients to afford it. In addition, individuals with low incomes in United States struggle to pay high prices set by pharmaceutical companies for antiretroviral drugs. As a result, it was implausible for a global treatment system or policy to be put into place since no universal HIV/AIDS test and medication regimen existed and due to technology and wealth disparities worldwide. However, with the advent of rapid HIV testing (including self testing), viral load testing, and effective ART regimens at less than $100 per year treatment scale up (read widespread implementation of TasP) is now a reality in many settings.
=== Side effects caused by ART ===
Newer ART regimens are largely side effect free and side effects are no longer a major barrier to starting treatment. Additionally, newer regimens are almost 100% resistance free and can translate into lifelong effective therapy. In the past antiretroviral drugs can also cause patients to experience various side effects including becoming nauseated or developing gastrointestinal pains and issues, as a results of medications at times being too toxic for a specific individual. In addition, in low and middle income countries (LMICs), an increase in the number of side effects expressed in a country leads to the underdeveloped health care systems of said country having to use their limited funds to account for service delivery costs of medications to counter the newly inflicted problems among infected individuals.
=== HIV-1 drug resistance ===
HIV drug resistance has also come to the forefront of worries in regards to how effective TasP can be against the spread of the virus. The widespread global use of ARVs is feared to lead to an increase in drug resistance as a result of interrupted treatment and a lack of adherence. Despite these fears widespread resistance threatening the efficacy of ART has not emerged despite tens of millions of people being on treatment in the harshest conditions. Likewise fears of non-adherence also proved to be overblown.
Developed countries, when first discussing the implementation of ART in the developing world, believed that the allowance of third-world countries to have early access to antiretroviral drugs would potentially lead to the development of drug resistance. Recently, such resistance has developed in third-world countries as a result of medication combinations failing to diminish the viral load of HIV-1 in infected individuals, the lack of existence of virological testing to discover such failures in patients in these regions of the world and the lack of different variants of medication regimens to suppress the evolution of the infection.
In the case of resistance to the first-line of combination medications for the HIV-1 virus, mutations occurred within genes of HIV-1 viral RNA that enters T-cells within the human body. Mutations are the result of reverse transcriptase, the enzyme that is responsible for reverse-transcribing the viral RNA into viral DNA, having a high error rate when copying the viral RNA. The mutations occur within the nucleotide bases of the new viral DNA.
After the mutated viral DNA is implemented into the host cell's DNA, the DNA is translated to produce viral proteins that will assist in the infecting of other surrounding cells. When translated, the mutations lead to different amino acids formulating the viral proteins. The primary proteins that are focused upon in relation to HIV-1 are the viral protease and reverse transcriptase because these enzymes are the ones that are inhibited by antiretroviral medications.
Overall, the transmitted drug resistance (TDR) among resource-limited setting (RLS) adults in regions such as Africa, Asia and Brazil has increased, the calculated rate of TDR being 6.6% as of 2015. In addition, studies that were conducted within these regions revealed a correlation between the length of time ART was implemented as a method of treatment and the likelihood of the establishment of TDR. The studies concluded that the likelihood of TDR in LMICs is 1.7 times greater if ART is implemented for equal to or more than five years.
=== Necessity for adherence ===
Antiretroviral therapy requires HIV-positive individuals to abide by strict adherence and thrives when countries have the necessary HIV services available for infected individuals to access. Management of HIV/AIDS includes services such as HIV testing and diagnosing, consistent HIV care and treatment, education lessons regarding how to use ART effectively and distribution methods to ensure individuals receive their medications. In LMICs, HIV testing has expanded, which, in turn, creates the opportunity for the initiation of treatment as a preventative method as an increasing number of infected individuals are aware of their HIV status.
== Short-term and long-term solutions ==
=== Global Fund ===
In 2002, The Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund) was a financial initiative developed to raise and provide funding to the developing world in an attempt to enhance their care and treatment programs for individuals who are living with HIV/AIDS, TB and malaria. For the international organization to be successful, developed countries must work in conjunction with third-world countries, private organizations, civil society and affected communities to ease the impact of the epidemics. In an attempt to prevent the misuse of funding provided by the Global Fund, a system has been set in place for countries to apply for funding through submission of proposals and implementation plans. As a result of the impact of the Global Fund, seventeen and a half million people are being treated with antiretroviral therapy as of 2017.
=== PEPFAR ===
In 2003, in an attempt to promote the importance of HIV research and funding, George W. Bush enacted the President's Emergency Plan for AIDS Relief (PEPFAR/Emergency Plan), committing the United States government to authorize $15 billion to support HIV/AIDS, tuberculosis (TB) and malaria over a five-year period in third-world countries. With the improvement of ART treatment as a result of PEPFAR, the number of new infections has declined by 51-76% worldwide since the enactment of the Emergency Plan. In addition, the funding received from PEPFAR has allowed developing countries to treat millions, prevent millions of new infections and provide other care services to millions of already infected individuals.
=== Generic drugs ===
Antiretroviral generic drugs are medications that are identical to brand names drugs. Pharmaceutical companies in Brazil and India like Cipla and Farmanguinhos have dedicated their efforts to reduce the prices of ART drugs. For example, Cipla has reduced prices of antiretroviral drugs for poor third-world countries to practically zero. Through their initiatives in combination with pharmaceutical companies in Brazil, individuals in third-world countries are being provided access to antiretroviral treatment regimens that they could not afford before. Today, ART drug combinations cost $75 in Africa.
With the providing of generic drugs at such low costs in the developing world brings about turmoil regarding the current expensive prices of antiretroviral drugs in the United States. Antiretroviral drug regimens in the United States range in price from $10,000 to $40,000 as a result of pharmaceutical companies having control of price regulation. With this, the future of price reduction in the United States depends on pharmaceutical competition and negotiation to make antiretroviral drugs available to all low- and middle-income individuals despite where they may live in the world.
=== Community-based care ===
"Community-based care" refers to communities with high rates of HIV transmission and infected individuals taking the initiative to end the spread of AIDS within their own community. Community based care services include access to:
HIV testing
directly observed therapy with HAART (DOT-HAART)
DOT-HAART refers to the administration and delivery of antiretroviral drugs by community members to ensure individuals adhere to drug regimens. Such community members observe the taking of medications to provide guidance and clarify any questions infected individuals may have.
educational services regarding HIV transmission and prevention methods
condoms and other barrier methods
maternal-child transmission packages
social services for families and orphaned children
other services to ensure suppression of HIV transmission
The utilization of community-based care assists in the efforts in diminishing HIV transmission to reduce the number of new infections annually.
There have been studies of key populations in communities like Cape Town, South Africa that assert the benefits of community-based approaches, like adherence "clubs", where participants meet every two months for group counseling and the distribution of their ARV treatments.
=== Cost-effectiveness ===
In South Africa and India, a clinical trial was completed to determine the cost-effectiveness of administering antiretroviral drugs early to treat HIV. Sero-discordant couples were used in the study and each couple was provided either early or delayed antiretroviral treatment. Over a five-year period, researchers concluded that early ART was cost-saving in South Africa and cost-effective in India. Over a lifetime, early ART was determined to be very cost-effective in both countries. After the release of such results, other countries have concluded that it is cost-effective to utilize combination therapy resources especially when implementing them early into practice.
=== Single-tablet regimens ===
When doctors prescribe antiretroviral drugs to patients, the initial prescriptions consist of drug regimens that contain multiple pills of different classes that must be taken daily. Although triple therapy is most commonly used, there are single-tablet regimens (STRs) that exist to treat AIDS. STRs are created through combining three antiretroviral drugs into one pill. Single-tablet regimens are only available at specific clinics around the world—meaning there is limited access to these regimens—and are only prescribed if a doctor feels a patient will struggle with the treatment schedule of antiretroviral therapy. The implementation of STRs worldwide could serve as a replacement for the triple-drug antiretroviral therapy and allow patients to have a less strict ART schedule to abide by.
=== Injectable HIV-1 treatment ===
The greatest struggle faced by HIV-positive individuals is maintaining compliance of taking the ART pills every day. The lack of compliance can lead to drug failure or drug resistance. In July 2017, The Lancet released an article revealing the results of a study conducted involving an injectable HIV-1 treatment to serve as a future replacement for the three-drug oral combination therapy. This new treatment would consist of two drugs: cabotegravir and rilpivirine, and injections would occur every four to eight weeks for each patient. Thus far, the treatment has passed Phase II of the clinical trial and has been proven to be just as effective as the oral regimen.
In August 2018, ViiV Healthcare, a collaboration between GlaxoSmithKline and Pfizer revealed the findings of a study that found that receiving monthly injections of two long-acting ARVs over a course of 48 weeks is just as effective as taking daily pills. However, logistical questions still remain about cost, the effect of missed shots, and side effects of taking monthly injections. The study, which is called Antiretroviral Therapy as Long-Acting Suppression (ATLAS) is experimenting with the drugs cabotegravir—made by ViiV—and rilpivrine, which is a licensed drug from Janssen Sciences Ireland UC. ATLAS has a scope of 618 HIV-positive individuals from 13 countries, all of which had reached undetectability. Half of the participants continued with daily pills, while the others switched to receiving an injection each month. Viral suppression was the same in both groups. The results of the ATLAS study may also impact those who are not yet infected and are participating in PrEP, yet are reluctant to take daily pills. Other studies are underway which are testing viral suppression in HIV-positive people who have never taken antiretrovirals, and whether the injectables are still effective when only taken once every 8 weeks. With the introduction of long-acting drugs come questions on the optimal dose and timing, and how the virus may mutate to become resistant to the new form of treatment.
== Moving forward ==
Treatment as prevention has the ability to shift the paradigm of how HIV is received and treated. The effects of universal testing and treatment, and connecting people with resources for care will allow for global effects in terms of reduced rates of new HIV infections. The success of TasP is contingent upon innovation in strategies to increase the rate of HIV testing, along with exploring other dimensions of improving adherence, such as including cognitive and emotional support in those efforts. The cost of viral load testing is another factor in TasP's longevity, and increased access to that resource will allow for greater access to the beneficial effects of treatment as prevention.
== References == | Wikipedia/Treatment_as_prevention |
The expressive therapies are the use of the creative arts as a form of therapy, including the distinct disciplines expressive arts therapy and the creative arts therapies (art therapy, dance/movement therapy, drama therapy, music therapy, writing therapy, poetry therapy, and psychodrama). The expressive therapies are based on the assumption that people can heal through the various forms of creative expression. Expressive therapists share the belief that through creative expression and the tapping of the imagination, people can examine their body, feelings, emotions, and thought process.
== Definition and credentialing ==
Expressive arts therapy is the practice of using imagery, storytelling, dance, music, drama, poetry, movement, horticulture, dreamwork, and visual arts together, in an integrated way, to foster human growth, development, and healing. Expressive arts therapy is its own distinct therapeutic discipline, an inter-modal discipline where the therapist and client move freely between drawing, dancing, music, drama, and poetry.
According to the National Organization for Arts in Health (NOAH), what distinguishes the six creative arts therapies—art, dance/movement, drama, music and poetry therapy as well as psychodrama—from expressive arts therapy is that expressive arts therapy interventions are designed to include more than one of the "expressive" art forms (art, dance, drama, music, poetry), whereas creative arts therapists, such as art, dance/movement, drama, music, poetry and psychodrama therapists, are often intensively trained and educated to use only one modality in their practice.: 6–7 But NOAH also acknowledged that the terms "are often used interchangeably in the field", and that in any case all such professionals should collaborate closely.: 10, 18, 22
The International Expressive Arts Therapy Association (IEATA) is the responsible organization handling the credentialing of expressive arts therapists.
The National Coalition of Creative Arts Therapies Association (NCCATA) connects all six modalities of the creative arts therapies. However, each modality of the creative arts therapies has its own national association that regulates professional credentials, establishes educational standards and hosts annual conferences for the purpose of exchanging new ideas and research.
== History ==
=== Early years ===
Margaret Naumburg, Edith Kramer, Hanna Kwiatkowska and Elinor Ulman have been credited with being the pioneers of the field of sensory art therapy. While all of these scientists made significant contributions, Margaret Naumburg has been hailed the "Mother of Art Therapy". Her work focused on the use of art, mainly as a psychoanalytic diagnostic tool. It followed closely other psychoanalytic practices of the time, and was viewed as the communication of unconscious ideas and emotions that were being expressed by the patient.
== Modern approaches ==
Today's art therapy is broken down into three different approaches: psychodynamic, humanistic, and learning and developmental. The psychodynamic approach uses terms such as "transference" and defense mechanism to describe why individuals express the art in the way they do, and why this is an expression of the subconscious. The humanistic approach is more of a positive psychology approach, and is defined by an optimistic view of humans, and how expression through their art allows them to take control over these emotions. The learning and developmental approach focuses on the art therapy as a method to assist children who have emotional and developmental disabilities.
== Education ==
Each national association of the different modalities of expressive therapies sets its own educational standards. In the United States, there are a fair number of colleges that offer approved programs in compliance with the national associations' credentialing requirements.
There are 37 universities for music therapy, 34 universities for art therapy, seven universities for dance/movement therapy, and five universities for drama therapy, as well as 5 universities for expressive arts therapy, that have approved master's degree programs in the United States. In addition, the American Music Therapy Association (AMTA) has 75 undergraduate music therapy programs approved. Once finished with an academic degree, potential therapists have to apply for credentialing at the responsible national association.
== Creative arts therapies modalities ==
There are six creative arts therapy modalities, recognized by the NCCATA, including art therapy, dance therapy, drama therapy, music therapy, poetry therapy and psychodrama. In some areas, the terms Creative Arts Therapy and Creative Arts Therapist may only be used by those who are properly licensed, as is the case in the State of New York.
=== Art therapy ===
Created in the 1940s, Art therapy consists of the combination of psychotherapy and art. The creative process as well as the created art piece serves as a foundation for self-exploration, understanding, acceptance and eventually healing and personal growth. The creative act in therapy therefore can be seen as a means of re-experiencing inner conflict connected to resolution. The four main types are expression, imagination, active participation, and mind-body connection. Assisting in those with depression, breast cancer, and asthma, art therapy can be done at any age and does not require and skill set. Art Therapy has undergone extensive research which revealed that it decreases anxiety, increases self-concept and quality of life, and reduces negative thoughts. With two main goals in mind, Art Therapy strives to enhance personal and relational goals for those in need. Self-esteem, social skills, and cognitive functions are also said to be an area of importance. A certified art therapist is essential in order for the therapy to ensure improvement, however common art therapy using even a friend to discuss trauma can be enough to help someone.
=== Dance/movement therapy ===
Like other creative arts therapy modalities, dance/movement therapy is based on the assumption that "mind, body and spirit are inseparable and interconnected" (ADTA). Movement is the primary tool of intervention in a therapy session, but dance/movement therapy also uses the art of play in therapy. Like other creative art therapies it uses primarily nonverbal communication. Dance and movement therapy has shown to be the most beneficial in those who enjoy exercises that involve less talking an expression through movements.
=== Drama therapy ===
Drama therapy refers to the combination of the two disciplines drama/theatre and psychotherapy. Drama Therapy, as a hybrid of both disciplines, uses theater techniques to treat individuals with mental health, cognitive, and developmental disorders. Through the art of play and pretend, patients gain perspective in therapy to their life experiences, which in the field is referred to as "aesthetic distance".
=== Music therapy ===
Music Therapy is the use of music, music-making, or other music-related interventions within a therapeutic relationship. Music therapy is a broad field with many areas and populations to specialize in. A holistic practice, music therapy can address emotional/psychological, cognitive, communication, motor, sensory, pain, social, behavioral, end of life, and even spiritual needs. This is due in part to music being processed in many areas of the brain. Music therapy helps patients "communicate, process difficult experiences, and improve motor or cognitive functioning" (Jenni Rook, MT-BC, LCPC, 2016). When used as psychotherapy, at its core, music therapy may use music as a symbolic representation and expression of the psychological world of the individual.
Townsend's study in the "Journal of Child Psychology and Psychiatry and Allied Disciplines" has shown that 1 in 5 children who lost their parent are most likely to develop a psychiatric disorder. This finding underscored the significance of instructors to initiate writing on the subjects of "death" and "loss" in academic writing. One of the few ways to bring this into practice is through music-making or songwriting.
Songwriting allows individual to process the trauma they experience in their life in three ways: By telling stories that have been passed down to them; by connecting their songs to cultural traditions; and by sharing their feelings with each other and their community. Songwriting is a way to organize a narrative. Through forming a coherent story, an unpleasant or chaotic situation can be made more approachable.
Deroo's research focuses on the Black teenage girl, Noriah, who wrote the song named "Air I Breathe" in remembrance of her passing mother and sister. Through Noriah's story, Deroo tries to find the answer to how can youths tackle the nuanced implications of loss using creative expression. Noriah's experience shows that there can be many therapeutic possibilities with songwriting. By using eulogies in her songs, Noriah is able to communicate her bond with her lost ones through lyrics. As demonstrated with the composition of "Air I Breathe", while the memories of Noriah and her departed would eventually fade, "Air I Breathe" serves as a permanent reminder for Noriah to keep in mind the memories. During a speech in the university classroom, Noriah expressed her purpose in writing the song. “I wrote a song about the loss of my little sister and biological mother, back to back, and so much love I had for them, and what I couldn't get out. It was a way to get out the rest of the feeling that I had—telling that story to you directly, but I could sing it instantly. It was like a form of therapy” (Deroo).
In addition, writing and sharing about lost can benefit the community who then can learn from the experiences that were previously private. As Ryden argues, audiences embrace the story as if they are their own, making meaning of the experience in their own ways. This idea was further demonstrated through the interaction between Noriah and Wendy. Being inspired by Noriah's song, Wendy entered the room with her own experience of loss.
Music Therapy also benefits a variety of disorders, like cardiac and mental disorders. It aids those who suffer from depression, anxiety, autism, substance abuse, and Alzheimer's. In cases where a person is suffering from mental disorders, music relieves stress, improves self-esteem, etc. Evidence has shown that people who have used Music Therapy in the past have improved in several aspects of life that do not concern just those suffering from mental illness. In music therapy, people may improve their singing which may then impact their ability to speak. Therefore, it can change several aspects of life, not just those of helping mental illness.
=== Poetry therapy ===
Poetry therapy (also referred to using the broader term bibliotherapy) stands out from other creative arts therapies, which are all based on the assumption of the existence of a language that functions without words. Poetry therapy, however, is the use of the written word to bring healing and personal growth. For instance, To, The Bravest Person I Know is one of the classic illustrations of how to use poetry to overcome anxiety, depression (mood), and other sorts of insecurity.
In Manning's research about high school poetry classes, he found that through poetry classes, students are able to reimagine their struggles as a source of strength, develop a sense of possibility, and build bonds that empower them to speak through the silence that surrounded their life struggles. Manning advocated the need for opportunities for creative expression in classroom spaces. Not only would this practice encourage youth to express themselves authentically using their own words in an environment where their voice is constrained by school literacy, but it would also contribute to positive changes to the current school environment by honoring students' voices and life experiences.
=== Psychodrama ===
Psychodrama is a distinct form of psychotherapy developed by Jacob L. Moreno in the early 20th century. Moreno, a trained psychiatrist himself, had the goal of creating a more effective, action-based form of psychotherapy. Later it was modified by other authors according to Sigmund Freud and C.G. Jung. He developed a clear three phase structure (warm up, action, sharing) to his therapy as well as multiple intervention-methods that are still used by psychodrama therapists today.
Although related, psychodrama and drama therapy describe different modalities within the field of creative arts therapies. Whereas psychodrama uses real-life experience of the patients in therapy to "practice new and more effective roles and behaviors" (ASGPP), drama therapy lets the patients explore more fictional stories, such as improvised scenes, myths or fairy tales.
== Benefits ==
=== Self-discovery ===
This discovery often leads to a relief of emotional tension caused by past events, and can be used as a coping mechanism.
Given the ability to claim your own story, which helps with personal affirmation.
=== Empowerment ===
Expressive therapy gives individuals the ability to articulate their fears and stresses in a non-conventional way, and often leads to sense of control over these emotions.
Particularly beneficial for vulnerable populations such as youth experiencing homelessness, as it helps them process trauma, regulate emotions, and rebuild a sense of identity and self-worth.
=== Stress relief ===
Effective for stress relief by itself, but can provide even better results if paired with other relaxation devices such as guided imagery.
Expressive therapy provides individuals with a foundation on which they can recognize and confront pain.
=== Physical pain relief and rehabilitation ===
Expressive therapy has been shown to help decrease pain in patients who are recovering from illness and injury. It has also been used in patients who are chronically or terminally ill, to provide relief and pain control.
== Empirical evidence ==
=== Ball (2002) ===
Ball conducted long-term research on five children who were considered to be severely emotionally disturbed. These children participated in 50 art therapy sessions, and the results suggested that the art therapy was successful, and the children showed marked progress in their treatment over the course of the 50 sessions.
=== Pifalo (2006) ===
In this study, 41 girls or young women who had been sexually abused were given structured group art therapy for eight weeks, and were measured before treatment using the Briere's Trauma Symptom Checklist for Children (TSCC). They were given the test again after the treatment, and for 9 out of 10 of the girls, a statistically significant reduction in scores on the test was observed.
=== Bar-Sela, Atid, Danos, Gabay & Epelbaum (2007) ===
This study worked with 60 adults who had cancer. These adults attended weekly individual art therapy, in addition to watercolor painting classes. After just four sessions, the experimental group saw marked and significant improvement in depression and fatigue, as measured by the Hospital Anxiety and Depression Scale and a brief fatigue inventory. While they showed a decrease in depression, there was no significant difference in the levels of anxiety of the patients.
=== Gusak (2006) ===
In this study, the researcher worked with 29 incarcerated men. The men attended eight sessions of group art therapy, and were tested before and after the treatment using the Beck Depression Inventory Short Form. After the eight sessions, all of the men showed significant improvement in the symptoms of depression and their score on the Beck Depression Inventory reflected these improvements.
=== Bulfone et al. (2009) ===
In this study Bulfone et al. utilized music therapy as their treatment. 60 women who had been diagnosed with stage 1 or 2 breast cancer were randomly assigned to a control or experimental group. The control group received standard assistance before chemotherapy, while the experimental group had the chance to listen to music before the chemotherapy began. The results showed that the anxiety levels of the experimental group were significantly lower than those of the control group, and also showed a significantly lower level of depression.
== Applications ==
=== Expressive writing therapy in virtual setting (2024) ===
Virtual settings have expanded the reach of expressive writing therapy. A study on intimate partner violence (IPV) survivors demonstrated that online writing sessions in a structured environment significantly reduced trauma symptoms, providing a safe and accessible space for emotional processing.
== See also ==
Cinema therapy
Clinical psychology
Counseling psychology
Expressive therapies continuum
Freedom of speech
Psychotherapy
== References ==
== External links ==
International Expressive Arts Therapy Association (Worldwide)
National Coalition of Creative Arts Therapies Associations (United States)
American Art Therapy Association
American Dance Therapy Association Archived 2020-02-10 at the Wayback Machine
North American Drama Therapy Association
American Music Therapy Association
National Association for Poetry Therapy
American Society for Group Psychotherapy and Psychodrama
Expressive Arts Therapy Association of Hong Kong (Hong Kong and Mainland China) | Wikipedia/Expressive_therapy |
Bibliotherapy (also referred to as book therapy, reading therapy, poetry therapy or therapeutic storytelling) is a creative arts therapy that involves storytelling or the reading of specific texts. It uses an individual's relationship to the content of books and poetry and other written words as therapy. Bibliotherapy partially overlaps with, and is often combined with, writing therapy.
Distinct from the creative arts therapy is bibliotherapy as a supportive psychotherapy, a brief self-help intervention where through the reading of a chosen standard manual, emotion regulation skills are acquired through either behavioral therapy or cognitive therapy techniques. Two popular books used for this are The Feeling Good Handbook for cognitive therapy and Control Your Depression for behavioral therapy. The main advantage of this psychotherapy compared to cognitive behavioral therapy (CBT) is its cost-effectiveness, although, especially for complex presentations, CBT tends to have more positive treatment outcomes. It has been shown to be effective in the treatment of mild to moderate depression, with cognitive bibliotherapy having a long-lasting effect. Modest evidence also exists to the symptom reduction of alcohol dependence, self-harm and panic disorder.
Unstructured and more informal bibliotherapy fits under creative arts therapies, possibly including reading or activity recommendations by a librarian or health professional based on perceived therapeutic value. More structured bibliotherapy can be described as supportive psychotherapy, where more consideration is placed on the therapist in the selection of reading material and in including other activities to facilitate skill acquisition and symptom reduction. An important difference between the two is the greater empirical support of symptom reduction in bibliotherapy as a supportive psychotherapy.
== History ==
Bibliotherapy is an old concept in library science. According to the Greek historian Diodorus Siculus, in his monumental work Bibliotheca historica, there was a phrase above the entrance to the royal chamber where books were stored by King Ramses II of Egypt. Considered to be the oldest known library motto in the world, ψῡχῆς ἰατρεῖον on, is translated: "the house of healing for the soul". Galen, the extraordinary philosopher and physician to Marcus Aurelius of Rome, maintained a medical library in the first century A.D., used not only by himself but by the staff of the Sanctuary Asclepion, a Roman spa famous for its therapeutic waters and considered to be one of the first hospital centers in the world. As far back as 1272, the Koran was prescribed reading in the Al-Mansur Hospital in Cairo as medical treatment.
In the early nineteenth century, Benjamin Rush favored the use of literature in hospitals for both the "amusement and instruction of patients". By the middle of the century, Minson Galt II wrote on the uses of bibliotherapy in mental institutions, and by 1900 libraries were an important part of European psychiatric institutions.
After the term bibliotherapy was coined by Samuel McChord Crothers in an August 1916 Atlantic Monthly article, it eventually found its way into the medical lexicon. During World War I, the Library War Service stationed librarians in military hospitals, where they dispensed books to patients and developed the emerging "science" of bibliotherapy with hospital physicians. When they returned from the war, they tried to implement these ideas in hospital libraries. E. Kathleen Jones, the editor of the book series Hospital Libraries, was the library administrator for the McLean Hospital in Massachusetts. This influential work was first published in 1923, and then updated in 1939, and again in 1953. Pioneer librarian Sadie Peterson Delaney used bibliotherapy in her work at the VA Hospital in Tuskegee, Alabama from 1924 to her death in 1958. Elizabeth Pomeroy, director of the Veterans Administration Library Service, published the results of her research in 1937 on the efficacy of bibliotherapy at VA hospitals. The United Kingdom, beginning in the 1930s, also began to show growth in the use of reading therapy in hospital libraries. Charles Hagberg-Wright, librarian of the London Library, speaking at the 1930 British Empire Red Cross Conference, spoke about the importance of bibliotherapy as part of "curative medicine" in hospitals. In addition, reports from the 1930 Public Health Conference about bibliotherapy were included in the British journal Lancet. By the 1920s, there were also training programs in bibliotherapy. One of the first to offer such training was the School of Library Science at Western Reserve University followed by a program at the University of Minnesota School of Medicine.
With hospitals taking the lead, bibliotherapy principles and practice developed in the United States. In the United Kingdom, some felt that bibliotherapy lagged behind the US and Joyce Coates, writing in the Library Association Record, felt that "the possibilities of bibliotherapy have yet to be fully explored". In 1966, the Association of Hospital and Institution Libraries, a division of the American Library Association, issued a working definition of bibliotherapy in recognition of its growing influence. Then, in the 1970s, Arleen McCarty Hynes, a proponent for the use of bibliotherapy, created the "Bibliotherapy Round Table" which sponsored lectures and publications dedicated to the practice.
== Changing definitions ==
In its most basic form, bibliotherapy is using books to aid people in solving the issues that they may be facing at a particular time. It consists of selecting reading material relevant to a client's life situation. Bibliotherapy has also been explained as "a process of dynamic interaction between the personality of the reader and literature – interaction which may be utilized for personal assessment, adjustment, and growth." Bibliotherapy for adults is a form of self-administered treatment in which structured materials provide a means to alleviate distress. The concept of the treatment is based on the human inclination to identify with others through their expressions in literature and art. For instance, a grieving child who reads, or is read a story about another child who has lost a parent may feel less alone in the world.
The concept of bibliotherapy has widened over time, to include self-help manuals without therapeutic intervention, or a therapist "prescribing" a movie that might provide needed catharsis to a client.
The Online Dictionary for Library and Information Science (2011) defines bibliotherapy as:
The use of books selected on the basis of content in a planned reading program designed to facilitate the recovery of patients suffering from mental illness or emotional disturbance. Ideally, the process occurs in three phases: personal identification of the reader with a particular character in the recommended work, resulting in psychological catharsis, which leads to rational insight concerning the relevance of the solution suggested in the text to the reader's own experience. Assistance of a trained psychotherapist is advised.
Two forms of bibliotherapy exist: clinical and developmental. Clinical bibliotherapy is solely used by qualified personnel in a therapeutic setting and developmental bibliotherapy is a useful tool to utilize before a problem arises. Developmental bibliotherapy can be useful for issues such as nightmares as children age. Developmental bibliotherapy is often used by teachers or parents, however, if an issue arises that a teacher or parent cannot handle, clinical bibliotherapy is needed.
== Clinical use ==
Although the term "bibliotherapy" was first coined by Samuel Crothers in 1916, the use of books to change behavior and reduce distress has a long history, dating back to the Middle Ages. When applied in a therapeutic context, bibliotherapy can comprise both fictional and non-fictional materials. Fictional bibliotherapy (e.g., novels, poetry) is a dynamic process, where the material is actively interpreted in light of the reader's circumstances. From a psychodynamic perspective, fictional materials are believed to be effective through the processes of identification, catharsis and insight. Through identification with a character in the story the reader gains an alternative position from which to view their own issues. By empathizing with the character the client undergoes a form of catharsis through gaining hope and releasing emotional tension, which consequently leads to insights and behavioral change. Working with an imaginative journey and a specific selection of metaphors, proponents claim that a therapeutic story approach has the potential to shift an out of balance behavior or situation back towards wholeness or balance. A patient might also find it easier to talk about his issues if he and the therapist can pretend that they are talking about the character's issues. Proponents suggest that the story form offers a healing medium that allows the listener to embark on an imaginative journey, rather than being lectured or directly addressed about the issue.
McKenna et al. (2010) conducted a review on psychotherapies for older depressed people, which concluded that bibliotherapy is effective. Glavin et al. (2017) also conducted a review and concluded that bibliotherapy could effectively treat post-traumatic stress disorder, even though well-designed RTCs still need to ascertain this statement.
The use of bibliotherapy in mental health programs, including those for substance abuse, has been shown to be beneficial to patients in the United Kingdom where it is a popular resource.
=== Treatment tracks ===
Bibliotherapy can be performed using affective treatment techniques, cognitive behavioral therapy (CBT), and visual-based materials. Affective bibliotherapy relies upon fiction which can aid participants. By empathizing with a story's character, the client undergoes a form of catharsis by gaining hope and releasing emotional tension. There can also be a connection made between the circumstances in a story and the reader's own personal issues. This, consequently, leads to insights and behavioral change. Bibliotherapy using CBT relies mainly on self-help books which work to correct negative behaviors by offering alternative, positive actions. Visual-based materials, such as graphic novels, utilize both affective and CBT techniques.
==== Cognitive treatment ====
The gains achieved in cognitive bibliotherapy illustrate that the most important element in cognitive bibliotherapy is content of the program and not the individual interactions with a therapist. Bibliotherapy using CBT have been empirically tested the most and directed CBT appears to be the most prevalent methodology in the literature. The selection of CBT books is important since there are many on the market that purport to help. Pardeck's analysis on choosing books is quite instructive and much of his criteria mirror what librarians teach in information literacy. These include the authority of the author on the topic, the type of empirical support offered for treatment claims, the existence of studies testing its clinical efficacy, and a comparative review of other books.
==== Affective treatment ====
There is not as much research on using fiction in bibliotherapy when compared to cognitive self-help books. The recent work of Shechtman has been important in investigating the use of affective literature for bibliotherapy. In her work on counseling with aggressive boys, Shechtman discusses the deficits these children exhibit and describes affect disorders with symptoms of emotional arousal, low levels of empathy, and difficulties in self-expression. Using integrative treatment whereby the patient explores the problem, gains insight, and commits to change, Shechtman found that using affective bibliotherapy techniques achieved therapeutic change while indicating gains in empathy and insight.
==== Visual treatment and graphic novels ====
In the simplest sense, graphic novels are long-form comic books, usually 100 pages or more in length. The application of graphic novels in this context will allow people struggling with literacy to have better access to materials. Dozens of graphic novels have been published over the last decade that address public health topics, such as depression, drug abuse, and PTSD. Public health-based comic books originated in the 1940s. The earliest public health comics averaged around twelve pages and were aimed at preventive instruction for children. Over the last fifteen years, however, the genre has evolved and public health graphic novels and are now commonly 150 pages long and focus more on adult struggles with physical or mental illness. This change has gotten the attention of medical professionals who gather and evaluate these materials. Currently, a group of physicians, professors, artists, and bioethicists run the website Graphic Medicine and hosts an annual conference to discuss the use of graphic novels and comic books in health.
There is a wide range of research that indicates graphic novels are an effective tool for people struggling with literacy and communication problems. They also have been shown to be effective with populations that have trouble with traditional literacy instruction. Resistance to learning can take many forms, some of which can be seen in populations involved with the criminal justice system. Graphic novels are most often used to entice the group referred to as "reluctant readers", people who have abandoned reading for pleasure. While this group may be literate in the basic sense, research shows that people who read for pleasure continuously improve vocabulary and language skills, skills that can help people rehabilitate after incarceration. Research shows graphic novels are of use to students with traditional learning disabilities, like dyslexia and also have been shown to be effective when used in a bibliotherapeutic context to assist people with mental illness in explaining their own struggles to others. Graphic novels have also been described by professionals in the field as especially apt for portraying the struggles associated with mental illness.
== Non-clinical use ==
Non-clinical bibliotherapy can consist solely of reading, or it can be complemented by discussion or play activity. A child might be asked to draw a scene from the book or asked whether commonality is felt with a particular character in the book. The book can be used to draw out a child on a subject (s)he has been hesitant to discuss.
Of necessity, bibliotherapy originally used existing texts. Literature that touched on the particular subject relevant to the child provided the source material. (For example, Romeo and Juliet is typically read in 8th or 9th grade as Romeo is 15 and Juliet is 13; students at that age can identify with them.) Recently it has become possible to find texts targeted to the situation; e.g. many of the Berenstain Bears books target particular behaviors and responses to certain situations.
Many therapeutic stories are written for specific individual needs, but practitioners have also used them to build psychological resilience when groups and communities face challenges. For example, therapeutic storytelling can play a role in creating inclusive classroom and work communities. Therapeutic stories are also sometimes referred to as "healing stories". In the US, the National Storytelling Network has a special interest group called the Healing Story Alliance.
=== In pedagogy ===
Claimed advantages of bibliotherapy include teaching students to solve problems, help students cope with teasing, name-calling, mockery, fears, sexuality changes, anxiety, and death.
Implementing bibliotherapy in an elementary classroom can be very beneficial to both the students and the teacher. Teachers who use bibliotherapy in their classroom also learn much about the children they teach. Teachers as practitioners of bibliotherapy select appropriate reading materials and match them to the needs of individual students to assist them in the development of self-awareness, problem-solving skills, perspective-taking, and understanding of problems. The materials may include "any literacy activity, including reading (fiction, nonfiction, or poetry), creative writing, or storytelling." Teachers that select appropriate literature for their classroom needs may provide a child with a "character in a story to help the child understand himself Classroom story time and a guided discussion allows students to "become aware of problems of other children and develop empathy".
In the article "Read two books and write me in the morning", the authors highlight the fact that teachers are an integral part of a student's therapeutic team. It is the teacher who may be the first person to notice that something is troubling a child. They also note that teachers have been referred to as carryover agents, who carry out recommendations from other professionals who have suggested accommodations necessary to ensure a particular student's well-being or success in their classroom. In inclusive classrooms, the teacher and the whole class play a role in meeting directly or indirectly, the needs of students with exceptionalities. Bibliotherapy can help the students in the class to learn coping skills that will help them deal with the social and emotional challenges that may occur. Books and reading are an integral part of classroom life. Through books, "children are able to see reflections of themselves, their times, their country, their concerns... well-written realistic fiction will always help readers gain a deeper understanding of themselves and others."
Bibliotherapy has three recognized stages: (1) identification, (2) catharsis, and (3) insight. Identification is when a reader associates themselves with the character or situation in the literary work. Catharsis is when the reader shares many of the same thoughts and feelings of the characters in the literary work, and insight is when the reader realizes that they relate to the character or situation and learn to deal more effectively with their own personal issues. Literary pieces allow teachers to identify for their class, or an individual student, a particular issue that they are dealing with directly or indirectly. In a class with a special needs student, for example, books featuring a character with the same needs will help students experience living with a chronic condition; through a guided discussion, they will be able to verbalize their thoughts and concerns. This exercise will offer insight into the issue of how to help their classmate effectively. Bibliotherapy "does not prescribe meanings, nor is it a form of direct teaching; it is more an invitation and permission giving to children to unveil wisdom and insight that might otherwise be squelched."
Teachers who practice or need to use bibliotherapy can find connections to their state or provincial guidelines. A common challenge for classroom teachers is finding the right book, and although some annotated bibliographies are available online and in curriculum publications, not all issues are touched upon. A teacher may have to find their book. The following evaluation framework is suggested:
"Is the story simple, clear, brief, non repetitious, and believable? Is it at an appropriate reading level and developmental level? Does the story fit with relevant feelings, needs, interests, and goals? Does it demonstrate cultural diversity, gender inclusivity, and sensitivity to aggression? Do characters show coping skills and does the problem situation show resolution?"
There are steps that make bibliotherapy a more effective solution for dealing with the issues that a student may be facing, including developing support, trust, and confidence with the student with an issue, identifying other school personnel that could aid in implementing the therapy, seeking support from the student's parents or guardians, defining the issue that the student is facing and why the teacher wants to help solve it, creating goals that may help the student overcome the issue, researching books that may help with the specific problem, introducing the book to all the people that will be involved, incorporating reading activities, and evaluating the effects and successes that the book may have had on the student.
=== For older adults ===
Bibliotherapy has been studied by Jennie Bolitho (2011) in relationship to libraries, health and social connection for the elderly. Bolitho set up a pilot reading program where she read the text aloud to a group of participants at a local aged care hostel. Her evaluation at the end of the 12-week program described all responses as positive and participants commented that they "look forward to the group as it made them think for themselves and gave them something to think about aside from their ailments and the monotony of the day" (p. 90).
=== Criticism ===
Non-clinical bibliotherapy has not been vastly researched to ensure that it will be successful for all students. It has many drawbacks, which include unavailable literature on certain topics that students may be struggling with, many students not being ready to face their issues and read, and students and parents defensively implementing the therapy. The resistance of using bibliotherapy is based on a lack of assertiveness, negative attitudes, anxiety, depression, sexual dysfunctions, and negative behaviors. There has been advocacy for reading books containing difficult themes in advance, rather than in response to a parent or teacher identifying a specific issue in a child's life. The major issue that lies behind bibliotherapy is the lack of research that has been conducted on this therapy device.
== References ==
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Pierce, J. B. (2010). "Youth matters: A feeling for books". American Libraries. Archived from the original on 2013-03-22. Retrieved 2014-05-17.
Skočić Mihić, Sanja; Maich, Kimberly; Belcher, Christina; Perrow, Susan; Barišić, Ana; Ramić, Nadia Novak (2017). "The Role of Bibliotherapy and Therapeutic Storytelling in Creating Inclusive Classroom Communities". In Curran, Christina M; Petersen, Amy J. (eds.). Handbook of Research on Classroom Diversity and Inclusive Education Practice. IGI Global. Retrieved 2021-10-16.
Sunderland, Margot (2017). Using story telling as a therapeutic tool with children. London: Routledge. ISBN 978-0-86388-425-2.
U.S. Department of Veterans Affairs (February 2009). "VA bibliography reference guide" (PDF).
== Further reading ==
Cornett, Claudia E; Phi Delta Kappa; Educational Foundation (1980). Bibliotherapy: the right book at the right time. Bloomington, Indiana: Phi Delta Kappa Educational Foundation.
Betzalel, Nurit; Shechtman, Zipora (2017). "The impact of bibliotherapy superheroes on youth who experience parental absence". School Psychology International. 38 (5): 473–490. doi:10.1177/0143034317719943. ISSN 0143-0343. S2CID 149427811.
Gualano, M. R.; Bert, F.; Martorana, M.; Voglino, G.; Andriolo, V.; Thomas, R.; Gramaglia, C.; Zeppegno, P.; Siliquini, R. (2017). "The long-term effects of bibliotherapy in depression treatment: Systematic review of randomized clinical trials". Clinical Psychology Review. 58: 49–58. doi:10.1016/j.cpr.2017.09.006. hdl:2318/1662499. ISSN 0272-7358. PMID 28993103.
Pardeck, John T (2013). Using books in clinical social work practice: a guide to bibliotherapy. London; New York: Routledge. ISBN 978-1-317-82670-5. Retrieved 2021-10-16.
== External links ==
Bibliotherapy: American Library Association | Wikipedia/Bibliotherapy |
Empiric therapy or empirical therapy is medical treatment or therapy based on experience and, more specifically, therapy begun on the basis of a clinical "educated guess" in the absence of complete or perfect information. Thus it is applied before the confirmation of a definitive medical diagnosis or without complete understanding of an etiology, whether the biological mechanism of pathogenesis or the therapeutic mechanism of action. The name shares the same stem with empirical evidence, involving an idea of practical experience.
Empiric antimicrobial therapy is directed against an anticipated and likely cause of infectious disease. It is used when antimicrobials are given to a person before the specific bacterium or fungus causing an infection is known. When it becomes known, treatment that is used is called directed therapy. Fighting an infection sooner is important to minimize morbidity, risk, and complications for serious infections like sepsis and suspected bacterial meningitis.
== Empiric antimicrobial therapy ==
Empiric antimicrobial therapy is typically broad-spectrum, in that it treats both a multitude of either Gram-positive and/or Gram-negative bacteria, diverse fungi or parasites respectively. When more information is known (as from a blood culture), treatment may be changed to a narrow-spectrum antimicrobial which more specifically targets the bacterium or fungus known to be causing disease. Empiric antimicrobial therapy is a fairly sophisticated process which includes considering data such as a person's age, immune status, comorbidities, likelihood for a certain microbial etiology and pre-test probability for antimicrobial resistance prior to therapy, risk of bad outcomes, and to name a few.
Specimens are collected from affected body sites, preferably before antibiotics are given. For example, a person in an intensive care unit may develop a hospital-acquired pneumonia. There is a chance the causal bacteria, or its sensitivity to antibiotics, may be different to community-acquired pneumonia. Treatment is generally started empirically, on the basis of surveillance data about the local common bacterial causes. This first treatment, based on statistical information about former patients, and aimed at a large group of potentially involved microbes, is called empiric treatment.
The advantage of indicating antibiotics empirically exists where a causative pathogen is likely albeit unknown and where diagnostic tests will not be influential to treatment. In this case, there may be little if any perceived benefit of using what may be costly and inconclusive tests that will only delay treatment of the same antibiotics. The empirical use of broad-spectrum antibiotics increases, by selection, the prevalence of bacteria resistant to several antibiotics. However, the delay and expense that would be required to perform definitive species identification in every single clinical case are not affordable, so some degree of [trade-off] is accepted on the principle of the benefits outweighing the risk.
== Earlier senses of the term ==
Another now-dated sense of the term empiric therapy involves quackery, and empiric as a noun has been used as a synonym of quack.
This sense applies when the amount of guessing involved by the clinician transcends so far beyond science that the standard of care is not upheld. Whereas prescribing a broad-spectrum antibiotic to fight a clinically apparent infection as early as possible is entirely prudent and scientific despite the absence of confirmatory cultures, prescribing magic rituals or pseudoscientific schemes is not scientific.
The fact that "acting on practical experience in the absence of theory or complete knowledge" can have both legitimate and illegitimate forms stretches back to long before science existed. For example, in the era of ancient Greece, when medical science as we now know it did not yet exist, all medicine was unscientific and traditional; theories of etiology, pathogenetic mechanism, and therapeutic mechanism of action were based on religious, mythologic, or cosmologic ideas. For example, humorism could dictate that bloodletting was indicated for a certain disorder because a supposed excess of water could be rebalanced. However, because such theories involved a great deal of fanciful notions, their safety and efficacy could be slim to negative. In the example of bloodletting to correct excess water, the fact that fluid balance is a legitimate physiologic concern didn't mean that the then-state-of-the-art "understanding" of causation was well founded overall. In this environment where mainstream medicine was unscientific, a school of thought arose in which theory would be ignored and only practical results would be considered. This was the original introduction of empiricism into medicine, long before medical science would greatly extend it.
However, by the late 19th and early 20th centuries, as biological and medical science developed, the situation had reversed: because the state of the art in medicine was now scientific medicine, those physicians who ignored all etiologic theory in favor of only their own experience were now increasingly quackish, even though in the era of religion-based or mythology-based medicine (the era of medicine men) they might have been, as viewed through today's hindsight, admirably rational and in fact protoscientific. Thus as science became the norm, unscientific and pseudoscientific approaches qualified as quackery.
In the 21st century, the next phase of differentiation on this topic is underway. All clinical practice based on medical science is (by that fact) based on empirical evidence to a large degree, but efforts are underway to make sure that all of the science on any given medical topic is consistently applied in the clinic, with the best portions of it graded and weighted more heavily. This is the latest cycle in which personal experience (even expert opinion with scientific basis) is not considered good enough by itself. Thus, in evidence-based medicine, the goal is that every clinician will make decisions for every patient with total mastery and critical analysis of the entire scientific literature at their fingertips. This is a formidably vast goal to implement operationally (because it is not even possible for one person to master all extant biomedical knowledge on the basis of individual education), but development of health information technology such as expert systems and other artificial intelligence in medicine is underway in pursuit of it.
== See also ==
Broad-spectrum antibiotic
== References ==
=== Works cited ===
Burnett, David (2005). The Science of Laboratory Diagnosis. Chichester, West Sussex, England Hoboken, NJ: Wiley. ISBN 978-0-470-85912-4. OCLC 56650888. | Wikipedia/Empiric_therapy |
Destination therapy is a therapy that is final rather than being a transitional stage until another therapy—thus, in transportation metaphor, a destination in itself rather than merely a bridge or road to the destination. The term usually refers to ventricular assist devices or mechanical circulatory support to keep the existing heart going, not just until a heart transplant can occur, but for the rest of the patient's life expectancy. It is thus a course of treatment for severe (e.g., NYHA class IV/ACC stage D) heart failure patients who are not likely candidates for transplant. In contrast, bridge-to-transplant therapy is a way to stay alive long enough, and stay healthy enough, to await transplant while maintaining eligibility for transplant.
Heart failure is a leading cause of death in industrialized economies. Among those with serious heart illness some are, for a variety of possible medical circumstances, ineligible for a heart transplant. Destination therapy provides a possibility to extend their lives and improve their quality of life.
In addition, destination therapy may in some cases turn out to remedy the condition that excluded transplantation
Estimates place the population in the United States that may benefit from destination therapy at 50,000 – 100,000 patients per year. The addressable population outside of the US is thought be similar in size.
== Indications ==
In order for a patient to be recommended for destination therapy with an LVAD, he/she will have presented with end-stage heart failure, and will be ineligible for a transplant due to age, additional health problems, or other complications. In addition, patients may be eligible but are not suitable for heart transplant because they have other circulatory conditions unrelated to the heart.
== History ==
In 2000, the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial was conducted. REMATCH was a multi-center study supported by the National Heart, Lung, and Blood Institute to compare long-term implantation of left ventricular assist devices with optimal medical management for patients with end-stage heart failure who require, but do not qualify to receive cardiac transplantation. Based on the results of this study, the U.S. Food and Drug Administration (FDA) granted a Premarket Approval for the Thoratec HeartMate XVE LVAD to be used for destination therapy. In addition, the Centers for Medicare and Medicaid Services expanded Medicare coverage to include such therapy.
== Procedure ==
=== Pre-operative ===
Most LVADs are implanted in scheduled operations and require careful preparation of the patient for surgery, including an assessment by an anesthesiologist. The cardiologist in the coronary care unit (CCU) usually stabilizes and prepares the patient for surgery. Some patients will have invasive monitoring instituted in the CCU and will be supported with inotropes, vasopressors and IABP. In addition, recent laboratory results and assessment of the patient's physical status are required. Patients are typically cross-matched for four units of blood.
=== Peri-operative ===
Ventricular assist devices require open-heart surgery for implantation. An incision is made through the breastbone to expose the heart. Heparin will be given to keep the patients blood from clotting. The blood is rerouted to a heart-lung machine that will pump and oxygenate blood. A pocket for the LVAD is formed in the abdominal wall. A tube is then used to channel blood from the ventricle to the LVAD. Another tube is used to connect the pump to the aorta. When the pump is adequately supporting the heart, the patient will be removed from the heart-lung machine and the chest will be closed.
=== Post-operative ===
During the REMATCH trial, several complications were reported for patients who received the LVAD. They reported post-operative pain after LVAD implantation. During an average 400 days of survival, 30 percent of the devices had an internal failure requiring another operation, and almost every patient who had a re-operation did not survive. Other adverse effects included bleeding, infection and lengthened hospital stays.
Quality of Life (QoL) measures found that the LVAD group scored better or equal to the medical-therapy management group.
== Prognosis ==
The REMATCH study randomly assigned 129 patients with Class IV end-stage heart failure who were ineligible for cardiac transplantation. Within the study, 68 patients received an LVAD and 61 patients received optimal medical management. Among the patients who received the LVAD, there was a reduction of 48 percent in the risk of death from any cause, compared with the medical-therapy group.
Rates of survival among REMATCH study patients:
The frequency of serious adverse events in the LVAD group was 2.35 times that in the medical-therapy group, with a predominance of infection, bleeding and malfunction of the device. However, the quality of life was significantly improved at one year in the LVAD group.
== References == | Wikipedia/Destination_therapy |
Deep sleep therapy (DST), also called prolonged sleep treatment or continuous narcosis, is a discredited form of ostensibly psychiatric treatment in which drugs are used to keep patients unconscious for a period of days or weeks. The controversial practice led to the death of 25 patients in Chelmsford Private Hospital in New South Wales, Australia, from the early 1960s to late 1970s.
== History ==
Induction of sleep for psychiatric purposes was first tried by Scottish psychiatrist Neil Macleod at the turn of the 20th century. He used sodium bromide to induce sleep in a few psychiatric patients, one of whom died. His method was adopted by some other physicians but soon abandoned, perhaps because it was considered too toxic or reckless. In 1915, Giuseppe Epifanio tried barbiturate-induced sleep therapy in a psychiatric clinic in Italy, but his reports made little impact. Electronarcosis was also developed and used for various psychiatric disorders, involving current passed through the brain to induce deep sleep.
Deep sleep therapy was popularised in the early 1920s by Swiss psychiatrist Jakob Klaesi, using a combination of two barbiturates marketed as Somnifen by the pharmaceutical company Roche.: p 203 Most of the patients that were treated had schizophrenia. The method became widely known and was used in some mental hospitals in the 1930s and 1940s.: pp 100–110 It was adopted and promoted by some leading psychiatrists in the 1950s and 1960s, such as William Sargant in the United Kingdom and by Donald Ewen Cameron, a North American psychiatrist of Scottish origin practising in Canada, some of whose research was funded by the Central Intelligence Agency (CIA) as part of their Project MKULTRA.: pp 206–207
Sargant wrote in his standard textbook An introduction to physical methods of treatment in psychiatry:
Many patients unable to tolerate a long course of ECT, can do so when anxiety is relieved by narcosis ... What is so valuable is that they generally have no memory about the actual length of the treatment or the numbers of ECT used ... After 3 or 4 treatments they may ask for ECT to be discontinued because of an increasing dread of further treatments. Combining sleep with ECT avoids this ... All sorts of treatment can be given while the patient is kept sleeping, including a variety of drugs and ECT [which] together generally induce considerable memory loss for the period under narcosis. As a rule the patient does not know how long he has been asleep, or what treatment, even including ECT, he has been given. Under sleep ... one can now give many kinds of physical treatment, necessary, but often not easily tolerated. We may be seeing here a new exciting beginning in psychiatry and the possibility of a treatment era such as followed the introduction of anaesthesia in surgery.: pp. 89–96
== Australian Chelmsford scandal ==
Deep sleep therapy was also practiced (in combination with electroconvulsive therapy (ECT) and other therapies) by Dr Harry Bailey between 1962 and 1979 in Pennant Hills, New South Wales, at the Chelmsford Private Hospital. As practiced by Bailey, deep sleep therapy involved long periods of barbiturate-induced unconsciousness. It was prescribed for various conditions including schizophrenia, depression, obesity, premenstrual stress syndrome and addiction.
=== Resultant deaths ===
Twenty-five patients died at Chelmsford Private Hospital during the 1960s and 1970s. After the failure of the agencies of medical and criminal investigation to tackle complaints about Chelmsford, a series of articles in the early 1980s in the Sydney Morning Herald and television coverage on 60 Minutes exposed the abuses at the hospital, including 24 deaths from the treatment. That forced the authorities to take action, and the Chelmsford Royal Commission was appointed. The Citizens Commission on Human Rights, co-founded by the Church of Scientology and Professor of Psychiatry Emeritus Dr. Thomas Szasz in 1969, was an advocate for victims; it received documents from the hospital, copied by a nurse, "Rosa".
In 1978, Sydney psychiatrist Brian Boettcher had convened a meeting of doctors working at Chelmsford and found there was little support for deep sleep therapy (Bailey did not attend). However, the treatment continued to be used into 1979.
Legal action on behalf of former patients was pursued in New South Wales.
=== Patient testimony ===
In her book First Half, Toni Lamond described what it was like when she was admitted there in 1970. She had an addiction to prescription drugs and a friend told her about Bailey and he became her psychiatrist.
I was given a semi-private room. On the way to it I saw several beds along the corridors with sleeping patients. The patient in the other bed in my room was also asleep. I thought nothing of it at the time. Although it was mid-morning, the stillness was eerie for a hospital that looked to be full to overflowing. I was given a handful of pills to take and the next thing I remember was Dr Bailey standing by the bed asking how I felt. I told him I'd had a good night's sleep. He laughed and informed me it was ten days later and, what's more, he had taken some weight off me. I was checked out of the hospital and this time noticed the other patients were still asleep or being taken to the bathroom while out on their feet.
A 1992 British television documentary included the testimony of several former patients and relatives of those who died from treatment at Chelmsford Hospital.
=== 2011 controversy ===
In New South Wales in 2011, following the publication of a story in the Sydney Morning Herald, the Minister for Police and Emergency Services, representing the Minister for Health, in answer to a parliamentary question on notice, made a statement on the use of court-ordered prolonged sedation with ECT:
Prolonged sedation is used on rare occasions with the administration of ECT where there has been a clinical indication to combine the two procedures, such as in complex cases when the risk to the patient and others from severe mental illness is extreme and other treatments have been unable to safely contain this risk. The primary purpose of the sedation is to keep the patient and staff safe from the patient's severe aggression and to control agitation. The primary purpose of the ECT is to treat the underlying mental illness.
The minister said that all three cases had positive outcomes and "accepted procedures and clinical governance processes available at the time were followed". The New South Wales Mental Health Review Tribunal has power to approve or prohibit administration of ECT treatment in respect to both voluntary and involuntary patients.
=== HarperCollins Publishers and Steve Cannane ===
In 2017, doctors John Gill and John Herron, previously involved in the Chelmsford scandal, presented charges of defamation against author Steve Cannane and publisher HarperCollins following the publication of the book Fair Game: The Incredible Untold Story of Scientology in Australia. In his book, Cannane refers to the roles Chelmsford Royal Commission and Church of Scientology played in exposing the practices taking place at Chelmsford Private Hospital. In late 2020, judge Jayne Jagot dismissed the defamation case, finding that the claims were substantially true and that Cannane was entitled to trust the royal commission's findings, stating that the accusers tried to "rewrite history and vindicate their conduct", and ordered costs to be paid by Gill and Herron. An appeal was lodged, and in 2022 the court found that Gill was entitled to a retrial. The lawsuit was settled out of court.
== See also ==
Insulin shock therapy
== Notes ==
== References ==
The New South Wales Royal Commission into Chelmsford Private Hospital: Available in reference form at the N.S.W. State Library.
Jones, D. Gareth. (March 1990) "Contemporary Medical Scandals: A Challenge to Ethical Codes and Ethical Principles." Perspectives on Science and Christian Faith. No. 42, pp. 2–14
Anderson, Ian. (January 1991) "Nightmare on Chelmsford, Sydney." New Scientist, No. 1750, 5 January 1991 (subscription required for full article) | Wikipedia/Deep_sleep_therapy |
Medical gas therapy is a treatment involving the administration of various gases. It has been used in medicine since the use of oxygen therapy. Most of these gases are drugs, including oxygen. Many other gases, collectively known as factitious airs, were explored for medicinal value in the late eighteenth century. In addition to oxygen, medical gases include nitric oxide (NO), and helium-O2 mixtures (Heliox). Careful considerations and close monitoring needed when medical gases are in use. For the purpose of this article only gas mixtures are described.
== Gas mixtures therapies ==
== Nitric oxide ==
Nitric oxide is a substance that our body produces in its every cell and in its every organ. It has a number of functions. It take part in vasodilation, platelet inhibition, immune regulation, enzyme regulation, and neurotransmission.
Inhaled nitric oxide is a gas that is inhaled. It was initially described in 1987 as an "endothelial-derived relaxing factor" and has since been used to treat pulmonary disorders. It works by relaxing smooth muscle to widen (dilate) blood vessels, especially in the lungs. Inhaled nitric oxide selects only pulmonary smooth muscles. There will be no effect or minimal effect of inhaled nitric oxide on atelectatic or fluid-filled lung. It improves oxygenation and decreases pulmonary hypertension. Nitric oxide is used together with a mechanical ventilator to treat respiratory failure in premature infants. In adults nitric oxide can be used in treating pulmonary hypertension with acute respiratory distress syndrome. Thanks to the possible clinical successful outcomes of nitric oxide treatment patients can avoid need for extracorporeal membrane oxygenation treatment. The U.S. Food and Drug Administration has been approved the use of nitric oxide in term and near-term (greater than 34 weeks' gestation age) neonates with hypoxic respiratory failure with clinical or echocardiographic evidence of pulmonary hypertension.
=== Contraindications ===
Nitric oxide must not be used in neonates who depend on right-to-left shunting of blood.
=== Dosing of nitric oxide ===
Dose needed to achieve desired effect but avoid toxicity and adverse effects in neonates and adults is relatively low. Usually it is 5-20 ppm (parts per million). Regular arterial blood gas tests needed to assess the response to the therapy and signs of toxicity. Improvement in partial pressure of oxygen (PO2) and oxygen saturation would be indication of positive response to the nitric oxide therapy. If there is an evidence that nitric oxide works the same dose would be used till the hypoxemia and pulmonary hypertension resolved. When the hypoxemia and pulmonary hypertension resolved titration or slowly weaning of the nitric oxide initiates. Abrupt discontinuation of nitric oxide may lead to compromised oxygenation and pulmonary hypertension may rebound.
=== Side effects of the nitric oxide therapy ===
Methemoglobins level in the blood increases with the use of nitric oxide. Methemoglobin is abnormal form of molecule which can not carry oxygen. Methemoglobin turns blood brown. Other medications can produce methemoglobin too. Monitoring of methemoglobin needed when nitric oxide is in use.
Nitric oxide with oxygen (O2) in combination produces another by-product chemical compound nitrogen dioxide (NO2). The higher the oxygen concentration and nitric oxide therapy duration and lower ventilator flow rate the higher amount of NO2 will be produced. NO2 is toxic and its level should always be monitored in nitric oxide therapies. High level of NO2 can lead to cell damage, hemorrhage, pulmonary edema.
Use of nitric oxide in patients with left heart failure or congestive heart failure may lead to pulmonary edema or worsen pulmonary edema.
=== Nobel Prize for Nitric oxide discoveries ===
Three US scientist - Robert F. Furchgott, PhD, Louis J. Ignarro, PhD, and Ferid Murad, MD, PhD won Nobel Prize in Physiology and Medicine for their discovery of nitric oxide role in cardiovascular and nervous systems in 1998. Even though the nitric oxide effects on the body known for more than 25 years the clinical use is still in a development.
== Helium and oxygen ==
In medicine, Heliox generally refers to a mixture of 21% O2 (the same as air) and 79% He, although other combinations are available.
Heliox generates less airway resistance than air and thereby requires less mechanical energy to ventilate the lungs. "Work of Breathing" is reduced. It does this by two mechanisms:
increased tendency to laminar flow
reduced resistance in turbulent flow
The dry air on the Earth we inhale consists of 78.8% nitrogen, 20.95% oxygen and 0.93% argon. Heliox therapy is substitution of nitrogen with helium. Helium itself has no pharmacological value, it does not react in the body. Its only purpose is to make the flow less turbulent and help oxygen to get into the lungs. Less turbulent flow requires less work to breathe.
=== Helium and Heliox properties ===
Helium (He) is colorless, odorless, tasteless, and inert noble gas. Helium is second lightest gas after hydrogen.
Heliox has a similar viscosity to air but a significantly lower density (0.5 g/L versus 1.2 5g/L at STP). Flow of gas through the airways comprises laminar flow, transitional flow and turbulent flow. The tendency for each type of flow is described by the Reynolds number. Heliox's low density produces a lower Reynolds number and hence higher probability of laminar flow for any given airway. Laminar flow tends to generate less resistance than turbulent flow.
In the small airways where flow is laminar, resistance is proportional to gas viscosity and is not related to density and so heliox has little effect. The Hagen–Poiseuille equation describes laminar resistance. In the large airways where flow is turbulent, resistance is proportional to density, so Heliox has a significant effect.
Heliox has been used medically since the early 1930s. It was the mainstay of treatment in acute asthma before the advent of bronchodilators. Currently, heliox is mainly used in conditions of large airway narrowing (upper airway obstruction from tumors or foreign bodies and vocal cord dysfunction). There is also some use of heliox in conditions of the medium airways (croup, asthma and chronic obstructive pulmonary disease).
Patients with these conditions may develop a range of symptoms including dyspnea (breathlessness), hypoxemia (below-normal oxygen content in the arterial blood) and eventually a weakening of the respiratory muscles due to exhaustion, which can lead to respiratory failure and require intubation and mechanical ventilation. Heliox may reduce all these effects, making it easier for the patient to breathe. Heliox has also found utility in the weaning of patients off mechanical ventilation, and in the nebulization of inhalable drugs, particularly for the elderly. Research has also indicated advantages in using helium–oxygen mixtures in delivery of anaesthesia.
=== Heliox side effect ===
Heliox side effect is that inhaled helium change voice. Speech will sound high pitched. This effect is caused by low density gas passing through the vocal cords. The effect is reversible.
== References == | Wikipedia/Medical_gas_therapy |
TK is an experimental cell therapy which may be used to treat high-risk leukemia. It is currently undergoing a Phase III clinical trial to determine efficacy and clinical usefulness.
TK is currently being investigated in patients with acute leukemia in first or subsequent complete remission and at high risk of relapse or in patients with relapsed disease who are candidates for haploidentical transplantation of hemopoietic stem cells (taken from a partially HLA-compatible family donor).
== Research ==
TK is a cellular therapy based on the genetical engineering of donor T lymphocytes in order to express a suicide gene (thymidine kinase of the Herpes simplex virus, namely TK).
Once the lymphocytes donated by partially compatible family donors (haplo-transplant) have been genetically modified, they can be infused in patients in need of hematopoietic cell transplantation.
The infusion of lymphocytes expressing the TK suicide gene, has the aim to prevent or treat leukemic relapse and promote immune reconstitution, necessary to protect patients from infections that often limit transplant efficacy.
The presence of TK allows for retention of immune protection and anti-leukaemic effects of donor T lymphocytes and at the same time to control and annul possible harmful reactions between these lymphocytes and healthy tissues of the patient, reaction known as graft-versus-host disease.
Activation of the cell suicide system is obtained by the administration of ganciglovir, an antiviral drug, which only leads to the death of cells expressing TK in patients with graft-versus-host disease.
TK has been granted Orphan Drug designation both in the EU and the United States.
== References ==
== External links ==
Official website
http://www.molmed.com/node/1866?language=en | Wikipedia/TK_cell_therapy |
Gender-affirming hormone therapy (GAHT), also called hormone replacement therapy (HRT) or transgender hormone therapy, is a form of hormone therapy in which sex hormones and other hormonal medications are administered to transgender or gender nonconforming individuals for the purpose of more closely aligning their secondary sexual characteristics with their gender identity. This form of hormone therapy is given as one of two types, based on whether the goal of treatment is masculinization or feminization:
Masculinizing hormone therapy – for transgender men or transmasculine people; consists of androgens and occasionally antiestrogens.
Feminizing hormone therapy – for transgender women or transfeminine people; consists of estrogens with or without antiandrogens.
Eligibility for GAHT may require an assessment for gender dysphoria or persistent gender incongruence; Many medical institutions now use an informed consent model, which ensures patients are informed of the procedure process, including possible benefits and risks, while removing many of the historical barriers needed to start hormone therapy. Treatment guidelines for therapy have been developed by several medical associations.
Non-binary people may also engage in hormone therapy in order to achieve a desired balance of sex hormones or to help align their bodies with their gender identities. Many transgender people obtain hormone replacement therapy from a licensed health care provider, while others obtain and self-administer hormones.
== History ==
== Requirements ==
The formal requirements to begin gender-affirming hormone therapy vary widely depending on geographic location and specific institution. Gender-affirming hormones can be prescribed by a wide range of medical providers including, but not limited to, primary care physicians, endocrinologists, and gynecologists. Requirements to be prescribed these hormones generally include a minimum age: According to the Endocrine Society, there has been little research on taking cross-sex hormones before the age of about 14.
Historically, many health centers required a psychiatric evaluation and/or a letter from a therapist before beginning hormone replacement therapy. Many centers now use an informed consent model that does not require any routine formal psychiatric evaluation, but rather focuses on reducing barriers to care while ensuring a person can understand the risks and benefits of treatment. Some LGBT health organizations, including Chicago's Howard Brown Health Center and Planned Parenthood, advocate for this type of informed consent model.
The World Professional Association for Transgender Health (WPATH) Standards of Care, 7th edition, note that both of these approaches to care are appropriate.
=== Gender dysphoria ===
Many international guidelines and institutions require persistent, well-documented gender dysphoria as a pre-requisite to starting gender-affirmation therapy. Gender dysphoria refers to the psychological discomfort or distress that an individual can experience if their sex assigned at birth is incongruent with that person's gender identity. Signs of gender dysphoria can include comorbid mental health stressors such as depression, anxiety, low self-esteem, and social isolation. Not all gender nonconforming individuals experience gender dysphoria, and measuring a person's gender dysphoria is critical when considering medical intervention for gender nonconformity.
== Treatment options ==
=== Guidelines ===
For transgender youth, the Dutch protocol existed as among the earlier guidelines for hormone therapy by delaying puberty until age 16. The World Professional Association for Transgender Health (WPATH) and the Endocrine Society later formulated guidelines that created a foundation for health care providers to care for transgender patients. UCSF guidelines are also sometimes used. There is no generally agreed-upon set of guidelines, however.
=== Delaying puberty in adolescents ===
Adolescents experiencing gender dysphoria may opt to undergo puberty-suppressing hormone therapy at the onset of puberty. The Standards of Care set forth by WPATH recommend individuals pursuing puberty-suppressing hormone therapy wait until at least experiencing Tanner Stage 2 pubertal development. Tanner Stage 2 is defined by the appearance of scant pubic hair, breast bud development, and/or slight testicular growth. WPATH classifies puberty-suppressing hormone therapy as a "fully reversible" intervention. Delaying puberty allows individuals more time to explore their gender identity before deciding on more permanent interventions and prevents the physical changes associated with puberty.
The preferred puberty-suppressing agent for both individuals assigned male at birth and individuals assigned female at birth is a GnRH Analogue. This approach temporarily shuts down the Hypothalamic-Pituitary-Gonadal (HPG) Axis, which is responsible for the production of hormones (estrogen, testosterone) that cause the development of secondary sexual characteristics in puberty.
According to a study by JAMA Pediatrics published in January of 2025, less than 0.1% of adolescents covered by private medical insurance in the US take gender-affirming medication to treat gender dysphoria.
=== Feminizing hormone therapy ===
Feminizing hormone therapy is typically used by transgender women, who desire the development of feminine secondary sex characteristics. Individuals who identify as non-binary may also opt-in for feminizing hormone treatment to better align their body with their desired gender expression. Feminizing hormone therapy usually includes medication to suppress testosterone production and induce feminization. Types of medications include estrogens, antiandrogens (testosterone blockers), and progestogens. Most commonly, an estrogen is combined with an antiandrogen to suppress and block testosterone. This allows for demasculinization and promotion of feminization and breast development. Estrogens are administered in various modalities including injection, transdermal patch, and oral tablets.
The desired effects of feminizing hormone therapy focus on the development of feminine secondary sex characteristics. These desired effects include: breast tissue development, redistribution of body fat, decreased body hair, reduction of muscle mass, and more. The table below summarizes some of the effects of feminizing hormone therapy in transgender women:
=== Masculinizing hormone therapy ===
Masculinizing hormone therapy is typically used by transgender men, who desire the development of masculine secondary sex characteristics. Masculinizing hormone therapy usually includes testosterone to produce masculinization and suppress the production of estrogen. Treatment options include oral, subcutaneous injections or implant, and transdermal (patches, gels). Dosing is patient-specific, depending on the patient's rate of metabolism, and is discussed with the physician. The most commonly prescribed methods are intramuscular and subcutaneous injections. This dosing can be daily, weekly or biweekly depending on the route of administration and the individual patient.
Unlike feminizing hormone therapy, individuals undergoing masculinizing hormone therapy do not usually require additional hormone suppression such as estrogen suppression. Therapeutic doses of testosterone are usually sufficient to inhibit the production of estrogen to desired physiologic levels.
The desired effects of masculinizing hormone therapy focus on the development of masculine secondary sex characteristics. These desired effects include: increased muscle mass, increased bone turnover, development of facial hair, voice deepening, increase and thickening of body hair, and more.
== Safety ==
Hormone therapy for transgender individuals has been shown in medical literature to be generally safe, when supervised by a qualified medical professional. There are potential risks with hormone treatment that will be monitored through screenings and lab tests such as blood count (hemoglobin), kidney and liver function, blood sugar, potassium, and cholesterol. Taking more medication than directed may lead to health problems such as increased risk of cancer, heart attack from thickening of the blood, blood clots, and elevated cholesterol. Hormone therapy has been shown to improve the psychosocial well-being among transgender individuals. It's been seen to lower levels of distress in transgender individuals.
=== Feminizing hormone therapy ===
The Standards of Care published by the World Professional Association for Transgender Health (WPATH) summarize many of the risks associated with feminizing hormone therapy (outlined below). For more in-depth information on the safety profile of estrogen-based feminizing hormone therapy visit the feminizing hormone therapy page.
=== Masculinizing hormone therapy ===
The Standards of Care published by the World Professional Association for Transgender Health (WPATH) summarize many of the risks associated with masculinizing hormone therapy (outlined below). For more in-depth information on the safety profile of testosterone-based masculinizing hormone therapy visit the masculinizing hormone therapy page.
=== Fertility consideration ===
GAHT may limit fertility potential. Should a transgender individual choose to undergo gender-affirming surgery, their fertility potential is lost completely. Before starting any treatment, individuals may consider fertility issues and fertility preservation. Options include semen cryopreservation, oocyte cryopreservation, and ovarian tissue cryopreservation.
A study presented at ENDO 2019 (the Endocrine Society's conference) shows that even after one year of treatment with testosterone, a transgender man can preserve his fertility potential.
=== Counterfeit products ===
Some online scammers have been targeting trans consumers with products that do not contain any hormones or contain ones that are opposite of what is advertised. This can happen when legislations outlaw or restrict access to treatments by legitimate medical professionals.
== Treatment eligibility ==
Many providers use informed consent, whereby someone seeking hormone therapy can sign a statement of informed consent and begin treatment without much gatekeeping. For other providers, eligibility is determined using major diagnostic tools such as ICD-11 or the Diagnostic and Statistical Manual of Mental Disorders (DSM) to classify a patient with gender dysphoria. The Endocrine Society requires physicians that diagnose gender dysphoria and gender incongruence to be trained in psychiatric disorders with competency in ICD-11 and DSM-5. The healthcare provider should also obtain a thorough assessment of the patient's mental health and identify potential psychosocial factors that can affect therapy.
=== WPATH Standards of Care ===
The WPATH Standards of Care, most recently published in 2022, outlines a series of guidelines which should be met before a patient should be allowed gender-affirming hormone therapy:
Gender incongruence is marked and sustained
Patient meets diagnostic criteria for gender incongruence prior to gender-affirming hormone treatment in regions where a diagnosis is necessary to access health care
Patient has capacity to consent to hormone therapy treatment
Other possible causes of apparent gender incongruence have been identified and excluded
Mental health and physical conditions that could negatively impact the outcome of treatment have been assessed
Understands the effect of gender-affirming hormone treatment on reproduction and they have explored reproductive options
The WPATH standards of care distinguish between gender-affirming hormone therapy, and hormone replacement therapy, with the latter referring to the replacement of endogenous hormones after a gonadectomy to prevent cardiovascular and musculoskeletal issues.
=== Readiness ===
Some organizations—but fewer than in the past—require that patients spend a certain period of time living in their desired gender role before starting hormone therapy. This period is sometimes called real-life experience (RLE).
In Sweden, for instance, patients seeking to access gender affirming healthcare must first undergo extended evaluations with psychiatric professionals, during which they must—without any form of medical transition—successfully live for one full year as their desired gender in all professional, social, and personal matters. Gender clinics are recommended to provide patients with wigs and breast prostheses for the endeavor. The evaluation additionally involves, if possible, meetings with family members and/or other individuals close to the patient. Patients may be denied care for any number of "psychosocial dimensions", including their choice of job or their marital status.
Transgender and gender non-conforming activists, such as Kate Bornstein, have asserted that RLE is psychologically harmful and is a form of "gatekeeping", effectively barring individuals from transitioning for as long as possible, if not permanently.
In September 2022, the World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People (SOC) Version 8 were released and removed the requirement of RLE for all gender-affirming treatments, including gender-affirming surgery.
== Accessibility ==
Some transgender people choose to self-administer hormone replacement medications, often because doctors have too little experience in this area, or because no doctor is available. Others self-administer because their doctor will not prescribe hormones without an approval letter from a psychotherapist. Many therapists require extended periods of continuous psychotherapy and/or real-life experience before they will write such a letter. Because many individuals must pay for evaluation and care out-of-pocket, costs can be prohibitive.
Access to medication can be poor even where health care is provided free. In a patient survey conducted by the United Kingdom's National Health Service in 2008, 5% of respondents acknowledged resorting to self-medication, and 46% were dissatisfied with the amount of time it took to receive hormone therapy. The report concluded in part: "The NHS must provide a service that is easy to access so that vulnerable patients do not feel forced to turn to DIY remedies such as buying drugs online with all the risks that entails. Patients must be able to access professional help and advice so that they can make informed decisions about their care, whether they wish to take the NHS or private route without putting their health and indeed their lives in danger." Self-administration of cross-gender hormones without medical supervision may have untoward health effects and risks.
A number of private companies have attempted to increase accessibility for hormone replacement medications and help transgender people navigate the complexities of access to treatment.
== See also ==
Hormone therapy
Gender-affirming surgery
Real-life experience (transgender)
Hormone replacement therapy
Feminizing hormone therapy
== References == | Wikipedia/Transgender_hormone_therapy |
Grape therapy or grape diet, also known as ampelotherapy, is a diet that involves heavy consumption of grapes, including seeds, and parts of the vine, including leaves, that is a form of alternative medicine. The concept was developed in 19th-century Germany in spas such as Bad Duerkheim and Merano. The concept has no scientific basis and is regarded as quackery by scientific institutions like the American Cancer Society.
== Background ==
An assumption of some of grape therapy is that consuming grape constituents would provide unusual therapeutic or nutritional benefits. However, consuming grapes has unknown effects against cardiovascular diseases and other diseases, such as metabolic syndrome. Alternative medicine practitioners have recommended grapes and parts of the vine for treating various diseases, but there is no clinical evidence for any such effects.
Grape pomace contains various micronutrients, but the resulting flour from pomace has variable nutrient contents due to processing, drying, and storage conditions. Raw grapes are mostly devoid of nutritional benefit, except for moderate amounts of carbohydrates and vitamin K (see grape nutrition).
Proanthocyanidins, anthocyanins and resveratrol extracted from grape seeds and grape skins are under basic research for their possible biological effects. Pomace also contains organic acids (tartaric, malic, citric, tannic), but there is no evidence for health effects from these phytochemicals.
== History ==
The documentation of a grape diet was first seen in a publication by Dr. Veit Kaufmann, a family doctor in the viticultural city of Bad Duerkheim, Germany, called "Die Traubenkur in Dürkheim a.d. Haardt" (The Grape Treatment Course in Duerkheim at Haardt River) (1856). Kaufmann was well known locally, and a personal friend of Rudolph Virchow, who underwent the treatment regularly.
In the USSR, the principles of a grape cure were developed in the 1920s by a group of physicians of the Semashko Institute (Yalta), headed by A.V. D'iakov. Ampelotherapy is offered in alternative medicine clinics and spas, particularly in Europe, together with vinotherapy, a cosmetic treatment that involves rubbing grapes into the skin.
Johanna Brandt, a South African author, popularized the grape diet as a treatment for cancer from 1925. She published about twenty pamphlets on the subject of natural remedies for health problems with her book The Grape Cure, which is said to have been written after Brandt had cured herself of stomach cancer by following the diet. The book was republished in 1989 as How to Conquer Cancer, Naturally, including an endorsement of Brandt's work by Benedict Lust, who is commonly referred to as "the father of naturopathy".
Although commonly used as a dietary supplement and studied in human trials at an amount much higher than can be consumed from drinking red wine, there is no high-quality evidence that resveratrol provides any benefits for cardiovascular risk factors. Advocates of grape therapy argue that grape phytochemicals inhibit the development of cancer, arthritis or diabetes, but there is no scientific evidence for such effects.
== Treatments ==
The diet proposed by Veit Kaufmann recommended the consumption of several pounds of freshly picked grapes a day, spread over 4 portions, combined with walks, sports and light healthy meals, over a course of three to six weeks in a spa, overseen by medical personnel. The diet proposed by Johanna Brandt recommended fasting for two or three days, consuming only cold water, followed by a diet of only grapes and water for one to two weeks, with seven meals a day. Fresh fruits, tomatoes, and sour milk or cottage cheese are then introduced to the diet followed by raw vegetables.
== Criticisms ==
Available scientific evidence does not support claims that a diet of grapes is effective for treating cancer or any other disease. The Brandt diet, in particular, has been described as "quackery" by Barrett who notes that the American Cancer Society reviewed The Grape Cure in 1965, 1971, 1974, and 2000 and found no evidence of benefit against human cancer or any other disease. Grape seed extract has been identified by the U.S. Food and Drug Administration as a "fake cancer 'cure'".
== See also ==
Urine therapy
Gerson therapy
List of unproven and disproven cancer treatments
== References == | Wikipedia/Grape_therapy |
Cognitive rehabilitation refers to a wide range of evidence-based interventions designed to improve cognitive functioning in brain-injured or otherwise cognitively impaired individuals to restore normal functioning, or to compensate for cognitive deficits. It entails an individualized program of specific skills training and practice plus metacognitive strategies. Metacognitive strategies include helping the patient increase self-awareness regarding problem-solving skills by learning how to monitor the effectiveness of these skills and self-correct when necessary.
Cognitive rehabilitation therapy (offered by a trained therapist) is a subset of Cognitive Rehabilitation (community-based rehabilitation, often in traumatic brain injury; provided by rehabilitation professionals) and has been shown to be effective for individuals who had a stroke in the left or right hemisphere. or brain trauma. A computer-assisted type of cognitive rehabilitation therapy called cognitive remediation therapy has been used to treat schizophrenia, ADHD, and major depressive disorder.
Cognitive rehabilitation builds upon brain injury strategies involving memory, executive functions, activities planning and "follow through" (e.g., memory, task sequencing, lists).
It may also be recommended for traumatic brain injury, the primary population for which it was developed in the university medical and rehabilitation communities, such as that sustained by U.S. Representative Gabby Giffords, according to Dr. Gregory J. O'Shanick of the Brain Injury Association of America. Her new doctor has confirmed that it will be part of her rehabilitation.
Cognitive rehabilitation may be part of a comprehensive community services program and integrated into residential services, such as supported living, supported employment, family support, professional education, home health (as personal assistance), recreation, or education programs in the community.
Cognitive rehabilitation for spatial neglect following stroke
The current body of evidence is uncertain on the efficacy of cognitive rehabilitation for reducing the disabling effects of neglect and increasing independence remains unproven. However, there is limited evidence that cognitive rehabilitation may have an immediate beneficial effect on tests of neglect. Overall, no rehabilitation approach can be supported by evidence for spatial neglect.
== Assessments ==
According to the standard text by Sohlberg and Mateer:Individuals and families respond differently to different interventions, in different ways, at different times after injury. Premorbid functioning, personality, social support, and environmental demands are but a few of the factors that can profoundly influence outcome. In this variable response to treatment, cognitive rehabilitation is no different from treatment for cancer, diabetes, heart disease, Parkinson's disease, spinal cord injury, psychiatric disorders, or any other injury or disease process for which variable response to different treatments is the norm.
Nevertheless, many different statistical analyses of the benefits of this therapy have been carried out. One study made in 2002 analyzed 47 treatment comparisons and reported "a differential benefit in favor of cognitive rehabilitation in 37 of 47 (78.7%) comparisons, with no comparison demonstrating a benefit in favor of the alternative treatment condition."
An internal study conducted by the Tricare Management Agency in 2009 is cited by the US Department of Defense as its reason for refusing to pay for this therapy for veterans who have had traumatic brain injury. According to Tricare, "There is insufficient, evidence-based research available to conclude that cognitive rehabilitation therapy is beneficial in treating traumatic brain injury." The ECRI Institute, whose report serves as the basis for this decision by the Department of Defense, has summed up their own findings this way:In our report, we carried out several meta-analyses using data from 18 randomized controlled trials. Based on data from these studies, we were able to conclude the following:
Adults with moderate to severe traumatic brain injury who receive social skills training perform significantly better on measures of social communication than patients who receive no treatment.
Adults with traumatic brain injury who receive comprehensive cognitive rehabilitation therapy report significant improvement on measures of quality of life compared to patients who receive a less intense form of therapy.
The strength of the evidence supporting our conclusions was low due to the small number of studies that addressed the outcomes of interest. Further, the evidence was too weak to draw any definitive conclusions about the effectiveness of cognitive rehabilitation therapy for treating deficits related to the following cognitive areas: attention, memory, visuospacial skills, and executive function. The following factors contributed to the weakness of the evidence: differences in the outcomes assessed in the studies, differences in the types of cognitive rehabilitation therapy methods/strategies employed across studies, differences in the control conditions, and/or insufficient number of studies addressing an outcome.
Citing this 2009 assessment, US Department of Defense, one of the federal agencies not responsible for health care decisions in the US, has declared that cognitive rehabilitation therapy is scientifically unproved and should refer their concerns to the US Department of Health and Human Services, US Budget and Management, and/or the Government Accountability Office (GAO). As a result, it refuses to cover the cost of cognitive rehabilitation for brain-injured veterans.
Cost-benefit and cost-effectiveness studies, together with an analysis of personnel and veterans' services for new our emerging groups in head and brain injuries, are recommended.
== See also ==
Rehabilitation (neuropsychology)
Cognitive remediation therapy
Rehabilitation psychology
Rehabilitation: Community-based
Rehabilitation: Hospital-based units
== References == | Wikipedia/Cognitive_rehabilitation_therapy |
Androgen deprivation therapy (ADT), also called androgen ablation therapy or androgen suppression therapy, is an antihormone therapy whose main use is in treating prostate cancer. Prostate cancer cells usually require androgen hormones, such as testosterone, to grow. ADT reduces the levels of androgen hormones, with drugs or surgery, to prevent the prostate cancer cells from growing. The pharmaceutical approaches include antiandrogens and chemical castration.
Several studies have concluded that ADT has demonstrated benefit in patients with metastatic disease, and as an adjunct to radiation therapy in patients with locally advanced disease, as well as those with unfavorable intermediate-risk or high-risk localized disease. However, in patients with low-risk prostate cancer, ADT has demonstrated no survival advantage, and significant harm, such as impotence, diabetes and bone loss.
The therapy can also eliminate cancer cells by inducing androgen deprivation-induced senescence. Lowering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancer shrink or grow more slowly for a time. However, this treatment needs to be combined with radiation therapy (RT) because ADT itself does not eradicate the cancer; it just decreases its aggressiveness.
== Types ==
=== Method based on surgery ===
Orchiectomy (surgical castration)
It consists of removing the testicles, the organ where androgens are synthesized, of the cancer patient. It is the most radical treatment for ending the production of androgens. Moreover it is the easiest and least expensive one. The main disadvantage is that surgical castration is a permanent method.
=== Methods based on drugs ===
Chemical castration
The synthesis of testosterone is mediated by a chain of processes that start in the brain. When the body detects a low level of testosterone, the hypothalamus starts to produce LHRH. LHRH activates the synthesis of LH (Luteinizing hormone) within the pituitary gland. LH induces testosterone synthesis within the testicles. There are two different medicines, LHRH agonists and antagonists, which both lower the amount of testosterone made by the testicles. They work by inhibiting the formation of LH in the pituitary gland. The LHRH agonists produce a sudden increase on levels of testosterone followed by a huge falling, process called flare, whereas LHRH antagonists decrease directly the amount of testosterone. LHRH agonists and antagonists used in androgen deprivation therapy include leuprorelin (leuprolide), goserelin, triptorelin, histrelin, buserelin, and degarelix.
These drugs are injected under the skin achieving the same result as surgical castration. Chemical castration may be preferred to surgical castration as it keeps the testes intact.
Antiandrogen therapy
Adrenal glands were discovered as another center of androgen production even after a castration process. Therefore a complementary treatment was developed that uses antiandrogens to block the body's ability to use any androgens. Prostate cells contain an Androgen Receptor (AR), that when stimulated by androgens like testosterone, promotes growth and maintains prostatic differentiation. These pro-growth signals, however, can be problematic when they occur in a cancer cell. Antiandrogens can enter cells and prevent the binding of testosterone to the receptor proteins, due to their higher affinity for the Androgen Receptor.
The main antiandrogens are cyproterone acetate, flutamide, nilutamide, bicalutamide, and enzalutamide which are all administered in oral pill form.
New antiandrogens that target testosterone synthesis (abiraterone acetate and seviteronel) or AR nuclear translocation (enzalutamide, apalutamide, and darolutamide), as well as combined therapies (galeterone) have been recently developed and may function to better target androgen-responsive cells in combination with ADT. But these too may have negative adverse roles in the development of CRPC.
== Effects on men's sexuality ==
Normal male sexuality seems to depend upon very specific and complicated hormonal patterns that are not completely understood. One study suggests that ADT can alter the hormonal balance necessary for male sexual activity. As men age, testosterone levels decrease by about 1% a year after age 30; however, it is important to determine whether low testosterone is due to normal aging, or to a disease, such as hypogonadism. Testosterone plays a significant role in sexual functioning; therefore, naturally declining levels of testosterone can lead to reduction in normal sexual functioning. Further decreases in serum testosterone can have a negative impact on normal sexual function, leading to a decline in quality of life.
Erectile dysfunction is not uncommon after radical prostatectomy and men who undergo ADT in addition to this are likely to show further decline in their ability to engage in penetrative intercourse, as well as their desire to do so. A study looking at the differences of using GnRH-A (and androgen suppressant) or an orchiectomy report differences in sexual interest, the experience of erections, and the prevalence of participating in sexual activity. Men reporting no sexual interest increased from 27.6% to 63.6% after orchiectomy, and from 31.7% to 58.0% after GnRH-A; men who experienced no erections increased from 35.0% to 78.6%; and men who did not report engaging in sexual activity increased from 47.9% to 82.8% after orchiectomy and 45.0% to 80.2%. This study suggests that the GnRH-A and orchiectomy had similar effects on sexual functioning. A vicious cycle whereby lowering testosterone levels leads to decreased sexual activity, which in turn cause both free and total testosterone levels to decline even further. This demonstrates the importance of androgens for maintaining sexual structures and functions.
== Adverse effects ==
Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens has been shown to activate epithelial–mesenchymal transition (EMT), neuroendocrine transdifferentiation (NEtD) and cancer stem cell-like gene programs.
EMT has established roles in promoting biological phenotypes associated with tumor progression (migration/invasion, tumor cell survival, cancer stem cell-like properties, resistance to radiation and chemotherapy) in multiple human cancer types.
NEtD in prostate cancer is associated with resistance to therapy, visceral metastasis, and aggressive disease.
Cancer Stem Cell phenotypes are associated with disease recurrence, metastasis, and cell survival in circulation as Circulating tumor cells.
Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression.
Orchiectomy, LHRH analogs and LHRH antagonists can all cause similar side effects, due to changes in the levels of sex hormones (testosterone).
A program has been developed for patients and their partners to recognize and manage the more burdensome side effects of androgen deprivation therapy. One program is built around the 2014 book "Androgen Deprivation Therapy: An Essential Guide for Prostate Cancer Patients and Their Loved Ones", which is endorsed by the Canadian Urological Association.
Recent studies have shown ADT may increase the risk of Alzheimer's disease or dementia. The increase in risk may be associated with duration of ADT. While some studies report a decline in certain areas of cognitive function such as spatial abilities, attention, and verbal memory associated with ADT, evidence as a whole remains contradictory. Useful preventative interventions may include social interaction, physical exercise and a "Mediterranean diet", among others. There is an additional small risk of cardiac arrhythmias.
== See also ==
Estrogen deprivation therapy
Maximum androgen blockade
== References == | Wikipedia/Androgen_deprivation_therapy |
Mild total body hypothermia, induced by cooling a baby to 33-34°C for three days after birth, is nowadays a standardized treatment after moderate to severe hypoxic ischemic encephalopathy in full-term and near to fullterm neonates. It has recently been proven to be the only medical intervention which reduces brain damage, and improves an infant's chance of survival and reduced disability.
Hypoxic ischemic encephalopathy has many causes and is defined essentially as the reduction in the supply of blood or oxygen to a baby's brain before, during, or even after birth. It is a major cause of death and disability, occurring in approximately 2–3 per 1000 births and causing around 20% of all cases of cerebral palsy. A 2013 Cochrane review found that therapeutic hypothermia is useful in full term babies with encephalopathy.
== Medical uses ==
=== Extended follow-up of trial participants ===
Studies have been undertaken to determine the effects of hypothermia beyond early childhood. Participants in the CoolCap, NICHD and TOBY trials were entered into extended follow-up programmes. None of these programmes have sufficient power to make confident assessments of the long-term effect of hypothermia, however even these underpowered studies give important information on whether the therapeutic effects of cooling are sustained beyond the first two years after birth.
The most significant follow-up study published so far is the assessment of the NICHD trial participants at 6–7 years. Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P=0.06); death occurred in 27 (28%) and 41 (44%) (P=0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P=0.03). The CoolCap study gathered data using the WeeFim questionnaire at 7–8 years of age, but only collected information on 62 (32 cooled; 30 standard care) of 135 surviving children who had had neurodevelopmental assessment at 18 months. Disability status at 18 months was strongly associated with WeeFIM ratings (P < 0.001) suggesting that the therapeutic effect persisted, but there was no significant effect of treatment (P = 0.83).
These results were not quite conclusive, as the effect in the NICHD trial appears to be on mortality rather than neurological function, but they gave considerable confidence that the therapeutic effects of hypothermia following birth asphyxia are sustained into later childhood, and when the Toby trial childhood follow up was published in the New England Journal of Medicine it confirmed the persistence of the effect
=== Current state of the evidence ===
Hypothermic neural rescue therapy is an evidence-based clinical treatment which increases a severely injured full term infant's chance of surviving without brain damage detectable at 18 months by about 50%, an effect which seems to be sustained into later childhood.
At present data relate only to full term infants, and all human studies of hypothermia treatment have so far been restricted to infants >36 weeks out of an expected 40 weeks gestation. There are both more potential side effects on the developing premature with lung disease, and there is more evident protection by hypothermia when a greater volume of complex brain is actively developing. During mid gestation to late term the fetal brain is undergoing increasingly complex progressive growth of first the mid-brain and then development of the cortex and "higher" centers. The effects of fetal asphyxia on the developing brain in sheep are dependent on gestational age with near term fetuses showing both less tolerance of asphyxia and maximal damage in the rapidly expanding cortex; while fetuses prior to the last third of development experience more extended tolerance of asphyxia with maximal effects on the growing mid-brain. The fetal sheep asphyxia model also suggests a six-hour window post asphyxia in which hypothermia will have greatest benefit.
Since the prerequisites regarding immediate closeness after giving birth radically chances, researchers have become curious regarding parent's experiences and how to improve the nursing care around effects families. In interviews made by different researchers in different countries it has been clear the parents want clear communication with the NICU staff, but also in between the NICU staff and the obstetrics staff. They also described a strong wish touching and being really close to their baby but also actively participate in the baby's care
There remains much that is unknown. Recognition of infants with marginal external signs of asphyctic damage at birth, who still develop moderate hypoxic ischemic encephalopathy would be enhanced by finding more reliable bio-markers or physiologic tests accurately predicting the risk for progressive damage. These tests could also prevent unwarranted, expensive treatment of many infants. Long-term follow-up has yet to demonstrate show persisting benefit, but available data together with an imaging study nested in TOBY also found reduced brain tissue damage in cooled infants are encouraging.
The simplicity that attracted empiricists to cooling centuries ago now makes hypothermic neural rescue with accurate patient selection a potentially transforming therapy for low-resource environments where birth asphyxia remains a major cause of death and disability. Ironically this brings back the problem of cooling infants in an environment where modern resuscitation and intensive care are not available.
== Mechanisms of action ==
Much of what is known about the mechanisms of hypothermic neuroprotection is gathered from studies in mature and adult models. What follows uses some of these data while trying to focus on the immature brain.
=== Hypoxia-ischaemia ===
Cerebral hypoxia-ischaemia results in reduced cerebral oxidative metabolism, cerebral lactic acidosis and cell membrane ionic transport failure; if prolonged there is necrotic cell death. Although rapid recovery of cerebral energy metabolism occurs following successful resuscitation this is followed some hours later by a secondary fall in cerebral high energy phosphates accompanied by a rise in intracellular pH, and the characteristic cerebral biochemical disturbance at this stage is a lactic alkalosis. In neonates, the severity of this secondary impairment in cerebral metabolism are associated with abnormal subsequent neurodevelopmental outcome and reduced head growth.
Several adverse biological events contribute to this secondary deterioration, including: release of excitatory amino acids which activate N-methyl-D-aspartate (NMDA) and amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors on neurons (30,37) and oligodendroglial precursors, accumulation of excitatory neurotransmitters, generation of reactive oxygen radicals, intracellular calcium accumulation and mitochondrial dysfunction. Whilst necrotic cell death is prominent in the immediate and acute phases of severe cerebral insults, the predominant mode of death during the delayed phase of injury appears to be apoptosis. Neuroprotective mechanisms need to interact with these mechanisms to have beneficial effect.
Newborn hypoxic-ischaemic brain injury differs from injury in the adult brain in several ways: NMDA receptor toxicity is much higher in the immature brain. Apoptotic mechanisms including activation of caspases, translocation of apoptosis-inducing factor and cytochrome-c release are much greater in the immature than the adult. The inflammatory activation is different with less contribution from polymorphonuclear cells and a more prominent role of IL-18 whereas IL-1, which is critical in the adult brain, is less important. The anti-oxidant system is underdeveloped with reduced capacity to inactivate hydrogen peroxide.
=== Actions of hypothermia ===
Mild hypothermia helps prevent disruptions to cerebral metabolism both during and following cerebral insults. Hypothermia decreases the cerebral metabolic rate for glucose and oxygen and reduces the loss of high energy phosphates during hypoxia-ischaemia and during secondary cerebral energy failure, and reduces delayed cerebral lactic alkalosis. The simultaneous increase in cytotoxic oedema and loss of cerebral cortical activity that accompanies secondary energy failure is also prevented.
Hypothermia appears to have multiple effects at a cellular level following cerebral injury. Hypothermia reduces vasogenic oedema, haemorrhage and neutrophil infiltration after trauma. The release of excitatory neurotransmitters is reduced, limiting intracellular calcium accumulation. Free radical production is lessened, which protects cells and cellular organelles from oxidative damage during reperfusion. In addition mild hypothermia may reduce the activation of the cytokine and coagulation cascades through increased activation of suppressor signalling pathways, and by inhibiting release of platelet activating factor.
Many of the effects induced by mild hypothermia may help to reduce the number of cells undergoing apoptosis. Experimental and clinical studies indicate that the number of apoptotic neurons is reduced caspase activity is lessened and cytochrome c translocation is diminished by mild hypothermia, and there may be an increase in expression of the anti-apoptotic protein BCl-2.
== History ==
Many physicians over the centuries have tried to resuscitate babies after birth by altering their body temperatures, essentially aiming to animate the infant by inducing the onset of breathing. Little thought was given to brain protection, because cerebral hypoxia during birth was not linked with later neurological problems until William John Little in 1861, and even then this was controversial; Sigmund Freud, for example, famously disagreed, and when scientific studies of neonatal therapeutic hypothermia were begun in the 1950s researchers like Bjorn Westin still reported their work in terms of re-animation rather than neuroprotection. Investigators such as James Miller and Clement Smith carried out clinical observations and careful physiological experiments, but although some babies were conscientiously followed up, they were not mainly concerned with long term neurological outcome.
However, by the 1960s physicians saw hypothermia after delivery as something to be avoided. The problem of infants who failed to breathe at birth had been solved by the invention of mechanical ventilation, so any benefit cooling might have for re-animation was no longer needed, and an influential trial showed that keeping small and preterm infants warm increased survival. These results, together with observational and experimental data made it an article of medical faith for decades that babies should not be allowed to get cold.
Consequently, during the next two decades studies of neonatal hypothermia in Europe and the USA were sporadic and often unsuccessful. An interest in cooling for brain protection was beginning to emerge, but contemporary neuroscience provided few useful concepts to guide this research and little progress was made. Although across the Iron Curtain in the Soviet Union cooling was being applied empirically following birth asphyxia, the language barrier, cold war politics and the Russians' failure to carry out randomised controlled trials contributed to an almost total ignorance of this work in the West. Indeed, a group of Russian neonatologists who described hypothermic neural rescue during a visit to the Neonatal Unit in Bristol, UK, met with little interest.
=== Neural rescue ===
In the late 1980s the development of a new set of concepts and problems led to a re-examination. A new generation of neonatal researchers were influenced by the growing evidence that protecting the brain against the effects of oxygen deprivation during labour might be possible. These researchers were aware that cooling produced powerful intra-ischaemic neuroprotection during cardiac surgery but a new concept of hypothermic post-insult neural rescue developed. This shift in thinking was possible because of at least three major new ideas that were developing at the same time: delayed post-ischaemic cell death; excitotoxicity; and apoptosis.
=== Delayed cell death ===
The first paradigm shift that affected neonatal researchers in particular was the idea that if a baby was resuscitated after cerebral hypoxia-ischaemia there was a period of time before brain cells started to die. Osmund Reynolds at University College London used the newly developed technique of Magnetic Resonance Spectroscopy (MRS) to show that the infant brain metabolism is normal in the hours after birth asphyxia and deteriorated only after a distinct delay. Robert Vannucci confirmed the effect with painstaking biochemistry, and delayed injury was also reported in neuropathological studies.
Delayed brain injury (called 'secondary energy failure' by Reynolds) was a critical new idea. If brain cells remained normal for a time and the mechanism of the delayed death could be unravelled, it opened the possibility of therapeutic intervention in what had previously seemed an impossible situation.
=== Excitotoxicity ===
The new and transforming concept of excitotoxicity developed from the seminal experiments of John Olney and Brian Meldrum. They showed that at least some of the neural cell death caused by hypoxia-ischaemia is mediated by excess production of the excitatory neurotransmitter glutamate, and that pharmacological blockade of the N-methyl-D-aspartate receptor could provide good protection against hypoxic damage. Olney and Meldrum had shifted the paradigm, allowing researchers to think of hypoxic-ischaemic damage as a treatable disease.
=== Apoptosis ===
However, it was still a mystery how and why cells triggered by hypoxia-ischaemia should die hours or days later, particularly when it became clear that glutamate levels were not particularly high during secondary energy failure. The next critical idea came with the discovery of programmed cell death, a novel form of cell suicide. Originally observed as a pathological appearance and named apoptosis ("falling off", as of leaves) in the 1970s, Horvitz, Raff and Evan provided a molecular understanding and showed that apoptosis could be triggered by cellular insults. The radical idea that hypoxia-ischaemia triggered a cell suicide programme which could explain the perplexing phenomenon of delayed cell death was soon supported by experimental and human data, and many researchers believe this helps explain why neural rescue works in the newborn. However the picture is complex: both apoptosis and necrosis are present in variable proportions; and there seems to be prolonged neurodegeneration after an insult. Research into this problem continues.
=== Neonatal neural rescue ===
These ideas flowed through the perinatal research community, producing a new belief that neural rescue after birth asphyxia should be possible. Amongst the first to have attempt neonatal neural rescue in animals were Ingmar Kjellmer and Henrik Hagberg in Gothenburg, and Michael Johnston in Baltimore. The potential began to draw in other neonatal researchers from diverse fields to begin neuroprotection research, including those who came to form the informal neonatal hypothermia research group:
Peter Gluckman and Tania Gunn were endocrinologists in the University of Auckland New Zealand and interested in cooling for its effect on thyroid function; they had first cooled a sheep fetus for endocrine studies in 1983. Denis Azzopardi, John Wyatt and David Edwards, then young researchers working for Reynolds, were using Reynolds's sophisticated MRS approach to replicate secondary energy failure in newborn piglets and immature rats; in Gluckman's laboratory Alistair Gunn and Chris Williams developed a simple and elegant biophysical method using cerebral impedance to do essentially the same thing in fetal sheep. Marianne Thoresen, who was working on cerebral perfusion, was prompted to think about neuroprotection by stories of children who fell through the Norwegian ice and suffering prolonged drowning in iced water but emerged with preserved cerebral function.
There were many potential therapies around which might achieve neural rescue, and most of these workers did not immediately move to hypothermia. Magnesium was an appealingly simple excitoxin receptor antagonist that protected cells in culture: the Reynolds group tested it in their piglet model without success. Gluckman and Gunn started by looking unsuccessfully at flunarizine, a calcium entry inhibitor. Edwards picked on nitric oxide synthase inhibition which was also a failure. Gluckman had success with his innovative studies of IGF-1, but could not immediately translate this to clinical practice.
== References == | Wikipedia/Hypothermia_therapy_for_neonatal_encephalopathy |
An aquarium (pl.: aquariums or aquaria) is a vivarium of any size having at least one transparent side in which aquatic plants or animals are kept and displayed. Fishkeepers use aquaria to keep fish, invertebrates, amphibians, aquatic reptiles, such as turtles, and aquatic plants. The term aquarium, coined by English naturalist Philip Henry Gosse, combines the Latin root aqua, meaning 'water', with the suffix -arium, meaning 'a place for relating to'.
The aquarium principle was fully developed in 1850 by the chemist Robert Warington, who explained that plants added to water in a container would give off enough oxygen to support animals, so long as the numbers of animals did not grow too large. The aquarium craze was launched in early Victorian England by Gosse, who created and stocked the first public aquarium at the London Zoo in 1853, and published the first manual, The Aquarium: An Unveiling of the Wonders of the Deep Sea in 1854. Small aquariums are kept in the home by hobbyists. There are large public aquariums in many cities. Public aquariums keep fish and other aquatic animals in large tanks. A large aquarium may have otters, dolphins, sharks, penguins, seals, and whales. Many aquarium tanks also have plants.
An aquarist owns fish or maintains an aquarium, typically constructed of glass or high-strength acrylic. Aquaria with flat walls are known as fish tanks or simply tanks, while those with rounded walls are known as fish bowls. Size can range from a small glass bowl, a few liters in volume, to immense public aquaria of thousands of liters. Specialized equipment maintains appropriate water quality and other characteristics suitable for the aquarium's residents.
== History and popularization ==
=== Antiquity ===
In 1369, the Hongwu Emperor of China established a porcelain company that produced large porcelain tubs for maintaining goldfish; over time, people produced tubs that approached the shape of modern fish bowls. Leonhard Baldner, who wrote Vogel-, Fisch- und Tierbuch (Bird, Fish, and Animal Book) in 1666, maintained weather loaches and newts. It is sometimes held that the aquarium was invented by the Romans, who are said to have kept sea barbels in marble-and-glass tanks, but scholars doubt the veracity of this.
=== Nineteenth century ===
In 1832, Jeanne Villepreux-Power, a pioneering French marine biologist, became the first person to create aquaria for experimenting with aquatic organisms. This experimentation lead to several discoveries, including the first direct evidence that argonauts, a marine cephalopod, create their own shells. In 1836, soon after his invention of the Wardian case, Dr. Nathaniel Bagshaw Ward proposed to use his tanks for tropical animals. In 1841 he did so, though only with aquatic plants and toy fish. However, he soon housed real animals. In 1838, Félix Dujardin noted owning a saltwater aquarium, though he did not use the term. In 1846, Anne Thynne maintained stony corals and seaweed for almost three years, and was credited as the creator of the first balanced marine aquarium in London. English chemist Robert Warington experimented with a 13-gallon container, which contained goldfish, eelgrass, and snails, creating one of the first stable aquaria. The aquarium principle was fully developed by Warington, explaining that plants added to water in a container would give off enough oxygen to support animals, so long as their numbers do not grow too large. He published his findings in 1850 in the Chemical Society's journal.
The keeping of fish in an aquarium became a popular hobby and spread quickly. In the United Kingdom, it became popular after ornate aquaria in cast-iron frames were featured at the Great Exhibition of 1851. In 1853, the aquarium craze was launched in England, spreading from there to Germany, the United States and France as the result of the publications and activity of Philip Henry Gosse, the marine zoologist known as the "Father of the Aquarium". He created and stocked the first public aquarium at the London Zoo in Regent's Park, which came to be known as the Fish House. The Regent's Park aquarium, initially indiscriminately referred to as the "Fish House," "Vivarium," "Aquavivarium" or "Marine vivarium", soon yielded to the word "aquarium", a term coined by Gosse used as the title of his 1854 book The Aquarium: An Unveiling of the Wonders of the Deep Water. In this book, Gosse primarily discussed saltwater aquaria. The high-water mark of the popular aquarium movement in Britain lasted from 1853–1860.
Tank designs and techniques for maintaining water quality were developed by Warington, later cooperating with Gosse until his critical review of the tank water composition. Edward Edwards developed these glass-fronted aquaria in his 1858 patent for a "dark-water-chamber slope-back tank", with water slowly circulating to a reservoir beneath.
Influenced by Gosse, the German Emil Adolf Rossmässler promoted the value of the aquarium movement in the educational field. Rossmässler wrote of its use in an 1855 article in Die Gartenlaube (The Gazebo) and in his 1857 book Das Susswasser-Aquarium (The Freshwater Aquarium), the freshwater aquarium being much easier to maintain in landlocked areas. In 1862 William Alford Lloyd, then bankrupt because of the craze in England being over, moved to Grindel Dammthor, Hamburg, to supervise the installation of the circulating system and tanks at the Hamburg Aquarium. During the 1870s, some of the first aquarist societies were appearing in Germany. The United States soon followed. Published in 1858, Henry D. Butler's The Family Aquarium was one of the first books written in the United States solely about the aquarium. According to the July issue of The North American Review of the same year, William Stimson may have owned some of the first functional aquaria, and had as many as seven or eight. The first aquarist society in the United States was founded in New York City in 1893, followed by others. The New York Aquarium Journal, first published in October 1876, is considered to be the world's first aquarium magazine.
In the Victorian era in the United Kingdom, a common design for the home aquarium was a glass front with the other sides made of wood (made watertight with a pitch coating). The bottom would be made of slate and heated from below. More advanced systems soon began to be introduced, along with tanks of glass in metal frames. During the latter half of the 19th century, a variety of aquarium designs were explored, such as hanging the aquarium on a wall, mounting it as part of a window, or even combining it with a birdcage.
=== Twentieth century ===
Around 1908, the first mechanical aquarium air pump was invented, powered by running water, instead of electricity. The introduction of the air pump into the hobby is considered by several historians of the hobby to be a pivotal moment in its development.
Aquaria became more widely popular as houses had an electricity supply after World War I. Electricity allowed artificial lighting, as well as aeration, filtration, and heating of the water. Initially, amateur aquarists kept native fish (with the exception of goldfish); the availability of exotic species from overseas further increased the popularity of the aquarium. Jugs made from a variety of materials were used to import fish from overseas, with a bicycle foot pump for aeration. Plastic shipping bags were introduced in the 1950s, making it easier to ship fish. The eventual availability of air freight allowed fish to be successfully imported from distant regions. Popular publications started by Herbert R. Axelrod influenced many more hobbyists to start keeping fish. In the 1960s, metal frames made marine aquaria almost impossible due to corrosion, but the development of tar and silicone sealant allowed the first all-glass aquaria made by Martin Horowitz in Los Angeles, CA. The frames remained, however, though purely for aesthetic reasons.
Japan played an increasingly important role in shaping aquarium design in the latter part of the twentieth century, with the aquascaping designs of Takashi Amano influencing fishkeepers to treat home aquariums as aesthetically pleasing compositions, rather than simply as a way of displaying fish specimens.
In the United States, as of 1996, aquarium keeping is the second-most popular hobby after stamp collecting. In 1999, an estimated 9.6 million US households owned an aquarium. Figures from the 2005/2006 APPMA National Pet Owners Survey report that Americans own approximately 139 million freshwater fish and 9.6 million saltwater fish. Estimates of the numbers of fish kept in aquaria in Germany suggest at least 36 million. The hobby has the strongest following in Europe, Asia, and North America. In the United States, 40% of aquarists maintain two or more tanks.
Over time, there has been an increasing appreciation of the usefulness of access to an aquarium to provide potential stress reduction and improvement of mood in people observing aquatic life. According to the research of having an aquarium is many health benefits like reduce stress, blood pressure and heart rate improvement, better quality sleep, reduce anxiety and pain, therapy of excited children, Alzheimer's therapy and improve productivity.
== Design ==
=== Materials ===
==== Glass ====
The first modern aquarium made of glass was developed in the 19th century by Robert Warrington. During the Victorian age, glass aquariums commonly had slate or steel bottoms, which allowed them to be heated underneath by an open-flame heat source. These aquariums had the glass panels attached with metal frames and sealed with putty. Metal-framed aquariums were still available until the mid-1960s, when the modern, silicone-sealed style replaced them. Acrylic aquariums first became available to the public in the 1970s. Laminated glass is sometimes used, which combines the advantages of both glass and acrylic.
Today, most aquaria consist of glass panes bonded together by 100% silicone sealant, with plastic frames attached to the upper and lower edges for decoration. The glass aquarium is standard for sizes up to about 1,000 litres (260 US gal; 220 imp gal). However, glass is brittle and has very little give before fracturing, though generally the sealant fails first. Aquaria are made in a variety of shapes, such as cuboid, hexagonal, angled to fit in a corner (L-shaped), and bow-front (the front side curves outwards). Fish bowls are generally either made of plastic or glass, and are either spherical or some other round configuration in shape.
Glass aquaria have been a popular choice for many home and hobbyist aquarists for many years. Once silicone sealant became strong enough to ensure a long-term water-tight seal, it eliminated the need for a structural frame. In addition to lower cost, glass aquaria are more scratch resistant than acrylic. Although the price is one of the main considerations for aquarists when deciding which of these two types of aquaria to purchase, for very large tanks, the price difference tends to disappear.
==== Acrylic ====
Acrylic aquaria are now the primary competitor with glass. Prior to the invention of UV stabilization, early acrylic aquaria discolored over time with exposure to light; this is no longer the case. Acrylic is generally stronger than glass, weighs less, and provides a certain amount of temperature insulation. In colder climates or environments, it is easier to achieve and maintain a tropical temperature and requires less capacity from an aquarium heater. Acrylic-soluble cements are used to directly fuse acrylic together. Acrylic allows for the formation of unusual shapes, such as the hexagonal tank. Acrylics are easier to scratch than glass, but unlike glass, scratches in acrylic can be polished out.
==== Other materials ====
Large aquaria might instead use stronger materials such as fiberglass-reinforced plastics. However, this material is not transparent. Reinforced concrete is used for aquaria where weight and space are not factors. Concrete must be coated with a waterproof layer to prevent the water from breaking down the concrete, as well as preventing contamination of the water by the concrete.
Plywood can also be used when building aquaria. The benefits of using plywood include: lower construction costs, less weight, and better insulation. A popular positioning choice for plywood aquaria is keeping them in a wall. Here the use of plywood is hidden by sinking the aquarium inside the wall. Putting insulation between the two helps with the insulation of a heated tank.
=== Styles ===
Objects used for aquariums include: coffee tables, sinks, and even toilets. Another such example is the MacQuarium, an aquarium made from the shell of an Apple Macintosh computer. In recent years, elaborate custom-designed home aquariums costing hundreds of thousands of dollars have become status symbols—according to The New York Times, "among people of means, a dazzling aquarium is one of the last surefire ways to impress their peers."
==== Kreisel ====
A kreisel tank (kreisel being German for "spinning top" or "gyroscope") is an aquarium shaped like a horizontal cylinder that is designed to hold delicate animals such as jellyfish and newborn seahorses. These aquariums provide slow, circular water flow with a bare minimum of interior hardware to prevent the inhabitants from becoming injured by pumps or the tank itself. The tank has no sharp angles around its sides and keeps the housed animals away from plumbing. Water moving into the tank gives a gentle flow that keeps the inhabitants suspended. Water leaves the tank through a screen which prevents animals from being drawn into the pump intake or overflow line.
There are several types of kreisel tanks. In a true kreisel, a circular tank has a circular, submerged lid. Pseudokreisels are "U" or semicircle shaped, usually without a lid. Stretch kreisels are a "double gyre" kreisel design, where the tank length is at least twice the height. Using two downwelling inlets on both sides of the tank lets gravity create two gyres in the tank. A single downwelling inlet may be used in the middle as well. The top of a stretch kreisel may be open or closed with a lid. There may also be screens about midway down the sides of the tank, or at the top on the sides. It is possible to combine these designs; a circular shaped tank is used without a lid or cover, and the surface of the water acts as the continuation of circular flow.
==== Biotope ====
Another popular setup is the biotope aquarium. A biotope aquarium is a recreation of a specific natural environment. Some of the most popular biotopes are the freshwater habitats of the Amazon River, the Rio Negro River, the African rift lake environments of Lake Malawi and Lake Tanganyika, and saltwater coral reefs of Australia, the Red Sea, and the Caribbean Sea. The fish, plants, substrate, rocks, wood, coral, and any other component of the display should completely match that of the local natural environment. It can be a challenge to recreate such environments, and most "true" biotopes will only have a few (if not only one) species of fish and invertebrates.
Finally, an emerging concept for the home is that of a wall mounted aquarium.
=== Aquarium size and volume ===
An aquarium can range from a small glass bowl containing less than 1 litre (2.1 US pt) of water to immense public aquaria that house entire ecosystems such as kelp forests. Relatively large home aquaria resist rapid fluctuations of temperature and pH, allowing for greater system stability. Beginner aquarists are advised to consider larger tanks to begin with, as controlling water parameters in smaller tanks can prove difficult.
Small, unfiltered bowl-shaped aquaria are now widely regarded as unsuitable for most fish. In order to keep water conditions at suitable levels, aquariums should contain at least two forms of filtration: biological and mechanical. Chemical filtration should also be considered under some circumstances for optimum water quality. Chemical filtration is frequently achieved via activated carbon, to filter medications, tannins, and/or other known impurities from the water.
Reef aquaria under 100 litres (26 US gal; 22 imp gal) have a special place in the aquarium hobby; these aquaria, termed nano reefs (when used in reefkeeping), have a small water volume, under 40 litres (11 US gal; 9 imp gal).
Practical limitations, most notably the weight of water (1 kilogram per litre (8.345 lb/U.S. gal; 10.022 lb/imp gal)) and internal water pressure (requiring thick glass siding) of a large aquarium, restrict most home aquaria to a maximum of around 1 cubic metre in volume (1000 L, weighing 1,000 kg or 2,200 lb). Some aquarists, however, have constructed aquaria of many thousands of litres.
Public aquariums and oceanariums designed for exhibition of large species or environments can be dramatically larger than any home aquarium. The Georgia Aquarium, for example, features an individual aquarium of 6,300,000 US gallons (24,000,000 L).
==== Nano aquariums ====
A new trend is to have very small aquariums, termed mini aquariums (less than 150 litres or 40 gallons) or nano aquariums (less than 75 litres or 20 gallons). These can be either freshwater or saltwater, and are intended to display a tiny but self-contained ecosystem.
== Components ==
The typical hobbyist aquarium includes a filtration system, an artificial lighting system, an air diffuser and pump, and a heater or chiller depending on the aquarium's inhabitants. Many aquaria incorporate a hood, containing the lights, to decrease evaporation and prevent fish from leaving the aquarium (and anything else from entering the aquarium).
Combined biological and mechanical aquarium filtration systems are common. These either convert ammonia to nitrate (removing nitrogen at the expense of aquatic plants), or to sometimes remove phosphate. Filter media can house microbes that mediate nitrification. Filtration systems are sometimes the most complex component of home aquaria.
Aquarium heaters combine a heating element with a thermostat, allowing the aquarist to regulate water temperature at a level above that of the surrounding air, whereas coolers and chillers (refrigeration devices) are for use anywhere, such as cold water aquaria, where the ambient room temperature is above the desired tank temperature. Thermometers used include glass alcohol thermometers, adhesive external plastic strip thermometers, and battery-powered LCD thermometers. In addition, some aquarists use air pumps attached to airstones or water pumps to increase water circulation and supply adequate gas exchange at the water surface. Wave-making devices have also been constructed to provide wave action.
An aquarium's physical characteristics form another aspect of aquarium design. Size, lighting conditions, density of floating and rooted plants, placement of bog-wood, creation of caves or overhangs, type of substrate, and other factors (including an aquarium's positioning within a room) can all affect the behavior and survival of tank inhabitants.
An aquarium can be placed on an aquarium stand. Because of the weight of the aquarium, a stand must be strong as well as level. A tank that is not level may distort, leak, or crack. These are often built with cabinets to allow storage, available in many styles to match room decor. Simple metal tank stands are also available. Most aquaria should be placed on polystyrene to cushion any irregularities on the underlying surface or the bottom of the tank itself that may cause cracks. However, some tanks have an underframe making this unnecessary.
Another important consideration for aquariums is their electrical usage. Water is expensive to keep heated, along with the lights that many aquariums, especially those with live plants have. New aquarists should also pay close attention to their electrical setup for their aquarium, taking care to set up power connections with drip loops to prevent water from getting to outlets.
== Aquarium maintenance ==
Large volumes of water enable more stability in a tank by diluting effects from death or contamination events that push an aquarium away from equilibrium. The bigger the tank, the easier such a systemic shock is to absorb, because the effects of that event are diluted. For example, the death of the only fish in an 11-litre (3 US gal; 2 imp gal) tank causes dramatic changes in the system, while the death of that same fish in a 400-litre (110 US gal; 88 imp gal) tank with many other fish in it represents only a minor change. For this reason, hobbyists often favor larger tanks, as they require less attention.
Several nutrient cycles are important in the aquarium. Dissolved oxygen enters the system at the surface water-air interface. Similarly, carbon dioxide escapes the system into the air. The phosphate cycle is an important, although often overlooked, nutrient cycle. Sulfur, iron, and micronutrients also cycle through the system, entering as food and exiting as waste. Appropriate handling of the nitrogen cycle, along with supplying an adequately balanced food supply and considered biological loading, is enough to keep these other nutrient cycles in approximate equilibrium.
An aquarium must be maintained regularly to ensure that the fish are kept healthy. Daily maintenance consists of checking the fish for signs of stress and disease. Also, aquarists must make sure that the water has a good quality and it is not cloudy or foamy and the temperature of the water is appropriate for the particular species of fish that live in the aquarium.
Typical weekly maintenance includes changing around 10–30% or more of the water while cleaning the gravel, or other substrate if the aquarium has one; however some manage to avoid this entirely by keeping it somewhat self-sufficient. A good habit is to remove the water being replaced by "vacuuming" the gravel with suitable implements, as this will eliminate uneaten foods and other residues that settle on the substrate. In many areas tap water is not considered to be safe for fish to live in because it contains chemicals that harm the fish. Tap water from those areas must be treated with a suitable water conditioner, such as a product which removes chlorine and chloramine and neutralizes any heavy metals present. The water conditions must be checked both in the tank and in the replacement water, to make sure they are suitable for the species.
=== Water conditions ===
The solute content of water is perhaps the most important aspect of water conditions, as total dissolved solids and other constituents dramatically impact basic water chemistry, and therefore how organisms interact with their environment. Salt content, or salinity, is the most basic measure of water conditions. An aquarium may have freshwater (salinity below 500 parts per million), simulating a lake or river environment; brackish water (a salt level of 500 to 30,000 PPM), simulating environments lying between fresh and salt, such as estuaries; and salt water or seawater (a salt level of 30,000 to 40,000 PPM), simulating an ocean environment. Rarely, higher salt concentrations are maintained in specialized tanks for raising brine organisms.
Saltwater is usually alkaline, while the pH (alkalinity or acidity) of fresh water varies more. Hardness measures overall dissolved mineral content; hard or soft water may be preferred. Hard water is usually alkaline, while soft water is usually neutral to acidic. Dissolved organic content and dissolved gases content are also important factors.
Home aquarists typically use tap water supplied through their local water supply network to fill their tanks. Straight tap water cannot be used in localities that pipe chlorinated water. In the past, it was possible to "condition" the water by simply letting the water stand for a day or two, which allows the chlorine time to dissipate. However, chloramine is now used more often and does not leave the water as readily. Water conditioners formulated to remove chlorine or chloramine are often all that is needed to make the water ready for aquarium use. Brackish or saltwater aquaria require the addition of a commercially available mixture of salts and other minerals.
Some aquarists modify water's alkalinity, hardness, or dissolved content of organics and gases, before adding it to their aquaria. This can be accomplished by additives, such as sodium bicarbonate, to raise pH. Some aquarists filter or purify their water through deionization or reverse osmosis prior to using it. In contrast, public aquaria with large water needs often locate themselves near a natural water source (such as a river, lake, or ocean) to reduce the level of treatment. Some hobbyists use an algae scrubber to filter the water naturally.
Water temperature determines the two most basic aquarium classifications: tropical versus cold water. Most fish and plant species tolerate only a limited temperature range; tropical aquaria, with an average temperature of about 25 °C (77 °F), are much more common. Temperate or coldwater aquaria are for fish that are better suited to a cooler environment. Temperature consistency is more important than range. Most organisms are not accustomed to sudden changes in temperatures, which can cause shock and lead to disease. Water temperature can be regulated with a thermostat and heater (or cooler).
Water movement can also be important in simulating a natural ecosystem. Aquarists may prefer anything from still water up to swift currents, depending on the aquarium's inhabitants. Water movement can be controlled via aeration from air pumps, powerheads, and careful design of internal water flow (such as location of filtration system points of inflow and outflow).
=== Nitrogen cycle ===
Of primary concern to the aquarist is management of the waste produced by an aquarium's inhabitants. Fish, invertebrates, fungi, and some bacteria excrete nitrogen waste in the form of ammonia (which converts to ammonium, in water) and must then either pass through the nitrogen cycle or be removed by passing through zeolite. Ammonia is also produced through the decomposition of plant and animal matter, including fecal matter and other detritus. Nitrogen waste products become toxic to fish and other aquarium inhabitants at high concentrations. In the wild, the vast amount of water surrounding the fish dilutes ammonia and other waste materials. When fish are put into an aquarium, waste can quickly reach toxic concentrations in the enclosed environment unless the tank is cycled to remove waste.
==== The process ====
A well-balanced tank contains organisms that are able to metabolize the waste products of other aquarium residents, recreating a portion of the nitrogen cycle. Bacteria known as nitrifiers (genus Nitrosomonas) metabolize nitrogen waste. Nitrifying bacteria capture ammonia from the water and metabolize it to produce nitrite. Nitrite is toxic to fish in high concentrations. Another type of bacteria (genus Nitrospira) converts nitrite into nitrate, a less toxic substance. (Nitrobacter bacteria were previously believed to fill this role. While biologically they could theoretically fill the same niche as Nitrospira, it has recently been found that Nitrobacter are not present in detectable levels in established aquaria, while Nitrospira are plentiful.) However, commercial products sold as kits to "jump start" the nitrogen cycle often still contain Nitrobacter.
Aquatic plants also eliminate nitrogen waste by metabolizing ammonia and nitrate. When plants metabolize nitrogen compounds, they remove nitrogen from the water by using it to build biomass that decays more slowly than ammonia-driven plankton already dissolved in the water. Some hobbyists also use "anoxic filtration," which relies on bacteria that live in low-oxygen environments.
==== Maintaining the nitrogen cycle ====
The nitrogen cycle in an aquarium is only a portion of the complete cycle: nitrogen must be added to the system (usually through food provided to the tank inhabitants), and nitrates accumulate in the water at the end of the process, or become bound in the biomass of plants. The aquarium keeper must remove water once nitrate concentrations grow, or remove plants which have grown from the nitrates.
Hobbyist aquaria often do not have sufficient bacteria populations to adequately denitrify waste. This problem is most often addressed through two filtration solutions: Activated carbon filters absorb nitrogen compounds and other toxins, while biological filters provide a medium designed to enhance bacterial colonization. Activated carbon and other substances, such as ammonia absorbing resins, stop working when their pores fill, so these components have to be replaced regularly.
New aquaria often have problems associated with the nitrogen cycle due to insufficient beneficial bacteria. Therefore, fresh water has to be matured before stocking them with fish. There are three basic approaches to this: the "fishless cycle", the "silent cycle" and "slow growth".
In a fishless cycle, small amounts of ammonia are added to an unpopulated tank to feed the bacteria. During this process, ammonia, nitrite, and nitrate levels are tested to monitor progress. The "silent" cycle is basically nothing more than densely stocking the aquarium with fast-growing aquatic plants and relying on them to consume the nitrogen, allowing the necessary bacterial populations time to develop. According to anecdotal reports, the plants can consume nitrogenous waste so efficiently that ammonia and nitrite level spikes seen in more traditional cycling methods are greatly reduced or disappear. "Slow growth" entails slowly increasing the population of fish over a period of 6 to 8 weeks, giving bacteria colonies time to grow and stabilize with the increase in fish waste. This method is usually done with a small starter population of hardier fish which can survive the ammonia and nitrite spikes, whether they are intended to be permanent residents or to be traded out later for the desired occupants.
The largest bacterial populations are found in the filter, where there is high water flow and plentiful surface available for their growth, so effective and efficient filtration is vital. Sometimes, a vigorous cleaning of the filter is enough to seriously disturb the biological balance of an aquarium. Therefore, it is recommended to rinse mechanical filters in an outside bucket of aquarium water to dislodge organic materials that contribute to nitrate problems, while preserving bacteria populations. Another safe practice consists of cleaning only half of the filter media during each service, or using two filters, only one of which is cleaned at a time.
=== Biological load ===
The biological load, or bioload is a measure of the burden placed on the aquarium ecosystem by its inhabitants. High biological loading presents a more complicated tank ecology, which in turn means that equilibrium is easier to upset. Several fundamental constraints on biological loading depend on aquarium size. The water's surface area limits oxygen intake. The bacteria population depends on the physical space they have available to colonize. Physically, only a limited size and number of plants and animals can fit into an aquarium while still providing room for movement. Biologically, biological loading refers to the rate of biological decay in proportion to tank volume. Adding plants to an aquarium will sometimes help greatly with taking up fish waste as plant nutrients. Although an aquarium can be overloaded with fish, an excess of plants is unlikely to cause harm. Decaying plant material, such as decaying plant leaves, can add these nutrients back into the aquarium if not promptly removed. The bioload is processed by the aquarium's biofilter filtration system.
==== Calculating capacity ====
Limiting factors include the oxygen availability and filtration processing. Aquarists have rules of thumb to estimate the number of fish that can be kept in an aquarium. The examples below are for small freshwater fish; larger freshwater fishes and most marine fishes need much more generous allowances.
3 cm of adult fish length per 4 litres of water (i.e., a 6 cm-long fish would need about 8 litres of water).
1 cm of adult fish length per 30 square centimetres of surface area.
1 inch of adult fish length per US gallon of water.
1 inch of adult fish length per 12 square inches of surface area.
Experienced aquarists warn against applying these rules too strictly because they do not consider other important issues such as growth rate, activity level, social behaviour, filtration capacity, total biomass of plant life, and so on. It is better to apply the overall mass and size of a fish per gallon of water, than simply the length. This is because fish of different sizes produce quite differing amounts of waste. Establishing maximum capacity is often a matter of slowly adding fish and monitoring water quality over time, following a trial and error approach.
==== Other factors affecting capacity ====
One variable is differences between fish. Smaller fish consume more oxygen per gram of body weight than larger fish. Labyrinth fish can breathe atmospheric oxygen and do not need as much surface area (however, some of these fish are territorial, and do not appreciate crowding). Barbs also require more surface area than tetras of comparable size.
Oxygen exchange at the surface is an important constraint, and thus the surface area of the aquarium matters. Some aquarists claim that a deeper aquarium holds no more fish than a shallower aquarium with the same surface area. The capacity can be improved by surface movement and water circulation such as through aeration, which not only improves oxygen exchange, but also waste decomposition rates.
Waste density is another variable. Decomposition in solution consumes oxygen. Oxygen dissolves less readily in warmer water; this is a double-edged sword since warmer temperatures make fish more active, so they consume more oxygen.
In addition to bioload/chemical considerations, aquarists also consider the mutual compatibility of the fish. For instance, predatory fish are usually not kept with small, passive species, and territorial fish are often unsuitable tankmates for shoaling species. Furthermore, fish tend to fare better if given tanks conducive to their size. That is, large fish need large tanks and small fish can do well in smaller tanks. Lastly, the tank can become overcrowded without being overstocked. In other words, the aquarium can be suitable with regard to filtration capacity, oxygen load, and water, yet still be so crowded that the inhabitants are uncomfortable.
For planted freshwater aquariums, it is also important to maintain a balance between the duration and quality of light, the amount of plants, CO2 levels and nutrients. The amount of fish on the tank can also affect the nutrients levels. For a given amount of light, if there is insufficient number of plants or insufficient CO2 to support the growth of those plants, so as to consume all the nutrients in the tank, the result would be algae growth. While there are fishes and invertebrates that could be introduced in the tank to clean up this algae, the ideal solution would be to find the optimal balance between the above-mentioned factors. Supplemental CO2 can be provided, whose quantity has to be carefully regulated, as too much CO2 may harm the fishes.
== Aquarium classifications ==
From the outdoor ponds and glass jars of antiquity, modern aquaria have evolved into a wide range of specialized systems. Individual aquaria can vary in size from a small bowl large enough for only a single small fish, to the huge public aquaria that can simulate entire marine ecosystems.
One way to classify aquaria is by salinity. Freshwater aquaria are the most popular due to their lower cost. More expensive and complex equipment is required to set up and maintain marine aquaria. Marine aquaria frequently feature a diverse range of invertebrates in addition to species of fish. Brackish water aquaria combine elements of both marine and freshwater fishkeeping. Fish kept in brackish water aquaria generally come from habitats with varying salinity, such as mangrove swamps and estuaries. Subtypes exist within these types, such as the reef aquarium, a typically smaller marine aquarium that houses coral.
Another classification is by temperature range. Many aquarists choose a tropical aquarium because tropical fish tend to be more colorful. However, the coldwater aquarium is also popular, which includes fish from temperate areas worldwide.
Aquaria may be grouped by their species selection. In a community tank, several non-aggressive species live peacefully. In these aquaria, the fish, invertebrates, and plants probably do not originate from the same geographic region, but tolerate similar water conditions and each other. Aggressive tanks, by contrast, house a limited number of species that can be aggressive toward other fish, or are able to withstand aggression well. Most aquarists maintaining marine tanks and tanks housing cichlids have to take species aggressiveness into account when stocking. Specimen tanks usually only house one fish species, along with plants—sometimes those found in the fish species' natural environment—and decorations simulating a natural ecosystem. This type is useful for fish that cannot coexist with other fish, such as the electric eel, as an extreme example. Some tanks of this sort are used simply to house adults for breeding.
Biotope aquaria is another type based on species selection. In it, an aquarist attempts to simulate a specific natural ecosystem, assembling fish, invertebrate species, plants, decorations and water conditions all found in that ecosystem. Public aquaria often use this approach. Biotope aquaria simulates the experience of observing in the wild. It typically serves as the healthiest possible artificial environment for the tank's occupants.
== Public aquaria ==
Most public aquarium facilities feature a number of smaller aquaria, as well those too large for home aquarists. The largest tanks hold millions of gallons of water and can house large species, including sharks or beluga whales, which typically could not be housed properly in the home aquarium. Dolphinaria are specifically for dolphins. Aquatic and semiaquatic animals, including otters and penguins, may also be kept by public aquaria. Public aquaria may also be included in larger establishments such as a marine mammal park or a marine park. These are very popular around the world, especially with a new emergence in the Middle East.
== Virtual aquariums ==
A virtual aquarium is a computer program which uses 3D graphics to reproduce an aquarium on a personal computer. The swimming fish are rendered in real time, while the background of the tank is usually static. Objects on the floor of the tank may be mapped in simple planes so that the fish may appear to swim both in front and behind them, but a relatively simple 3D map of the general shape of such objects may be used to allow the light and ripples on the surface of the water to cast realistic shadows. Bubbles and water noises are common for virtual aquariums, which are often used as screensavers.
The number of each type of fish can usually be selected, often including other animals like starfish, jellyfish, seahorses, and even sea turtles. Most companies that produce virtual aquarium software also offer other types of fish for sale via Internet download. Other objects found in an aquarium can also be added and rearranged on some software, like treasure chests and giant clams that open and close with air bubbles, or a bobbing diver. There are also usually features that allow the user to tap on the glass or put food in the top, both of which the fish will react to. Some also have the ability to allow the user to edit fish and other objects to create new varieties.
== See also ==
List of aquaria
Association of Zoos and Aquariums (AZA)
List of aquarium diseases
List of aquarium fish by scientific name
List of brackish aquarium fish species
List of brackish aquarium plant species
List of freshwater aquarium amphibian species
List of freshwater aquarium fish species
List of freshwater aquarium invertebrate species
List of freshwater aquarium plant species
List of marine aquarium fish species
List of marine aquarium invertebrate species
List of marine aquarium plant species
Vivarium
== References ==
== External links ==
Ernest Ingersoll (1920). "Aquarium" . Encyclopedia Americana. | Wikipedia/Aquarium_therapy |
Compassion Focused Therapy (CFT) is a system of psychotherapy developed by Paul Gilbert that integrates techniques from cognitive behavioral therapy with concepts from evolutionary psychology, social psychology, developmental psychology, Buddhist psychology, and neuroscience. According to Gilbert, "One of its key concerns is to use compassionate mind training to help people develop and work with experiences of inner warmth, safeness and soothing, via compassion and self-compassion.": 199
== Overview ==
A central therapeutic technique of CFT is compassionate mind training, which teaches the skills and attributes of compassion. Compassionate mind training helps transform problematic patterns of cognition and emotion related to anxiety, anger, shame and self-criticism.: 208
Biological evolution forms the theoretical backbone of CFT. Humans have evolved with at least three primal types of emotion regulation system: the threat (protection) system, the drive (resource-seeking) system, and the soothing system.: 200 : 43 CFT emphasizes the links between cognitive patterns and these three emotion regulation systems.: 59 Through the use of techniques such as compassionate mind training and cognitive behavioral therapy (CBT), counseling clients can learn to manage each system more effectively and respond more appropriately to situations.
Compassion Focused Therapy is especially appropriate for people who have high levels of shame and self-criticism and who have difficulty in feeling warmth toward, and being kind to, themselves or others. CFT can help such people learn to feel more safeness and warmth in their interactions with others and themselves.
Numerous methods are used in CFT to develop a person's compassion. For example, people undergoing CFT are taught to understand compassion from the third person, before transferring these thought processes to themselves.: 317
== Core principles ==
CFT is largely built on the idea that the evolution of caring behavior has major regulatory and developmental functions.: 4 The central focus of CFT is to concentrate on helping clients relate to their difficulties in compassionate ways, as well as provide them with effective tools to work with challenging circumstances and emotions they encounter. CFT helps those learn tools to engage with their battles in accepting and encouraging ways, thereby aiding themselves to feel confident about accomplishing difficult tasks and dealing with challenging situations.
This is facilitated by:
Developing a positive therapeutic relationship that facilitates the process of engaging with one's challenges and development of skills to deal with them.
Developing non-blaming compassionate understandings into the nature of suffering.
Developing the ability to experience and cultivate compassionate attributes.
Developing the feeling of compassion for others, being open to compassion from others, and developing self-compassion.
According to evolutionary analysis, there are three types of functional emotion regulation systems: drive, safety and threat. CFT is based on the relationship and interactions between these systems. One is born with each system but our surroundings implicate whether one utilizes and sustains the non-survival-based systems (drive and caregiving).
Threat and self-protection focused system: evolved to alert and direct attention to detect and respond to threats. This system contains threat-based emotions (anger, anxiety, disgust), and threat-based behaviors (fight/flight, freezing).
Drive, seeking and acquisition focused system: pay attention and notice advantageous resources, experience drive and pleasure in securing them (positive system is activating).
Contentment, soothing and affiliative system: enables state of peacefulness when individuals are no longer focused on threats or seeking out resources (allows body to rest and digest and have open attention).
Using CFT enriches the compassion-based soothing system, while withdrawing from the threat-focused emotional regulation system. In turn, this will augment the ability to activate (drive) and work towards valued goals.: 11
== Applications ==
Compassion Focused Therapy has been investigated as a novel treatment for a wide variety of psychological disorders.
A 2012 randomized controlled trial showed CFT to be a safe and clinically effective treatment option for psychosis patients. CFT was shown to be more effective than "treatment as usual", with particular efficacy in reducing depression symptoms. A further 2015 literature review of 14 different studies showed promising psychotherapeutic benefits of CFT, especially when treating mood disorders. A recent meta analysis found good support for CFT as a treatment for a variety of psychological difficulties. However, further large-scale trials are necessary in order for CFT to become an accepted, "evidence-based" treatment for these disorders. For cancer patients, compassion-based interventions including CFT was shown to relieve depression and elevate self-compassion in this population.
CFT has also been explored as a treatment for individuals with eating disorders. This slightly modified version of CFT, CFT-E, has had promising results in treating adult outpatients with restrictive eating disorders as well as with binging and purging disorders. A 2014 literature review found CFT-E to be a particularly effective treatment for eating disorders due to the fact that it confronts the "high levels of shame and self‐criticism" that patients often experience. More recent primary studies have further proved CFT-E to be a safe and effective intervention for eating disorders.
CFT is also being studied as a rehabilitation method for patients with acquired brain injuries (ABI). Preliminary, small-scale studies have shown CFT to be safe and beneficial in treating anxiety and depressive symptoms of ABI patients, although further large-scale studies are needed.
As well as being a psychological therapy (for individuals and groups), Compassionate Mind Training (CMT) has been shown to be an effective approach for reducing psychological distress in the general public. A variety of studies have found that engaging in guided audios, online courses, an 8 week group and using an app (The Self-Compassion App) can lead to reductions in self-criticism, shame, attachment insecurity, depression and anxiety symptoms, as well as increasing self-compassion, positive emotions and wellbeing.
CMT has also been used as an effective approach in schools, with results suggesting a variety of benefits for teachers who engaged in an 8 week compassion training course.
== Limitations ==
Beaumont and Hollins Martin (2015) examined narrative reviews of 12 research findings that has shown use of CFT to treat and experiment with psychological outcomes in clinical populations. The researchers found that overall, there are improvements of mental health issues with CFT intervention, especially when combined with approaches such as cognitive behavioral therapy (CBT).
Beaumont and Hollins Martin (2015) found a major limitation in the empirical studies are the small number of participants involved in each case. For instance, Gilbert and Proctor (2006) showed small reductions in depression, anxiety, self-criticism and shame, however their participant group involved only 6 members. The small number of participants can cause bias or facilitate a problem of generalization for the broader population. For instance, out of the twelve studies only two individually supported effectiveness of CFT. A study conducted by Lucre and Corten (2012) found CFT to be effective for treating patients with personality disorders, and another study by Heriot-Maitland et al. (2014) found that treating clients in acute inpatient settings was effective.
== Recommendations ==
The findings of Beaumont and Hollins Martin (2015) recommended that the effectiveness of CFT needs further extensive research in order to fully examine reductions in mental illnesses and overall improvements in quality of life. This study recommends for consideration of larger samples of participants in order to ensure that CFT can be independently effective without other psychotherapy interventions involved such as CBT.
== References == | Wikipedia/Compassion-focused_therapy |
Massage is the rubbing or kneading of the body's soft tissues. Massage techniques are commonly applied with hands, fingers, elbows, knees, forearms, feet, or a device. The purpose of massage is generally for the treatment of body stress or pain. In English-speaking European countries, traditionally a person professionally trained to give massages is known by the gendered French loanwords masseur (male) or masseuse (female). In the United States, these individuals are often referred to as "massage therapists". In some provinces of Canada, they are called "registered massage therapists."
In professional settings, clients are treated while lying on a massage table, sitting in a massage chair, or lying on a mat on the floor. There are many different modalities in the massage industry, including (but not limited to): deep tissue, manual lymphatic drainage, medical, sports, structural integration, Swedish, Thai and trigger point.
== Etymology ==
The word comes from the French massage 'friction of kneading', which, in turn, comes either from the Arabic word مَسَّ massa meaning 'to touch, feel', the Portuguese amassar 'knead', from the Latin massa meaning 'mass, dough', or the Greek verb μάσσω (massō) 'to handle, touch, to work with the hands, to knead dough'.
The ancient Greek word for massage was anatripsis and the Latin was frictio.
== History ==
=== Ancient times ===
Archaeological evidence of massage has been found in many ancient civilizations including China, India, Japan, Egypt, Rome, Greece, and Mesopotamia.
2330 BC: The Tomb of Akmanthor (also known as "The Tomb of the Physician") in Saqqara, Egypt, depicts two men having work done on their feet and hands, possibly depicting a massage.
1363–912 BC: The word muššuʾu ("massage") is written for the first time on a Middle Assyrian tablet. Its use is described in a list of recipes concerning diseases of the foot.
722–481 BC: Huangdi Neijing is composed during the Chinese Spring and Autumn period. The Nei-jing is a compilation of medical knowledge known up to that date, and is the foundation of traditional Chinese medicine. Massage is referred to in 30 different chapters of the Nei Jing. It specifies the use of different massage techniques and how they should be used in the treatment of specific ailments, and injuries. Also known as "The Yellow Emperor's Inner Canon," the text refers to previous medical knowledge from the time of the Yellow Emperor (c. 2700 BC), misleading some into believing the text itself was written during the time of the Yellow Emperor (which would predate written history).
762 BC: In the Iliad and the Odyssey, massage with oils and aromatic substances is mentioned as a means to relax the tired limbs of warriors and as a way to help the treatment of wounds.
700 BC: Bian Que, the earliest known Chinese physician, uses massage in medical practice.
500 BC: Jīvaka Komarabhācca was an Indian physician who according to the Pāli Buddhist Canon was Shakyamuni Buddha's physician. Jivaka is sometimes credited with founding and developing a style of massage that led to the type of massage practiced in modern Thailand. Though this claim is disputed.
493 BC: A possible biblical reference documents daily "treatments" with oil of myrrh as a part of the beauty regimen of the wives of Xerxes (Esther, 2:12).
460 BC: Hippocrates wrote "The physician must be experienced in many things, but assuredly in rubbing."
300 BC: Charaka Samhita, sometimes dated to 800 BCE, is one of the oldest of the three ancient treatises of Ayurvedic medicine, including massage. Sanskrit records indicate that massage had been practiced in India long before the beginning of recorded history.
AD 1st or 2nd: Galen mentioned Diogas (Διόγας) who was an iatralipta (ἰατραλείπτης) (rubber and anointer/physiotherapist).
AD 581: China establishes a department of massage therapy within the Office of Imperial Physicians.
=== Middle Ages ===
One of the greatest Persian medics was Avicenna, also known as Ibn Sina, who lived from 980 AD to 1037 AD. His works included a comprehensive collection and systematization of the fragmentary and unorganized Greco-Roman medical literature that had been translated Arabic by that time, augmented by notes from his own experiences. One of his books, Al-Qānūn fī aṭ-Ṭibb (The Canon of Medicine) has been called the most famous single book in the history of medicine in both East and West. Avicenna excelled in the logical assessment of conditions and comparison of symptoms and took special note of analgesics and their proper use as well as other methods of relieving pain, including massage.
AD 1150: Evidence of massage abortion, involving the application of pressure to the pregnant abdomen, can be found in one of the bas reliefs decorating the temple of Angkor Wat in Cambodia. It depicts a demon performing such an abortion upon a woman who has been sent to the underworld. This is the oldest known visual representation of abortion.
In Southeast Asia, massage traditions and techniques have already been entrenched in the people's diverse cultures for centuries before trade contact with Europe in the 16th century. In the Philippines, a distinct massage and healing tradition called hilot developed, while in Thailand, the tradition of massage that developed was called nuad thai. Nuad thai was declared in 2019 as a UNESCO intangible cultural heritage.
=== 18th and 19th centuries ===
AD 1776: Jean Joseph Marie Amiot and Pierre-Martial Cibot, French missionaries in China translate summaries of Huangdi Neijing, including a list of medical plants, exercises, and elaborate massage techniques, into the French language, thereby introducing Europe to the highly developed Chinese system of medicine, medical-gymnastics, and medical-massage.
AD 1776: Pehr Henrik Ling, a Swedish physical therapist and teacher of medical-gymnastics, is born. Ling has often been erroneously credited for having invented "Classic Massage", also known as "Swedish Massage", and has been called the "Father of Massage".
AD 1779: Frenchman Pierre-Martial Cibot publishes "Notice du Cong-fou des Bonzes Tao-see", also known as "The Cong-Fou of the Tao-Tse", a French language summary of medical techniques used by Taoist priests. According to English historian of China Joseph Needham, Cibot's work "was intended to present the physicists and physicians of Europe with a sketch of a system of medical gymnastics which they might like to adopt—or if they found it at fault they might be stimulated to invent something better. This work has long been regarded as of cardinal importance in the history of physiotherapy because it almost certainly influenced the Swedish founder of the modern phase of the art, Pehr Hendrik Ling. Cibot had studied at least one Chinese book but also got much from a Christian neophyte who had become expert in the subject before his conversion."
AD 1813: The Royal Gymnastic Central Institute for the training of gymnastic instructors was opened in Stockholm, Sweden, with Pehr Henrik Ling appointed as principal. Ling developed what he called the "Swedish Movement Cure". Ling died in 1839, having previously named his pupils as the repositories of his teaching. Ling and his assistants left a little proper written account of their methods.
AD 1868: Dutch massage practitioner Johan Georg Mezger applies French terms to name five basic massage techniques, and coins the phrase "Swedish massage system". These techniques are still known by their French names (effleurage (long, gliding strokes), petrissage (lifting and kneading the muscles), friction (firm, deep, circular rubbing movements), tapotement (brisk tapping or percussive movements) and vibration (rapidly shaking or vibrating specific muscles)).
=== Modern times ===
==== China ====
As of 2005, with the city of Shanghai alone there were an estimated 1,300–2,000 foot massage centers, with more than 3,000 in Shenzhen. It was also estimated that there were nearly 30,000 massage workers in Shanghai and over 40,000 in Shenzhen. The average rate of pay for a worker in the massage industry in China is over 10,000 yuan per month, making them a well-paying job in China's service sector.
==== United States ====
Massage started to become popular in the United States in the middle part of the 19th century and was introduced by two New York physicians, George and Charles Taylor, based on Pehr Henrik Ling's techniques developed in Sweden.
During the 1930s and 1940s, massage's influence decreased as a result of medical advancements of the time, while in the 1970s massage's influence grew once again with a notable rise among athletes. Until the 1970s, nurses used massage to reduce pain and aid sleep. Popular books and videos, such as Massage for Relaxation, helped introduce massage to popular culture outside of a health setting. The massage therapy industry is continuously increasing. In 2009, U.S. consumers spent between $4 and $6 billion on visits to massage therapists. In 2015, research estimates that massage therapy was a $12.1 billion industry.
All but five states require massage therapists to be licensed, and licensure requires the applicant to receive training at an accredited school, and to pass a comprehensive exam. Those states that require licensure also typically require continuing education in massage techniques and in ethics.
==== United Kingdom ====
The service of massage or "physiological shampooing" was advertised in The Times from as early as 1880. Adverts claimed it as a cure for obesity amongst other chronic ailments.
==== Sports, business and organizations ====
Massage developed alongside athletics in both Ancient China and Ancient Greece. Taoist priests developed massage in concert with their Kung Fu gymnastic movements, while Ancient Greek Olympians used a specific type of trainer ("aleiptes") who would rub their muscles with oil. Pehr Ling's introduction to massage also came about directly as a result of his study of gymnastic movements.
The 1984 Summer Olympics in Los Angeles was the first time that massage therapy was televised as it was being performed on the athletes. And then, during the 1996 Summer Olympics in Atlanta massage therapy was finally offered as a core medical service to the US Olympic Team. Massage has been employed by businesses and organizations such as the U.S. Department of Justice, Boeing and Reebok. Athletes such as Michael Jordan and LeBron James have personal massage therapists that at times even travel with them.
== Types and methods ==
=== Acupressure ===
Acupressure [from Latin acus "needle" (see acuity) + pressure (n.)] is a technique similar in principle to acupuncture. It is based on the concept of life energy which flows through "meridians" in the body. In treatment, physical pressure is applied to acupuncture points with the aim of clearing blockages in those meridians. Pressure may be applied by fingers, palm, elbow, toes or with various devices.
Some medical studies have suggested that acupressure may be effective at helping manage nausea and vomiting, for helping lower back pain, tension headaches, stomach ache, among other things, although such studies have been found to have a high likelihood of bias.
=== Ashiatsu ===
In ashiatsu, the practitioner uses their feet to deliver treatment. The name comes from the Japanese, ashi for foot and atsu for pressure. This technique typically uses the heel, sesamoid, arch, and/or whole plantar surface of foot, and offers large compression, tension and shear forces with less pressure than an elbow and is ideal for large muscles, such as in thigh, or for long-duration upper trapezius compressions. Other manual therapy techniques using the feet to provide treatment include Keralite, Barefoot Lomilomi, and Chavutti Thirumal.
=== Ayurvedic massage ===
Ayurvedic massage is known as Abhyangam in Sanskrit. According to the Ayurvedic Classics Abhyangam is an important dincharya (Daily Regimen) that is needed for maintaining a healthy lifestyle. The massage technique used during Ayurvedic Massage aims to stimulate the lymphatic system. Practitioners claim that the benefits of regular Ayurvedic massage include pain relief, reduction of fatigue, improved immune system and improved longevity.
=== Burmese massage ===
"Known in Myanmar as Yoe Yar Nhake Nal Chin, meaning 'traditional massage', Burmese massage has its ancient origins from Thai, Chinese and Indian medicine. It includes the use of local natural ingredients such as Thanaka which helps to promote smooth skin and prevents sunburn."
Burmese massage is a full body massage technique that starts from head to toes, drawing on acupuncture, reflexology and kneading. Signature massage strokes include acupressure using the elbows, quick gentle knocking of acupressure points, and slow kneading of tight muscles. The massage aims to improve blood circulation and quality of sleep, while at the same time help to promote better skin quality.
=== Biomechanical stimulation (BMS) massage ===
Biomechanical stimulation (BMS) is a term generally used for localised biomechanical oscillation methods, whereby local muscle groups are stimulated directly or via the associated tendons by means of special hand held mechanical vibration devices. Biomechanical oscillation therapy and training is offered in a variety of areas such as competitive sports, fitness, rehabilitation, medicine, prevention, beauty and used to improve performance of the muscles and to improve coordination and balance. It is often used in myofascial trigger point therapy to invoke reciprocal inhibition within the musculoskeletal system. Beneficial effects from this type of stimulation have been found to exist.
=== Biodynamic massage ===
Biodynamic massage was created by Gerda Boyesen as part of Biodynamic Psychotherapy. It uses a combination of hands-on work and "energy work" and also uses a stethoscope to hear the peristalsis.
=== Craniosacral therapy ===
Craniosacral therapy (CST) is a pseudoscience that aims to improve fluid movement and cranial bone motion by applying light touch to the skull, face, spine, and pelvis.
=== Erotic massage ===
A type of massage that is done in an erotic way via the use of massage techniques by a person on another person's erogenous zones to achieve or enhance their sexual excitation or arousal and to achieve orgasm.
It was also once used for medical purposes as well as for the treatment of "female hysteria" and "womb disease".
Nuru massage is a Japanese form of erotic massage.
=== Hammam ("Turkish bath") massage ===
In the traditional Hammam, massage involves not just vigorous muscle kneading, but also joint cracking, "not so much a tender working of the flesh as a pummeling, a cracking of joints, a twisting of limbs..." An 18th-century traveler reported:
...one of the attendants begins to press and handle the tops of the shoulders, the muscles of the arm, and successively the whole body; first gently, then by degrees increasing the pressure, till he comes to handle pretty roughly, but without giving pain. This is repeated at short intervals till the skin is perfectly softened. The attendant then taking hold of the bather's fingers, with a dexterous jerk makes each joint crack successively; after which, laying him flat on his back, and bringing the arms across the breast, the shoulder joints are made to crack in like manner.
=== Lomilomi and indigenous massage of Oceania ===
Lomilomi is the traditional massage of Hawaii. As an indigenous practice, it varies by island and by family. The word lomilomi also is used for massage in Samoa and East Futuna. In Samoa, it is also known as lolomi and milimili. In East Futuna, it is also called milimili, fakasolosolo, amoamo, lusilusi, kinikini, fai’ua. The Māori call it romiromi and mirimiri. In Tonga massage is fotofota, tolotolo, and amoamo. In Tahiti it is rumirumi. On Nanumea in Tuvalu, massage is known as popo, pressure application is kukumi, and heat application is tutu. Massage has also been documented in Tikopia in the Solomon Islands, in Rarotonga, in Pukapuka and in Western Samoa.
=== Lymphatic drainage ===
Manual lymphatic drainage is a technique used to gently work and stimulate the lymphatic system, to assist in reduction of localized swelling. The lymphatic system is a network of slow moving vessels in the body that carries cellular waste toward the liver, to be filtered and removed. Lymph also carries lymphocytes and other immune system agents. Manual lymphatic drainage claims to improve waste removal and immune function.
=== Medical massage ===
Medical massage is a controversial term in the massage profession. Many use it to describe a specific technique. Others use it to describe a general category of massage and many methods such as deep tissue massage, myofascial release and trigger-point therapy, as well as osteopathic techniques, cranial-sacral techniques and many more can be used to work with various medical conditions.
Massage used in the medical field includes decongestive therapy used for lymphedema which can be used in conjunction with the treatment of breast cancer. Light massage is also used in pain management and palliative care. Carotid sinus massage is used to diagnose carotid sinus syncope and is sometimes useful for differentiating supraventricular tachycardia (SVT) from ventricular tachycardia. It, like the valsalva maneuver, is a therapy for SVT. However, it is less effective than management of SVT with medications.
A 2004 systematic review found single applications of massage therapy "reduced state anxiety, blood pressure, and heart rate but not negative mood, immediate assessment of pain, and cortisol level," while "multiple applications reduced delayed assessment of pain," and found improvements in anxiety and depression similar to effects of psychotherapy. A subsequent systematic review published in 2008 found that there is little evidence supporting the use of massage therapy for depression in high quality studies from randomized controlled trials.
=== Myofascial release ===
Myofascial release refers to the manual massage technique that claims to release adhered fascia and muscles with the goal of eliminating pain, increasing range of motion and equilibrioception. Myofascial release usually involves applying shear compression or tension in various directions, cross fiber friction or by skin rolling.
=== Reflexology ===
Reflexology, also known as "zone therapy", is an alternative medicine involving application of pressure to the feet and hands with specific thumb, finger, and hand techniques without the use of oil or lotion. It is based on a pseudoscientific belief in a system of zones and reflex areas that purportedly reflect an image of the body on the feet and hands, with the premise that such work effects a physical change to the body.
=== Shiatsu ===
Shiatsu (指圧) (shi meaning finger and atsu meaning pressure) is a form of Japanese bodywork based on concepts in traditional Chinese medicine such as qi meridians. It consists of finger, palm pressure, stretches, and other massage techniques. There is no convincing data available to suggest that shiatsu is an effective treatment for any medical condition.
=== Sports massage ===
Sports massage is the use of specific massage therapy techniques in an athletic context to improve recovery time, enhance performance and reduce the risk of injury. This is accomplished using techniques that stimulate the flow of blood and lymph to and from muscles. Sports massage is often delivered before or after physical activity depending on the subject's needs, preferences and goals. Sports massages may help with flexibility, pain and recovery but the scientific evidence is mixed.
=== Structural Integration ===
Structural Integration's aim is to unwind the strain patterns in the body's myofascial system, restoring it to its natural balance, alignment, length and ease. This is accomplished by hands-on manipulation, coupled with movement re-education. There are about 15 schools of Structural Integration as recognized by the International Association of Structural Integration, including the Dr. Ida Rolf Institute (with the brand Rolfing), Hellerwork, Guild for Structural Integration, Aston Patterning, Soma, and Kinesis Myofascial Integration.
=== Swedish massage ===
The most widely recognized and commonly used category of massage is Swedish massage. The Swedish massage techniques vary from light to vigorous. Swedish massage uses five styles of strokes. The five basic strokes are effleurage (sliding or gliding), petrissage (kneading), tapotement (rhythmic tapping), friction (cross fiber or with the fibers) and vibration/shaking.
The development of Swedish massage is often inaccurately credited to Per Henrik Ling, though the Dutch practitioner Johann Georg Mezger applied the French terms to name the basic strokes. The term "Swedish massage" is actually only recognized in English- and Dutch-speaking countries, and in Hungary and Israel. Elsewhere the style is referred to as "classic massage".
Clinical studies have found that Swedish massage can reduce chronic pain, fatigue, joint stiffness and improve function in patients with osteoarthritis of the knee.
=== Thai massage ===
Known in Thailand as Nuat phaen boran, meaning "ancient/traditional massage", traditional Thai massage is generally based on a combination of Indian and Chinese traditions of medicine.
Thai massage combines both physical and energetic aspects. It is a deep, full-body massage progressing from the feet up, and focusing on sen or energy lines throughout the body, with the aim of clearing blockages in these lines, and thus stimulating the flow of blood and lymph throughout the body. It draws on yoga, acupressure and reflexology.
Thai massage is a popular massage therapy that is used for the management of conditions such as musculoskeletal pain and fatigue. Thai massage involves a number of stretching movements that improve body flexibility, joint movement and also improve blood circulation throughout the body. In one study scientists found that Thai massage showed comparable efficacy as the painkiller ibuprofen in the reduction of joint pain caused by osteoarthritis (OA) of the knee.
=== Traditional Chinese massage ===
Massage of Chinese Medicine is known as An Mo (按摩pinyin: Ànmó) (pressing and rubbing) or Qigong Massage and is the foundation of Japan's Anma. Categories include Pu Tong An Mo (普通按摩pinyin: Pǔtōng ànmó) (general massage), Tui Na An Mo (推拿按摩pinyin: Tuīná ànmó) (pushing and grasping massage), Dian Xue An Mo (cavity pressing massage), and Qi An Mo (氣按摩 pinyin: Qì ànmó) (energy massage). Tui na (推拿pinyin: Tuīná) focuses on pushing, stretching, and kneading muscles, and Zhi Ya(指壓pinyin: Zhǐ yā) focuses on pinching and pressing at acupressure points. Technique such as friction and vibration are used as well.
=== Trigger point therapy ===
Sometimes confused with pressure point massage, this involves deactivating trigger points that may cause local pain or refer pain and other sensations, such as headaches, in other parts of the body. Manual pressure, vibration, injection, or other treatment is applied to these points to relieve myofascial pain. Trigger points were first discovered and mapped by Janet G. Travell (President Kennedy's physician) and David Simons. Trigger points have been photomicrographed and measured electrically and in 2007 a paper was presented showing images of Trigger Points using MRI. These points relate to dysfunction in the myoneural junction, also called neuromuscular junction (NMJ), in muscle, and therefore this technique is different from reflexology acupressure and pressure point massage.
=== Tui na ===
Tui na is a Chinese manual therapy technique that includes many different types of strokes, aimed to improve the flow of chi through the meridians.
=== Watsu ===
Watsu, developed by Harold Dull at Harbin Hot Springs, California, is a type of aquatic bodywork performed in near-body-temperature water, and characterized by continuous support by the practitioner and gentle movement, including rocking, stretching of limbs, and massage. The technique combines hydrotherapy floating and immersion with shiatsu and other massage techniques. Watsu is used as a form of aquatic therapy for deep relaxation and other therapeutic intent. Related forms include Waterdance, Healing Dance, and Jahara technique.
== Facilities, equipment, and supplies ==
=== Massage tables and chairs ===
Specialized massage tables and chairs are used to position recipients during massages. A typical commercial massage table has an easily cleaned, heavily padded surface, and horseshoe-shaped head support that allows the client to breathe easily while lying face down and can be stationary or portable, while home versions are often lighter weight or designed to fold away easily. An orthopedic pillow or bolster can be used to correct body positioning.
Ergonomic chairs serve a similar function as a massage table. Chairs may be either stationary or portable models. Massage chairs are easier to transport than massage tables, and recipients do not need to disrobe to receive a chair massage. Due to these two factors, chair massage is often performed in settings such as corporate offices, outdoor festivals, shopping malls, and other public locations.
=== Warm-water therapy pools ===
Temperature-controlled warm-water therapy pools are used to perform aquatic bodywork. For example, Watsu requires a warm-water therapy pool that is approximately chest-deep (depending on the height of the therapist) and temperature-controlled to about 35 °C (95 °F).
=== Dry-water massage tables ===
A dry-water massage table uses jets of water to perform the massage of the patient's muscles. These tables differ from a Vichy shower in that the client usually stays dry. Two common types are one in which the client lies on a waterbed-like mattress which contains warm water and jets of water and air bubbles and one in which the client lies on a foam pad and is covered by a plastic sheet and is then sprayed by jets of warm water, similar to a Vichy shower. The first type is sometimes seen available for use in shopping centers for a small fee.
=== Vichy showers ===
A Vichy shower is a form of hydrotherapy that uses a series of shower nozzles that spray large quantities of water over the client while they lie in a shallow wet bed, similar to a massage table, but with drainage for the water. The nozzles may usually be adjusted for height, direction, and temperature to suit the patient's needs.
=== Cremes, lotions, gels, and oils ===
Many different types of massage cremes, lotions, gels, and oils are used to lubricate and moisturize the skin and reduce the friction between skin (hands of technician and client).
=== Massage tools ===
These instruments or devices are sometimes used during massages. Some tools are for use by individuals, others by the therapist.
==== Tools used by massage therapists ====
Instrument-assisted soft-tissue massage can deploy stainless-steel devices to manipulate tissue in a way that augments hands-on work.
A body rock is a serpentine-shaped tool, usually carved out of stone. It is used to amplify the therapist' strength and focus pressure on certain areas. It can be used directly on the skin with a lubricant such as oil or corn starch or directly over clothing.
Bamboo and rosewood tools are also commonly used. They originate from practices in southeast Asia, Thailand, Cambodia, and Burma. Some of them may be heated, oiled, or wrapped in cloth.
Cupping massage is often carried out using plastic cups and a manual hand-pump to create the vacuum. The vacuum draws the soft tissue perpendicular to the skin, providing a tensile force, which can be left in one site or moved along the tissue during the massage.
==== Tools used by both individuals and massagers ====
Hand-held battery-operated massaging and vibrating instruments are available, including devices for massaging the scalp following a haircut.
Vibrating massage pads come in a range of sizes, some with the option of heating.
Vibrating massage chairs can provide an alternative for therapy at home.
There is a widespread market in erotic massage instruments, including electric dildos and vibrators such as the massage wand.
== Medical and therapeutic use ==
The main professionals that provide therapeutic massage are massage therapists, athletic trainers, physical therapists, and practitioners of many traditional Chinese and other eastern medicines. Massage practitioners work in a variety of medical settings and may travel to private residences or businesses. Contraindications to massage include deep vein thrombosis, bleeding disorders, taking blood thinners such as warfarin, damaged blood vessels, or weakened bones from cancer, osteoporosis, fractures, and fever.
=== Beneficial effects ===
Peer-reviewed medical research has shown that the benefits of massage include pain relief, reduced trait anxiety and depression, temporarily reduced blood pressure, heart rate, and state of anxiety. Additional testing has shown an immediate increase in, and expedited recovery periods for, muscle performance. Theories behind what massage might do include: enhanced skeletal muscle regrowth and remodeling, blocking nociception (gate control theory), activating the parasympathetic nervous system (which may stimulate the release of endorphins and serotonin, preventing fibrosis or scar tissue), increasing the flow of lymph, and improving sleep.
Infant massage has been found to hold therapeutic benefits for premature infants and their parents. Premature infants are susceptible to low birth weight and decreased immune function; massage has been found to counter these effects, causing weight increase, reduced pain, and increased immune function. Administering infant massage also reduces stress and increased oxytocin in parental figures regardless of gender, and overall improves emotional attachment with their child.
Massage research is hindered from reaching the gold standard of scientific inquiry, which includes placebo-controlled and double blind clinical trials. Developing a "sham" manual therapy for massage would be difficult since even light touch massage could have effects on a subject. It would also be difficult to find a subject that would not notice that they were getting less of a massage, and it would be impossible to blind the therapist. Massage research can employ randomized controlled trials, which are published in peer reviewed medical journals. This type of study could increase the credibility of the profession because it displays that purported therapeutic effects are reproducible.
==== Single-dose effects ====
Pain relief: Relief from pain due to musculoskeletal injuries and other causes is cited as a major benefit of massage. A 2015 Cochrane Review concluded that there is very little evidence that massage is an effective treatment for lower back pain. A meta-analysis conducted by scientists at the University of Illinois Urbana-Champaign failed to find a statistically significant reduction in pain immediately following treatment. Weak evidence suggests that massage may improve pain in the short term for people with acute, sub-acute, and chronic lower back pain.
State anxiety: Massage has been shown to reduce state anxiety, a transient measure of anxiety in a given situation.
Blood pressure and heart rate: Massage has been shown to temporarily reduce blood pressure and heart rate.
==== Multiple-dose effects ====
Pain relief: Massage may reduce pain experienced in the days or weeks after treatment.
Trait anxiety: Massage has been shown to reduce trait anxiety; a person's general susceptibility to anxiety.
Depression: Massage has been shown to reduce sub-clinical depression.
==== Neuromuscular effects ====
Massage has been shown to reduce neuromuscular excitability by measuring changes in the Hoffman's reflex (H-reflex) amplitude. A decrease in peak-to-peak H-reflex amplitude suggests a decrease in motoneuron excitability. Others explain, "H-reflex is considered to be the electrical analogue of the stretch reflex... and the reduction" is due to a decrease in spinal reflex excitability. Field (2007) confirms that the inhibitory effects are due to deep tissue receptors and not superficial cutaneous receptors, as there was no decrease in H-reflex when looking at light fingertip pressure massage. It has been noted that "the receptors activated during massage are specific to the muscle being massaged," as other muscles did not produce a decrease in H-reflex amplitude.
== Global regulation and practice ==
Because the art and science of massage is a globally diverse phenomenon, different legal jurisdictions sometimes recognize and license individuals with titles, while other areas do not. Examples are:
Registered Massage Therapist (RMT) in Canada and New Zealand
Certified Massage Therapist (CMT) in New Zealand
Licensed Massage Practitioner (LMP)
Licensed Massage Therapist (LMT)
Licensed Massage and Bodywork Therapist (LMBT) in North Carolina
Therapeutic Massage Therapist (TMT) in South Africa
In some jurisdictions, practicing without a license is a crime. One such jurisdiction is Washington state, where any health professionals practicing without a license can be issued a fine and charged with a misdemeanor offense.
=== Canada ===
In regulated provinces massage therapists are known as Registered Massage Therapists, in Canada six provinces regulate massage therapy: British Columbia, Ontario, Newfoundland and Labrador, Prince Edward Island, Saskatchewan, and New Brunswick. Registered Massage Therapy in British Columbia is regulated by the College of Massage Therapists of British Columbia (CMTBC). Regulated provinces have, since 2012, established inter-jurisdiction competency standards. Quebec is not provincially regulated. Massage therapists may obtain a certification with one of the various associations operating. There is the Professional Association of Specialized Massage Therapists of Quebec, also named Mon Réseau Plus, which represents 6,300 massage therapists (including ortho therapist, natural therapists, and others), the Quebec Federation of massage therapists (FMQ), and the Association québécoise des thérapeutes naturals; however, none of these are regulated by provincial law.
Canadian educational institutions undergo a formal accreditation process through the Canadian Massage Therapy Council for Accreditation (CMTCA).
=== China ===
Most types of massage, with the exception of some traditional Chinese medicine, are not regulated in China. Although illegal in China, some of the smaller massage parlors are sometimes linked to the sex industry and the government has taken a number of measures in recent times to curb this. In a nationwide crackdown known as the yellow sweep ("Yellow" in Mandarin Chinese refers to sexual activities or pornographic content), limitations on the design and operation of massage parlors have been placed, going so far as requiring identification from customers who visit massage establishments late at night and logging their visits with the local police.
=== France ===
France requires three years of study and two final exams in order to apply for a license.
=== Germany ===
In Germany, massage is regulated by the government on a federal and national level. Only someone who has completed 3,200 hours of training (theoretical and practical) can use the professional title "Masseur und Medizinischer Bademeister" 'Masseur and Medical Spa Therapist'. This person can prolong his training depending on the length of professional experience to a Physiotherapist (1 year to 18 months additional training). The Masseur is trained in Classical Massage, Myofascial Massage, Exercise, and Movement Therapy. During the training, they will study anatomy, physiology, pathology, gynecology, podiatry, psychiatry, psychology, surgery, dermiatry, and orthopedics. They are trained in Electrotherapy and Hydrotherapy. Hydrotherapy includes Kneipp, Wraps, underwater massage, therapeutic washing, Sauna, and Steambath. A small part of their training will include special forms of massage which are decided by the local college, for example, foot reflex zone massage, Thai Massage, etc. Finally, a graduate is allowed to treat patients under the direction of a doctor. Graduates are regulated by the professional body which regulates Physiotherapists. This includes restrictions on advertising and the oath of confidentiality to clients.
=== India ===
In India, massage therapy is licensed by The Department of Ayurveda, Yoga & Naturopathy, Unani, Siddha, and Homoeopathy (AYUSH) under the Ministry of Health and Family Welfare (India) in March 1995. Massage therapy is based on Ayurveda, the ancient medicinal system that evolved around 600 BC. In ayurveda, massage is part of a set of holistic medicinal practices, contrary to the independent massage system popular in some other systems. In Siddha, Tamil traditional medicine from south India, massage is termed as "Thokkanam" and is classified into nine types, each for a specific variety of diseases.
=== Japan ===
In Japan, shiatsu is regulated but oil massage and Thai massage are not. Prostitution in Japan is not heavily policed, and prostitutes posing as massage therapists in "fashion health" shops and "pink salons" are fairly common in the larger cities.
=== Myanmar ===
In Myanmar, massage is unregulated. However, it is necessary to apply for a spa license with the government to operate a massage parlor in major cities such as Yangon. Blind and visually impaired people can become masseurs, but they are not issued licenses. There are a few professional spa training schools in Myanmar but these training centers are not accredited by the government.
=== Mexico ===
In Mexico massage therapists, called sobadores, combine massage using oil or lotion with a form of acupuncture and faith. Sobadores are used to relieve digestive system problems as well as knee and back pain. Many of these therapists work out of the back of a truck, with just a curtain for privacy. By learning additional holistic healer's skills in addition to massage, the practitioner may become a curandero.
In some jurisdictions, prostitution in Mexico is legal, and prostitutes are allowed to sell sexual massages. These businesses are often confined to a specific area of the city, such as the Zona Norte in Tijuana.
=== New Zealand ===
In New Zealand, massage is unregulated. There are two levels of registration with Massage New Zealand, the professional body for massage therapists within New Zealand, although neither of these levels are government recognized. Registration at the certified massage therapist level denotes competency in the practice of relaxation massage. Registration at the remedial massage therapist denotes competency in the practice of remedial or orthopedic massage. Both levels of registration are defined by agreed minimum competencies and minimum hours.
=== South Africa ===
In South Africa, massage is regulated, but enforcement is poor. The minimum legal requirement to be able to practice as a professional massage therapist is a two-year diploma in therapeutic massage and registration with the Allied Health Professions Council of SA (AHPCSA). The qualification includes 240 credits, about 80 case studies, and about 100 hours of community service.
=== South Korea ===
In South Korea, only blind and visually impaired people can become licensed masseurs.
=== Thailand ===
In Thailand, Thai massage is officially listed as one of the branches of traditional Thai medicine, recognized and regulated by the government. It is considered to be a medical discipline in its own right and is used for the treatment of a wide variety of ailments and conditions. Massage schools, centers, therapists, and practitioners are increasingly regulated by the Ministries of Education and Public Health in Thailand.
=== United Kingdom ===
To practice commercial massage or massage therapy in the UK, an ITEC or VTCT certificate must be obtained through training which includes Beauty and Spa Therapy, Hairdressing, Complementary Therapies, Sports & Fitness Training and Customer Service.
Therapists with appropriate paperwork and insurance may join the Complementary and Natural Healthcare Council (CNHC), a voluntary, government regulated, professional register. Its key aim is to protect the public.
In addition, there are many professional bodies that have a required minimum standard of education and hold relevant insurance policies including the Federation of Holistic Therapists (FHT), the Complementary Therapists Association (CThA), and the Complementary Health Professionals (CHP). In contrast to the CNHC these bodies exist to support therapists rather than clients.
=== United States ===
According to research done by the American Massage Therapy Association, as of 2012 in the United States, there are between 280,000 and 320,000 massage therapists and massage school students. As of 2022, there are an estimated 872 state-approved massage training programs operating in the U.S. Most states have licensing requirements that must be met before a practitioner can use the title "massage therapist", and some states and municipalities require a license to practice any form of massage. If a state does not have any massage laws then a practitioner need not apply for a license with the state. Training programs in the US are typically 500 hours to 1000 hours in total training time and can award a certificate, diploma, or degree depending on the particular school. Study will often include anatomy and physiology, kinesiology, massage techniques, first aid and CPR, business, ethical and legal issues, and hands-on practice along with continuing education requirements if regulated. The Commission on Massage Therapy Accreditation (COMTA) is one of the organizations that works with massage schools in the U.S. and there are almost 300 schools that are accredited through this agency.
Forty-seven states, Puerto Rico, and the District of Columbia offer some type of credential to professionals in the massage and bodywork field—usually licensure, certification or registration. Forty-five states require some type of licensing for massage therapists. There are two nationally recognized tests to gain a massage therapy license, as well as state-specific exams. In the US, 38 states accept the National Certification Board for Therapeutic Massage and Bodywork's (NCBTMB) later unavailable certification program as a basis for granting licenses either by rule or statute. The NCBTMB formerly offered the designation Nationally Certified in Therapeutic Massage and Bodywork (NCTMB) but as of 2024 only offers its certificate program, Board Certification in Therapeutic Massage and Bodywork (BCTMB) which does not qualify for licensure. Forty-three states, as well as Puerto Rico and the District of Columbia, accept the Massage & Bodywork Licensing Examination (MBLEx), administered by the Federation of State Massage Therapy Boards (FSMTB). Between 10% and 20% of towns or counties independently regulate the profession. These local regulations can range from prohibition on opposite sex massage, fingerprinting and venereal checks from a doctor, to prohibition on house calls because of concern regarding sale of sexual services.
In the US, licensure is the highest level of regulation and this restricts anyone without a license from practicing massage therapy or calling themselves by that protected title. Certification allows only those who meet certain educational criteria to use the protected title and registration only requires a listing of therapists who apply and meet an educational requirement. In the US, most certifications are locally based. A massage therapist may be certified, but not licensed. Licensing requirements vary per state, and often require additional criteria be met in addition to attending an accredited massage therapy school and passing a required state-specified exam. Only Kansas, Minnesota, and Wyoming, California and Vermont do not require a license or a certification at the state level. Some states allow license reciprocity, where licensed massage therapists who relocate can relatively easily obtain a license in their new state.
In New York State in 2024, a man was arrested and charged with three counts of third-degree Sexual Abuse and three counts of Forcible Touching, as well as New York State Education Department Law violations, for providing massage therapy services without a New York State license to do so.
In 1997 there were an estimated 114 million visits to massage therapists in the US. Massage therapy is the most used type of alternative medicine in hospitals in the United States. Between July 2010 and July 2011 roughly 38 million adult Americans (18 percent) had a massage at least once. People state that they use massage because they believe that it relieves pain from musculoskeletal injuries and other causes of pain, reduces stress and enhances relaxation, rehabilitates sports injuries, decreases feelings of anxiety and depression, and increases general well-being.
In a poll of 25–35-year-olds, 79% said they would like their health insurance plan to cover massage. In 2006 Duke University Health System opened up a center to integrate medical disciplines with CAM disciplines such as massage therapy and acupuncture. There were 15,500 spas in the United States in 2007, with about two-thirds of the visitors being women.
The number of visits rose from 91 million in 1999 to 136 million in 2003, generating a revenue that equals $11 billion. Job outlook for massage therapists was also projected to grow at 20% between 2010 and 2020 by the Bureau of Labor Statistics, faster than the average.
== See also ==
Manual therapy
Massage chair
Spa
== References ==
== External links ==
Shadwell, Arthur (1911). "Massage" . Encyclopædia Britannica (11th ed.). | Wikipedia/Massotherapy |
Sonodynamic therapy (SDT) is a noninvasive treatment, often used for tumor irradiation, that utilizes a sonosensitizer and the deep penetration of ultrasound to treat lesions of varying depths by reducing target cell number and preventing future tumor growth. Many existing cancer treatment strategies cause systemic toxicity or cannot penetrate tissue deep enough to reach the entire tumor; however, emerging ultrasound stimulated therapies could offer an alternative to these treatments with their increased efficiency, greater penetration depth, and reduced side effects. Sonodynamic therapy could be used to treat cancers and other diseases, such as atherosclerosis, and diminish the risk associated with other treatment strategies since it induces cytotoxic effects only when externally stimulated by ultrasound and only at the cancerous region, as opposed to the systemic administration of chemotherapy drugs.
Reactive oxygen species (ROS) are an essential component of SDT as they provide the cytotoxicity of sonodynamic therapy; they are produced when ultrasound is coupled with a sensitizing drug and molecular oxygen. Without ultrasound, the drug is not toxic. However, once the drug is exposed to ultrasound and molecular oxygen, it becomes toxic. Photodynamic therapy, from which sonodynamic therapy was derived, uses a similar mechanism. Instead of ultrasound, light is used to activate the drug. SDT allows the ultrasound to reach deeper into the tissue (to about 30 centimeters) compared to photodynamic therapy (PDT) since it can be highly focused. This increased penetration depth ultimately means that SDT can be utilized to treat deeper, less accessible tumors and is more cost-effective than PDT. Photodynamic therapy can be used in combination with sonodynamic therapy and is expanded upon in the Applications section of this article. Sonodynamic therapy can be used synergistically with other therapeutic methods such as drug-loaded microbubbles, nanoparticles, exosomes, liposomes, and genes for improved efficacy. Currently, SDT does not have any clinical products and acts as an adjuvant for the aforementioned therapeutic methods, but it has been explored for use in atherosclerosis and cancer treatment to reduce tumor size in breast, pancreas, liver, and spinal sarcomas.
== Mechanism of Action ==
The mechanism of action for sonodynamic therapy is the use of low-intensity ultrasound through the use of focused mechanical waves to create a cytotoxic effect. However, SDT itself is non-thermal, non-toxic, and is able to non-invasively penetrate deep into tissue compared to other delivery methods such as photodynamic therapy. SDT is often performed alongside the use of a sonosensitizer such as
porphyrin, phthalocyanines, xanthenes, and antitumor drugs. Ultrasound waves are also classified as acoustic waves, and the effect they have on the tissue of application can be described by a process called cavitation. Cavitation occurs as a specific interaction between ultrasound and aqueous surroundings and causes gas bubbles to break upon exposure to particular ultrasonic parameters, thus promoting penetration of the therapeutic into the biological tissues by generating cavities near the edge of the membrane.
Cavitation can be broken down into stable and inertial cavitation. In stable cavitation, the oscillation of gas bubbles causes the environmental media to intermix. In inertial cavitation, gas bubbles increase in volume and almost reach their resonance volume, swelling before aggressively collapsing. The implosion of vesicles results in a drastic temperature and pressure change, thereby increasing the cell membrane's permeability to various drugs. Microbubbles are created by the acoustic waves from the ultrasound that expand and collapse, releasing energy, bringing the sonosensitizer into an excited state, and generating a ROS. The cavitation of this gas bubble can form the ROS with different methodologies such as sonoluminescence and pyrolysis. Apoptosis results from the formation of ROS and mechanical forces of SDT through membrane disruption in a process called lipid peroxidation. Necrosis is also a potential result of SDT.
The influence of sonoluminescence on SDT and ROS has not been fully elaborated within literature. Currently, it is understood that sonoluminescence allows the emission of light upon bubble collapse which can activate sensitizers. A study by Hachimine et al. highlights the use of SDT as a method to activate a low photosensitive sonosensitizer, DCPH-P-Na(I), for cancer that is too deep within the tissue to combat utilizing PDT without skin irritation. Pyrolysis raises the surrounding temperature, enhances the cavitation process, breaks down the sensitizer, generating free radicals, and the free radicals interact within their environment to generate ROS. For both methods, the importance of the singlet oxygen compared to the hydroxyl radical to induce cytotoxicity has been highlighted. While other studies have found the singlet oxygen to not have a substantial effect. Overall, both of these methodologies lack significant breadth in literature to fully explain their role in ROS formation. However, literature has shown success in their analysis and application.
=== Sonoluminescence ===
Two primary mechanisms of ROS generation exist in sonodynamic therapy: sonoluminescence and pyrolysis. Sonoluminescence occurs when ultrasound produces light after irradiating an aqueous solution The exact mechanism with which light is produced remains unclear. However, it is suggested that inertial cavitation is a key element for this process. Other studies also indicate the potential role of stable cavitation
=== Pyrolysis ===
Pyrolysis is believed to occur when inertial cavitation induces an extreme temperature increase, degrades the sonosensitizers, thus producing free radicals that can react and ultimately produce ROS necessary for SDT. The localized temperature increase assists in the inertial cavitation and breakdown of the sonosensitizer in order to create ROS. The pyrolysis within the cavitation bubbles will produce H+ and OH- via weak bonding within the solute molecule.
=== Lipid Peroxidation ===
In addition to chemical methods, mechanical properties of the acoustic wave generated from the ultrasound can assist in initiating cytotoxic effects. This occurs through disruption of the membrane with a hydrophobic sonosensitizer. The mechanical disruption of the membrane causes a process called lipid peroxidation and adjustments to the cell membrane can change cell drug permeability. Both sonochemical and sonomechanical methodologies are used to generate ROS and release cargo from vesicles for applications such as tumor targeting.
=== Apoptosis ===
Low intensity ultrasound has been shown within past literature to induce apoptotic effects within surrounding cells. It has been found that it is not the initial ROS that causes apoptosis within the cells, but the free radicals within the mitochondria. In a study by Honda et al., it was determined that the mitochondria-caspase pathway is responsible for apoptosis through the increase of intracellular calcium. Outside of ROS induced apoptosis, cavitation is another factor involved within apoptosis of surrounding cells. Both cavitation types are able to induce apoptosis through damage to the membrane. Conditions such as frequency, duty cycle, pulse, and intensity can be manipulated to optimize cell death conditions such as necrosis, lysis, or apoptosis.
=== Autophagy ===
This method of cell death can occur by cell organelles becoming entrapped into autophagosomes that combine with lysosomes. Continuation of this process will lead to cell death and autophagy inhibitors or promoters can be controlled to encourage or discourage cell death and uptake of chemotherapeutics.
== Sonosensitizers ==
Sonosensitizers, or sonosensitizing therapeutics, are the primary element of SDT and can be tailored to treat various cancers and generate different effects. These therapeutics, often involving the use of porphyrin or xanthene, will initiate a toxic effect via the ROS upon exposure to ultrasound.
=== Porphyrin-based sensitizers ===
Porphyrin-based sensitizers, initially used as a photosensitizer in PDT, are fairly hydrophobic molecules derived from hematoporphyrin. Single oxygen atoms or hydroxyl radicals are produced by porphyrin-based sensitizers upon exposure to ultrasound or light, providing the cytotoxic effects desired with sonodynamic and photodynamic therapies. However, the result of porphyrin-based sensitizers is not as local as desired for sonodynamic therapy since they are also located in non-targeted tissue between the tumor and the ultrasound emitter.
=== Xanthene-based sensitizers ===
Xanthene-based sensitizers, on the other hand, have shown successful cytotoxicity in vitro by producing reactive oxygen species after being triggered by ultrasound. More research is necessary to improve its potential in vivo performance since it is quickly processed by the liver and cleared from the body. Rose Bengal is a commonly used xanthene-based sonosensitizer.
=== Additional sensitizers ===
Other sensitizers that have been investigated for their potential in sonodynamic therapy (and have also been used previously in PDT) include acridine orange, methylene blue, curcumin, and indocyanine green. A study by Suzuki et al. used acridine orange, a fluorescent cationic dye that can insert itself into nucleic acids, for treating sarcoma 180 cells with ultrasound and demonstrated that reactive oxygen species are a critical element of SDT considering that their absence decreased the efficacy of SDT. Similar to the previous study, a recent study by Komori et al. utilized ultrasound coupled with methylene blue (a phenothiazine dye commonly used in PDT that exhibits low toxicity) to irradiate sarcoma 180 cells and found that methylene blue was an effective sonosensitizer in decreasing cell viability. Interestingly, curcumin is a spice that also can act as a sensitizer for PDT and SDT. In a study by Waksman et al., curcumin was able to impact macrophages, which are important for development of plaques found in atherosclerosis patients, thus reducing the amount of plaque in an animal model. These findings along with other research indicate that curcumin sensitizers could be used in SDT cancer treatments. Indocyanine green is a dye that absorbs near infrared wavelengths and is another sensitizer that has been shown to reduce cell viability when coupled with ultrasound and/or light. An in vivo study demonstrated that treating a mouse tumor model with indocyanine green coupled with ultrasound and light resulted in a 98% reduction in tumor volume by 27 days after treatment.
== Carriers ==
As aforementioned, sonosensitizers are often used in conjunction with different drug carriers such as microbubbles, nanobubbles, liposomes, and exosomes to improve therapeutic agent concentration and penetration.
=== Liposomes ===
Liposomes are a common vehicle in drug delivery and specifically for the treatment of cancer. Liposomes contain a phospholipid bilayer. It is prevalent due to its ability to penetrate leaky vasculature and poor lymphatic drainage within tumors for enhanced permeability retention. These drug carriers can encapsulate hydrophobic and lipophilic molecules within their lipid bilayer and can be made naturally or synthetically. In addition, liposomes can entrap hydrophilic molecules in their hydrophilic core. Compared to the common cancer treatment chemotherapy, drugs loaded into liposomes allow for decreased systemic toxicity and a potential increase in the efficacy of targeted delivery. Success with liposomes as drug delivery systems has been shown both in vivo and in vitro. A study by Liu et al. showed that liposomes can be used alongside SDT to trigger the release of drugs via oxidation of the lipid components. Another study by Ninomiya et al. utilized nanoemulsion droplets exposed to ultrasonic waves for the formation of larger gas bubbles to disrupt the liposome membrane for drug release. Many properties and elements of liposomes can be altered for their specific purpose and to increase effectiveness, particularly their ability to travel in the blood and interact with cells and tissues in the body. These elements include their diameter, charge, arrangement, as well as the makeup of their membranes.
Dai et al. proposed the incorporation of sonosensitizers with liposomes to enhance target specificity. Since SDT stimulates cancerous tissues to absorb and retain sonosentizers followed by activation with extracorporeal ultrasound, Dai et al. investigated the effect of liposome-encapsulated drugs on the efficacy of targeted delivery in SDT. They found that, in addition to its convenience and practicality, SDT is a safe and effective option for treating cancer.
=== Exosomes ===
Exosomes are nanocarriers that can provide targeted drug delivery of therapeutics to enhance local cytotoxic effects while minimizing any systemic impact. They are acquired from cells and are used for transportation purposes within the cell as membrane-bound vesicles. Advantages of exosomes for drug delivery purposes include their ability to be manipulated and engineered, in addition to their low toxicity and immunogenicity. They have also inspired research into non-cell-based treatment methods for various cancers and diseases. Other desirable aspects of exosomes include their overall biocompatibility and stability.
A study by Nguyen Cao et al. investigated the use of exosomes for the delivery of indocyanine green (ICG), a sonosensitizer for breast cancer treatment. Significantly increased reactive oxygen species generation was observed in breast cancer cells treated with folic acid-conjugated exosomes. This is one example of a sonosensitizer used to treat a specific cancer using sonodynamic therapy. Another example of exosome-based sonodynamic therapy was illustrated by Liu et al. In this study, exosomes were decorated with porphyrin sensitizers and this system was used with an external ultrasound device to control and target drug delivery through SDT. Liu et al. provided a non-invasive method for treating cancer through extracorporeal activation of exosomes through ultrasound.
=== Microbubbles ===
Due to their ability to oscillate with exposure to low-frequency ultrasound, microbubbles have been used as contrast agents in order to visualize tissues in which the microbubbles have permeated. However, when these microspheres are exposed to higher pressure ultrasound, they can rupture, which could be beneficial for drug delivery purposes. Through SDT, these microbubbles could be selectively bursted at the tumor microenvironment in order to decrease systemic levels of the encapsulated drug and increase therapeutic efficacy. When applying SDT, the increase in acoustic pressure leads to the inertial cavitation, or collapse of the microbubble and local release of the cargo within. The inertial cavitation of the microbubbles when exposed to SDT is also referred to as ultrasound mediated microbubble destruction (UMMD). The shell of microbubbles can be decorated with different components, including polymers, lipids, or proteins depending on their intended purpose. Microbubbles have also been used for the localized release of attached cargo. This cargo is typically chemotherapeutics, antibiotics, or genes. Different drugs can be directly loaded into the microbubble with methods such as conjugation and nanoparticle, liposome loading, and genes. The combination of genes and SDT is referred to as sonotransfection. Examples of outer shell modifications can be seen in a study by McEwan et al. which found that lipid microbubbles showed reduced stability when sonosensitizers were added to their shells. However, attaching the polymer poly lactic-co-glycolic acid (PLGA) to the shell resulted in increased stability compared to the lipid microbubbles without losing other desirable properties such as targeted delivery and selective cytotoxicity. In another study, McEwan et al. investigated the ability of microbubbles carrying oxygen to increase production of reactive oxygen species, which are a necessary component of SDT, in the hypoxic environment of many solid tumors. These microbubbles were stabilized with lipids and a Rose Bengal sonosensitizer was attached to the surface to treat pancreatic cancer. Their work showed that coupling oxygen-loaded microbubbles that are sensitive to ultrasound with sonosensitizing drugs could allow for increased drug activation at the desired target even if hypoxia is present. Examples of therapeutics that have been loaded into microbubbles are gemcitabine, paclitaxel nanoparticles, plasmid DNA and 2,2′-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride loaded liposomes. Due to the targeting nature of the ligands connected to the microbubble, it allows for the controlled and specific targeting of the desired tissue for treatment. Another study performed by Nesbitt et al. has shown improved tumor reduction when gemcitabine was loaded into the microbubble and applied to a human pancreatic cancer xenograft model with SDT.
=== Nanobubbles ===
Similar to microbubbles, nanobubbles have shown efficacy in SDT. However, due to their smaller size, nanobubbles are able to reach targets that microbubbles cannot. Nanobubbles can reach deeper tissue and travel past the vasculature. Previous research has demonstrated that nanobubbles are more capable of reaching the tumor since they can permeate endothelial cells and migrate away from the vasculature.
One study by Nittayacharn et al. developed doxorubicin-loaded nanobubbles and paired them with porphyrin sensitizers to be used in SDT for treatment of breast and ovarian cancer cells in vitro. They found an almost 70% increase in cytotoxicity when using SDT compared to only perfluoropropane nanobubbles filled with iridium(III). Additionally, compared to empty nanobubbles and/or free iridium(III), they observed greatest reactive oxygen species generation in the iridium(III)-nanobubbles exposed to ultrasound. These results demonstrate that nanobubbles loaded with a sonosensitizer and exposed to ultrasound could be a potential effective treatment for cancer using SDT. As with microbubbles, nanobubbles have also shown promise as oxygen-delivering vesicles to enhance the effectiveness of SDT. In order to mitigate hypoxia of target tissue, Owen et al. used a pancreatic cancer rodent model to deliver phospholipid stabilized nanobubbles filled with oxygen. The mice were divided into groups, one that received oxygen-filled nanobubbles prior to injection of a sonosensitizer and one that didn't. A statistically significant difference between the levels of oxygen in the tumors of the two groups was observed, indicating that nanobubbles could be an effective addition to SDT to treat cancers in a hypoxic environment.
== Applications ==
=== Combination with other therapies ===
Sonodynamic therapy can be combined with other therapeutic techniques to enhance treatment efficacy for various types of cancers and diseases. SDT can be combined with photodynamic therapy, chemotherapy, radiation, MRI, and immunotherapy. PDT has often been used in combination with SDT as sonosensitizers are also photosensitive. During initial development of SDT, Umemura et al., have determined that hematoporphyrins were able to initiate cell death similarly to PDT. This is due to SDT being able to initiate sonoluminescence. However, the advantage of SDT over PDT is that it can penetrate deep and precisely into the targeted tissue. In a study by Lui et al., it was shown that using a combination of these two delivery methods results in increased cytotoxicity with sino porphyrin in a metastatic xenograft model. In another example of combining SDT with PDT, Borah et al. investigated the advantage of 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HHPH), a photodynamic therapy drug, as a sonosensitizer and a photosensitizer for treating glioblastoma. Combining these therapies showed increased cell kill/tumor response, possibly caused by synergistic effects.
The goal of a study by Browning et al. was to investigate the potential enhancement of chemoradiation efficacy through combining it with sonodynamic therapy in pancreatic cancer patients. In one model, survival increased with the combination compared to chemoradiation alone. Differences in the results for the two different models could be attributed to variations in tumor organization. The tumors that showed the greatest reduction in size were less vascularized, perhaps making them more vulnerable to SDT. Another study, by Huang et al. used elements of mesoporous organosilica-based nanosystems to fabricate a sonosensitizer to be used with MRI-guided SDT. Increased cell death and inhibiting tumor growth was induced by the sonosensitizers, indicating high SDT efficiency. This shows how SDT can assist with both removal and inhibition of tumor growth.
SDT has also been combined with immunotherapy. A study by Lin et al. aimed to use cascade immuno-sonodynamic therapy to enhance tumor treatment using antibodies. The nanosonosensitizers resulted in high drug loading efficiency and a tumor-specific adaptive immune response. This serves as an example as to how SDT can be coupled with checkpoint blockade immunotherapy to enhance efficiency in cancer treatments. Another study by Yue et al. strived to combine checkpoint-blockade immunotherapy with nanosonosensitizers-augmented noninvasive sonodynamic therapy. Along with inhibiting lung metastasis, this combination promoted an anti-tumor response that prohibited tumor growth. This provides a proof-of-concept for combining SDT with another therapy to enhance treatment effects for the short and long term.
=== Types of cancers SDT has been shown to treat ===
==== Cancer Treatment ====
The treatment of many different types of cancers has been investigated using sonodynamic therapy both in vitro and/or in vivo including, glioblastoma, pancreatic, breast, ovarian, lung, prostate, liver, stomach, and colon cancers. A study by Gao et al. showed that SDT is capable of inhibiting angiogenesis through the production of ROS. This hindered the proliferation, migration, and invasion of endothelial cells, tumor growth, intratumoral vascularity, and vascular endothelial growth factor expression within the tumor cell in xenograft rat models. Hachimine et al. performed a large in vitro study testing SDT on seventeen different cancer cell lines. The types of cancers included were pancreatic, breast, lung, prostate, liver, stomach, and colon cancers. The most successful treatment was that of lung cancer with 23.4% cell viability post-therapy. Qu et al. aimed to develop an "all-in-one" nanosensitizer platform triggered by SDT that combines various diagnostic and therapeutic effects to treat glioblastoma. Apoptosis was successfully induced and mitophagy was inhibited in glioma cells. This is an example of how SDT can be used with a different platform to treat glioblastoma. Borah et al., as mentioned above, also investigated the ability of SDT (and PDT) to treat glioblastoma and found that SDT (combined with PDT) was able to increase the number of tumor cells killed. McEwan et al. and Owen et al. both demonstrated the use of micro/nanobubbles to enhance the oxygen concentration near hypoxic pancreatic tumors, thereby increasing the efficacy of SDT.
==== Breast Cancer ====
12% of women in the US will be diagnosed with breast cancer. Metastasis and recurrence is a large challenge for deep-seated solid state tumors. SDT is currently being explored as a treatment method for breast cancer, while avoiding the side effects associated with current therapeutic methods. There has been shown success in utilizing SDT in animal and human clinical trials in reduction of tumor size through mitochondrial targeting to initiate apoptosis of tumor cells and autophagy and immune response regulation. However, there are still complications with proper therapeutic efficacy when used alone.
==== Glioma ====
Malignant glioma is an extremely difficult to treat brain tumor that is a leading cause of death worldwide and half of cancer-related deaths. Complications associated with treating glioma include the blood brain barrier (BBB). This protective mechanism for the brain also raises challenges for drug delivery through the tight junctions between endothelial cells, only allowing small lipid-soluble drugs (<400 Da) to permeate. Current delivery methods are surgery and chemotherapy. SDT has been implemented as a method to open the BBB and has shown success in opening tight junctions for delivery. Examples of sonosensitizers that have shown success in glioma treatment are hematopor-phyrin monomethyl ether (HMME), porfimer sodium (Photofrin), di-sulfo-di-phthalimidomethyl phthalolcyaninezinc (ZnPcS2P2), Photolon, 5-aminolevulinic acid (5-ALA), and rose bengal (RB). These have shown to induce effects such as opening of the BBB, improved vascular permeability, and apoptosis of glioma cells.
==== Prostate Cancer ====
Prostate cancer is the second cause of cancer and the most common malignancy associated with deaths in men worldwide. Current methods of treatments are invasive resection therapy, radiation therapy, and prostatectomy that can cause complications such as incontinence, impotence, and damage to surrounding organs and tissues. Current studies have shown success in using SDT as a stand-alone treatment. SDT uses mitochondria related apoptosis for the reduction of cell viability. SDT for prostate cancer treatment has also been used alongside chemotherapeutics such as docetaxel microbubbles. This has shown to enhance the effects of docetaxel through a reduction in tumor perfusion and enhanced necrosis and apoptosis. The SDT and docetaxel group showed reduction in tumor growth. Overall, the use of SDT has shown promising results in prostate cancer treatment.
==== Arterial Diseases ====
Sonodynamic therapy could be used to treat more than just cancers. Atherosclerosis, which is a chronic arterial disease, is another target that has been observed in the literature. This disease occurs when fatty plaques aggregate on the inner surface of the artery and could be caused by malfunctions in lipid metabolism. More specifically, atherosclerosis is caused by an increase in endothelial permeability causing low-density lipoprotein particles to become oxidized and undergo sedimentation. These lipoproteins cause an increase in macrophages and lead to intensified plaque build up. As a result, the high influx of macrophages is the target for AS treatment in order to slow plaque build-up. Alongside the relationship between plaque build-up and macrophages, monocyte's differentiation into macrophages exacerbates the aforementioned process in addition to causing inflammation.
A study by Wang et al. aimed to understand the underlying mechanisms regarding the potential effect of non-lethal SDT on atheroscleroic plaques. It was determined that non-lethal SDT prevents plaque development. A study performed by Jiang et al., showed success in SDT through the reduction of macrophage inflammatory factors such as TNF-alpha, IL-12, and IL-1B. They also showed that SDT could inhibit plaque inflammation in patients with peripheral artery disease and continue to promote positive results for longer than six months. Popular sonosensitizers for AS treatment are protoporphyrin IX (PpIX) and 5-aminolevulinic acid (5-ALA). PpIX is often used in PDT and is generated through 5-ALA, a non ultrasound-activated component, through increasing PpIX concentration within a cell. A study by Cheng et al. determined that THP-1 macrophage apoptosis is induced by an increase in PpiX concentration, leading to the production of large amounts of ROS. The use of SDT for AS treatment has also shown success in promoting the repopulation of vascular smooth muscle cells (VMSCs) through inducing further expression and autophagy to prevent VMSC evolution into plaque-holding macrophages. A study performed by Dan et al. showed the increase in smooth muscle a-actin, smooth muscle 22a, p38 mitogen-activated protein kinase phosphorylation. While a study by Geng et al. showed improved VMSC autophagy. Each of these factors contributed to the improved differentiation and development of VMSCs.
=== In Vitro and In Vivo Work ===
==== In vitro ====
In vitro experimentation provides great insight and knowledge to characterize the potential of sonosensitizer behavior in vivo. In addition, SDT has shown success through its low intensity allowing increased plasma membrane permeability without cell death. Sonosensitizers have also been used in vitro in applications with different cell lines and to further understand the mechanism of action for cell death. It is currently understood that PDT and SDT have similar mechanisms for free radical generation for inducing apoptosis and necrosis. However, each cell line is unique and can cause cell death with different efficacy. Some examples of in vitro work include initial studies that were performed by Yumita et al., 1989 who used haematoprophyrin and SDT for mouse sarcoma 180 and rat ascites hepatoma (AH) that showed a relationship between dosage and ultrasound, and microbubbles causing cavitation leading to cell damage without the use of drugs. This study also emphasized the difference in efficacy between cell lines through SDT 180 having less lysis compared to AH-130 cells. Another study by Hachimine et al. emphasized efficacy between cell lines by examining seven different cancers with 17 cell lines total under the use of DCPH-P-NA(I). This study revealed that the stomach and lung cancer lines of MKN-28 and LU65A respectively had the highest survival rate, but the stomach and lung cancer lines of RERFLC-KJ and MKN-45 respectively had the lowest survival rates. Another study by Honda et al., with U937 and K562 showed that sonication increases the intracellular calcium ion levels and decreases GSH concentration respectively. This increased concentration of calcium plays a significant role in cell death through DNA fragmentation and mitochondrial membrane disruption. While a decreased concentration of GSH plays a significant role in allowing the formation of more free radicals. A study by Umemura et al., found that ATX-70 versus hematoporphyrin has increased cytotoxic activity. Current research typically focuses on using tumor xenograft models to determine the effect of SDT on target cells and delivery efficacy.
==== In vivo ====
Building upon the study by Umemura et al. and ATX-70, it was found that 24h after administration of the sonosensitizer had improved efficacy when ultrasound was applied compared to immediate administration. It was also determined that most ultrasound frequencies range between 1-3 MHz and 0.5-4W/cm^2. Higher frequencies at values such as 20W/cm^2 and 25W/cm^2 resulted in large necrotic lesions. This established a relationship between sonosensitizer formulation and ultrasound intensity to necrosis. Other studies have continued to innovate upon this by controlling drug ultrasound interval (DUI) for different sonosensitizers in order to determine the optimal time period to apply the ultrasound for improved efficacy. In addition, it has been shown that SDT can disturb surrounding vasculature in tumors. This has been shown in studies by Gao et al. with 5-ALA in mice and human umbilical vein endothelial cell lines through inhibition of microvessel density and cell proliferation, migration, and invasion.
== Challenges and development ==
One of the many advantages of SDT compared to PDT is the ability of SDT to penetrate deeply placed solid tumors allowing a wider treatment range. Despite this fact, there are limitations to SDT that must be overcome or have optimized components in order to expand the effect and application of SDT. SDT does allow for precise activation of the therapeutic, but is limited in the delivery and accumulation of the delivery modality to penetrate deeply into the desired tumor site. This is often accommodated for through delivery vessels such as nanoparticles or liposomes. However, nanomedicine is limited by the enhanced permeability and retention effect and struggles to deliver in targeted abundance depending on the delivery vesicle. This can be seen in nanoparticles struggling with non-specific delivery. Future research has been focused on developing high targeting and penetrating nanoparticles for improved delivery and pharmacokinetics. Due to the complex nature of tumors and their microenvironments, they are difficult to treat with only one therapy. In order to enhance the oftentimes low production of reactive oxygen species to address the hypoxic tumor environment, SDT can be combined with other therapies, such as PDT, chemotherapy, and immunotherapy to improve patient outcomes. SDT alone does not respond well in hypoxic environments. However, bioreductive therapy could be used to reduce the impact of SDT's limitations regarding hypoxia in the tumor while leaving healthy/normal tissue alone. Sonosensitizers also require continuous high levels of oxygen to create ROS, which is not readily available within a hypoxic tumor microenvironment. However, strategies such as oxygen supplementation and production to supply the required oxygen and enhance cavitation, and glutathione depletion to avoid the reduction of the free radicals produced have been implemented alongside sonosensitizers to supply the required oxygen or reduce the combative function. In addition to its relatively low generation of reactive oxygen species, SDT also can cause permanent destruction of normal tissues. This lack of selectivity is caused by ultrasound divergence, resulting in heat and shear that impacts off-target tissues. Although advantages of organic sonosensitizers exist, such as high reproducibility, biocompatibility, production of reactive oxygen species, they also have limitations. Factors that limit the translation of organic sensitizers to clinical applications include low water solubility, sonotoxicity, and targetability as well as high phototoxiticty. Other properties could promote rapid clearance of the drug, which is why various nano and microparticles are used to transport the drug to the desired location. In addition, sonosensitizers in SDT often require increased dosage, and the relationship between therapeutic dosage and toxicity of sonosensitizers has not been properly characterized alongside other variables such as tissue type and acoustic pressure. Inorganic sensitizers produce reactive oxygen species, but in lower concentrations than desirable for SDT, limiting their ability to be used in a clinical setting. Another challenge is reflected in vitro and in vivo work. An example of this can be seen in a study using rose bengal, a xanthene dye. It was found to be successful in vitro, but in vivo showed significantly less efficacy due to liver squestation and clearance. Lastly, there are no current standardized computer simulations to predict the characteristics of different sonosenistizers within tissue, which would provide further insight into how sonosensitizers may behave.
== Current clinical use ==
SDT has been researched most commonly to combat cancers and atherosclerosis such as breast cancer, pancreatic cancer, liver, and spinal sarcomas. Currently, there are no FDA approved clinical applications of SDT. However, for PDT, Photofrin is an FDA approved hematoporphyrin (PHOTOFRIN®). However, SDT has been used in a clinical trial in combination with PDT to assess for reduction in tumor size in patients with breast cancer. However, it was difficult to determine if SDT PDT or the drug dosage was the primary mechanism of treatment. Another case study expanded on this by using SDT as a standalone treatment with a Gc protein hormone therapy with the use of 5-ALA or chlorin e6 as a sonosensitizer. It was shown that tumor markers significantly decreased during treatment.
== Future directions ==
The effectiveness of sonodynamic therapy as a cancer treatment is supported by many in vitro and in vivo studies. However, large-scale clinical trials are necessary for translation into the clinical setting. In order to mitigate the limitations aforementioned, new sonosensitizers are being developed and SDT is being combined with other therapies in novel ways. Particularly, organic sonosensitizers with high solubility in water, high sonotoxocity, increased ability to target tumors, and low phototoxicity need to be developed in order to improve the therapeutic efficacy of SDT and allow it to be used for treating cancers. In addition, the mechanisms by which ROS are produced by sonosensitizers upon exposure to ultrasound is yet to be determined, reducing the ability to control its function and outcomes. Ultimately, the synergistic effects of combining SDT with other therapies would allow each to compensate for the limitations of the other, improving their therapeutic efficacy and increasing their ability to destroy tumors.
== References == | Wikipedia/Sonodynamic_therapy |
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/Hippotherapy |
Negative air ionization therapy (NAIs) uses air ionisers as a non-pharmaceutical treatment for respiratory disease, allergy, or stress-related health conditions. The mainstream scientific community considers many applications of NAIs to be pseudoscience. Many negative ion products release ozone, a chemical known to cause lung damage.
== Research ==
For seasonal affective disorder (SAD), a randomized controlled trial (RCT) comparing high (4.5x1014 ions/second) and low (1.7x1011 ions/second) flow rate negative air ionization with bright light therapy found that the post-treatment improvement percentage was 57.1% for bright light, 47.9% for high-density ions and 22.7% for low-density ions. An older RCT conducted by the same authors also found air ionization effective for SAD. A 2007 review considers this therapy "under investigation" and suggests that it may be a helpful treatment for SAD.
An RCT comparing the short-term effects of bright light, an auditory stimulus, and high and low-density negative ions on mood and alertness in mildly depressed and non-depressed adults found that the three first (active) stimuli, but not the low-density placebo, reduced depression on the Beck Depression Inventory scale. The auditory stimulus, bright light, and high-density ions all produced rapid mood changes - with small to medium effect sizes - in depressed and non-depressed subjects.
Researchers have continued to cite a dearth of evidence about the effects of negative air ionization. "The presence of NAIs is credited for increasing psychological health, productivity, and overall well-being but without consistent or reliable evidence in therapeutic effects and with controversy in anti-microorganisms," researchers wrote in a 2018 article published in the International Journal of Molecular Sciences.
== See also ==
Topics characterized as pseudoscience
Ionized bracelet
Earthing therapy
Water ionizer
== References == | Wikipedia/Negative_air_ionization_therapy |
Hydrotherapy, formerly called hydropathy and also called water cure, is a branch of alternative medicine (particularly naturopathy), occupational therapy, and physiotherapy, that involves the use of water for pain relief and treatment. The term encompasses a broad range of approaches and therapeutic methods that take advantage of the physical properties of water, such as temperature and pressure, to stimulate blood circulation and treat the symptoms of certain diseases.
Various therapies used in the present-day hydrotherapy employ water jets, underwater massage and mineral baths (e.g. balneotherapy, Iodine-Grine therapy, Kneipp treatments, Scotch hose, Swiss shower, thalassotherapy) or whirlpool bath, hot Roman bath, hot tub, Jacuzzi, and cold plunge.
Hydrotherapy lacks robust evidence supporting its efficacy beyond placebo effects. Systematic reviews of randomized controlled trials have constitently found no clear evidence of curative effects, citing methodological flaws and insufficient data. Overall, the scientific consensus indicates that hydrotherapy's benefits are not conclusively greater than those of placebo treatments.
== Uses ==
Water therapy may be restricted to use as aquatic therapy, a form of physical therapy, and a cleansing agent. However, it is also used as a medium for delivering heat and cold to the body, which has long been the basis for its application. Hydrotherapy involves a range of methods and techniques, many of which use water as a medium to facilitate thermoregulatory reactions for therapeutic benefit.
Shower-based hydrotherapy techniques have been increasingly used in preference to full-immersion methods, partly for the ease of cleaning the equipment and reducing infections due to contamination. When removal of tissue is necessary for the treatment of wounds, hydrotherapy, which performs selective mechanical debridement can be used. Examples of this include directed wound irrigation and therapeutic irrigation with suction.
== Technique ==
The following methods are used for their hydrotherapeutic effects:
Packings, general and local;
Hot air and steam baths;
General baths;
Treadmills
Sitz (sitting), spinal, head, and foot baths;
Bandages or compresses, wet and dry; also;
Fomentations and poultices, sinapisms, stupes, rubbings, and water potations.
Hydrotherapy, which involves submerging all or part of the body in water, can involve several types of equipment:
Full body immersion tanks (a "Hubbard tank" is a large size)
Arm, hip, and leg whirlpool
Whirling water movement, provided by mechanical pumps, has been used in water tanks since at least the 1940s. Similar technologies have been marketed for recreational use under the terms "hot tub" or "spa".
In some cases, baths with whirlpool water flow are not used to manage wounds, as a whirlpool will not selectively target the tissue to be removed, and can damage all tissue. Whirlpools also create an unwanted risk of bacterial infection, can damage fragile body tissue, and in the case of treating arms and legs, bring risk of complications from edema.
== History ==
The therapeutic use of water has been recorded in ancient Egyptian, Greek and Roman civilizations. Egyptian royalty bathed with essential oils and flowers. Romans had communal public baths for their citizens. Hippocrates prescribed bathing in spring water for sickness. Other cultures noted for a long history of hydrotherapy include China and Japan, the latter being centred primarily around Japanese hot springs. Many such histories predate the Roman thermae.
=== Modern revival ===
Hydrotherapy became more prominent following the growth and development of modern medical practices in the 18th and 19th centuries. As traditional medical practice became increasingly professional, it was felt that medical treatment became increasingly less personalized. The development of hydrotherapy was believed to be a more personal form of medical treatment that did not necessarily present to patients the alienating scientific language that modern developments of medical treatment entailed.
==== 1700–1810 ====
Two English works on the medical uses of water were published in the 18th century that inaugurated the new fashion for hydrotherapy. One of these was by Sir John Floyer, a physician of Lichfield, who, struck by the remedial use of certain springs by the neighbouring peasantry, investigated the history of cold bathing and published a book on the subject in 1702. The book ran through six editions within a few years, and the translation of this book into German was largely drawn upon by J. S. Hahn of Silesia as the basis for his book called On the Healing Virtues of Cold Water, Inwardly and Outwardly Applied, as Proved by Experience, published in 1738.
The other work was a 1797 publication by James Currie of Liverpool on the use of hot and cold water in the treatment of fever and other illnesses, with a fourth edition published in 1805, not long before his death. It was also translated into German by Michaelis (1801) and Hegewisch (1807). It was highly popular and first placed the subject on a scientific basis. Hahn's writings had meanwhile created much enthusiasm among his countrymen, societies having been formed everywhere to promote the medicinal and dietetic use of water; and in 1804 Professor E.F.C. Oertel of Anspach republished them and quickened the popular movement by unqualified commendation of water drinking as a remedy for all diseases.
The general idea behind hydropathy during the 1800s was to be able to induce something called a crisis. The thinking was that water invaded any cracks, wounds, or imperfections in the skin, which were filled with impure fluids. Health was considered to be the body's natural state, and filling these spaces with pure water would flush the impurities out, which would rise to the skin's surface, producing pus. The event of this pus emerging was called a crisis, and was achieved through a multitude of methods. These methods included techniques such as sweating, the plunging bath, the half bath, the head bath, the sitting bath, and the douche bath. All of these were ways to gently expose the patient to cold water in different ways.
==== Vincenz Priessnitz (1799–1851) ====
Vincenz Priessnitz was the son of a peasant farmer who, as a young child, observed a wounded deer bathing a wound in a pond near his home. Over several days, he would see this deer return, and eventually the wound was healed. Later, as a teenager, Priessnitz was attending to a horse cart, when the cart ran him over, breaking three of his ribs. A physician told him that they would never heal. Priessnitz decided to try his hand at healing himself and wrapped his wounds with damp bandages. By daily changing his bandages and drinking large quantities of water, after about a year, his broken ribs had healed. Priessnitz quickly gained fame in his hometown and became the consulting physician.
Later in life, Priessnitz became the head of a hydropathy clinic in Gräfenberg in 1826. He was extremely successful and by 1840, he had 1600 patients in his clinic, including many fellow physicians, and important political figures such as nobles and prominent military officials. Treatment length at Priessnitz's clinic varied. Much of his theory was about inducing the aforementioned crisis, which could happen quickly or could occur after three to four years. Under the simplistic nature of hydropathy, a large part of the treatment was based on living a simple lifestyle. These lifestyle adjustments included dietary changes such as eating only very coarse food, such as jerky and bread, and of course, drinking large quantities of water. Priessnitz's treatments also included a great deal of less strenuous exercise, mostly including walking. Ultimately, Priessnitz's clinic was extremely successful, and he gained fame across the western world. His practice even influenced the hydropathy that took root overseas in America.
==== Sebastian Kneipp (1821–1897) ====
Sebastian Kneipp was born in Germany, and he considered his role in hydropathy to be that of continuing Priessnitz's work. Kneipp's practice of hydropathy was even gentler than the norm. He believed that typical hydropathic practices deployed were "too violent or too frequent," and he expressed concern that such techniques would cause emotional or physical trauma to the patient. Kneipp's practice was more all-encompassing than Priessnitz's, and his practice involved not only curing the patients' physical woes, but also emotional and mental as well.
Kneipp introduced four additional principles to the therapy: medicinal herbs, massages, balanced nutrition, and "regulative therapy to seek inner balance". Kneipp had a very simple view of an already simple practice. For him, hydropathy's primary goals were strengthening the constitution and removing poisons and toxins in the body. These basic interpretations of how hydropathy worked hinted at his complete lack of medical training. Kneipp did have, however, a very successful medical practice despite, perhaps even because of, his lack of medical training. As mentioned above, some patients were beginning to feel uncomfortable with traditional doctors because of the elitism of the medical profession. The new terms and techniques that doctors were using were difficult for the average person to understand. Having no formal training, all of his instructions and published works are described in easy-to-understand language and would have seemed very appealing to a patient who was displeased with the direction traditional medicine was taking.
A significant factor in the popular revival of hydrotherapy was that it could be practised relatively cheaply at home. The growth of hydrotherapy (or 'hydropathy' to use the name of the time) was thus partly derived from two interacting spheres: "the hydro and the home".
Hydrotherapy as a formal medical tool dates from about 1829 when Vincenz Priessnitz (1799–1851), a farmer of Gräfenberg in Silesia, then part of the Austrian Empire, began his public career in the paternal homestead, extended so as to accommodate the increasing numbers attracted by the fame of his cures.
At Gräfenberg, to which the fame of Priessnitz drew people of every rank and many countries, medical men were conspicuous by their numbers, some being attracted by curiosity, others by the desire of knowledge, but the majority by the hope of cure for ailments which had as yet proved incurable. Many records of experiences at Gräfenberg were published, all more or less favorable to the claims of Priessnitz, and some enthusiastic in their estimate of his genius and penetration.
=== Spread of hydrotherapy ===
Captain R. T. Claridge was responsible for introducing and promoting hydropathy in Britain, first in London in 1842, then with lecture tours in Ireland and Scotland in 1843. His 10-week tour in Ireland included Limerick, Cork, Wexford, Dublin and Belfast, over June, July and August 1843, with two subsequent lectures in Glasgow.
Some other Englishmen preceded Claridge to Graefenberg, although not many. One of these was James Wilson, who himself, along with James Manby Gully, established and operated a water cure establishment at Malvern in 1842. In 1843, Wilson and Gully published a comparison of the efficacy of the water-cure with drug treatments, including accounts of some cases treated at Malvern, combined with a prospectus of their Water Cure Establishment. Then in 1846 Gully published The Water Cure in Chronic Disease, further describing the treatments available at the clinic.
The fame of the water-cure establishment grew, and Gully and Wilson became well-known national figures. Two more clinics were opened at Malvern. Famous patients included Charles Darwin, Charles Dickens, Thomas Carlyle, Florence Nightingale, Lord Tennyson and Samuel Wilberforce. With his fame he also attracted criticism:
Sir Charles Hastings, a physician and founder of the British Medical Association, was a forthright critic of hydropathy, and Gully in particular.
From the 1840s, hydropathics were established across Britain. Initially, many of these were small institutions, catering to at most dozens of patients. By the later nineteenth century, the typical hydropathic establishment had evolved into a more substantial undertaking, with thousands of patients treated annually for weeks at a time in a large purpose-built building with lavish facilities – baths, recreation rooms and the like – under the supervision of fully trained and qualified medical practitioners and staff.
In Germany, France, America, and the UK (especially in Scotland), the number of hydropathic establishments rapidly increased. Antagonism ran high between the old practice and the new. Unsparing condemnation was heaped by each on the other; and a legal prosecution, leading to a royal commission of inquiry, served but to make Priessnitz and his system stand higher in public estimation.
Increasing popularity soon diminished caution about whether the new method would help minor ailments and benefit the more seriously injured. Hydropathists occupied themselves mainly with studying chronic invalids well able to bear a rigorous regimen and the severities of unrestricted crisis. The need of a radical adaptation to the former class was first adequately recognized by John Smedley, a manufacturer of Derbyshire, who, impressed in his own person with the severities as well as the benefits of the cold water cure, practised among his workpeople a milder form of hydropathy, and began about 1852 a new era in its history, founding at Matlock a counterpart of the establishment at Gräfenberg.
Ernst Brand (1827–1897) of Berlin, Raljen and Theodor von Jürgensen of Kiel, and Karl Liebermeister of Basel, between 1860 and 1870, employed the cooling bath in abdominal typhus with striking results, and led to its introduction to England by Wilson Fox. In the Franco-German War the cooling bath was largely employed, in conjunction frequently with quinine; and it was used in the treatment of hyperpyrexia.
=== Hot-air baths ===
Hydrotherapy, especially as promoted during the height of its Victorian revival, has often been associated with cold water, as evidenced by many titles from that era. However, not all therapists limited their practice of hydrotherapy to cold water, even during the height of this popular revival.
The specific use of heat was often associated with Victorian Turkish baths. Inspired by David Urquhart's travel book, The Pillars of Hercules, and with Urquhart’s help, Dr Richard Barter built the first such bath at his hydropathic establishment near Blarney, Co. Cork, Ireland in 1856. Urquhart built the first bath open to the general public in Manchester the following year, and soon baths were being opened around the whole of the then UK and British Empire. Over 800 such baths were opened in the British Isles between 1856 and the 1970s. Today, only 11 remain open. The Turkish bath became a public institution, and, with the morning tub and the general practice of water drinking, is the most noteworthy of the many contributions by hydropathy to public health.
=== Spread to the United States ===
The first U.S. hydropathic facilities were established by Joel Shew and Russell Thacher Trall in the 1840s. Charles Munde also established early hydrotherapy facilities in the 1850s. Trall also co-edited the Water Cure Journal.
By 1850, it was said that "there are probably more than one hundred" facilities, along with numerous books and periodicals, including the New York Water Cure Journal, which had "attained an extent of circulation equalled by few monthlies in the world". By 1855, there were attempts by some to weigh the evidence of treatments in vogue at that time.
By October 1863, Dr Charles Shepard had added a Victorian Turkish bath, the first in the United States, to his hydropathic Sanitorium in Brooklyn
Heights. Two years later, Dr Martin L Holbrook opened the first in Manhattan. They then spread across the country as fast as they did in the British Isles, making a similar impact on hydropathic practice.
Following the introduction of hydrotherapy to the U.S., John Harvey Kellogg employed it at Battle Creek Sanitarium, which opened in 1866, where he strove to improve the scientific foundation for hydrotherapy. Other notable hydropathic centers of the era included the Cleveland Water Cure Establishment, founded in 1848, which operated successfully for two decades, before being sold to an organization which transformed it into an orphanage.
At its height, there were over 200 water-cure establishments in the United States, most located in the northeast. Few of these lasted into the postbellum years, although some survived into the 20th century, including institutions in Scott (Cortland County), Elmira, Clifton Springs and Dansville. While none were in Jefferson County, the Oswego Water Cure operated in the city of Oswego.
=== Subsequent developments ===
In November 1881, the British Medical Journal noted that hydropathy was a specific instance, or "particular case", of general principles of thermodynamics. That is, "the application of heat and cold in general", as it applies to physiology, mediated by hydropathy. In 1883, another writer stated "Not, be it observed, that hydropathy is a water treatment after all, but that water is the medium for the application of heat and cold to the body".
Hydrotherapy was used to treat people with mental illness in the 19th and 20th centuries and before World War II, various forms of hydrotherapy were used to treat alcoholism. The basic text of the Alcoholics Anonymous fellowship, Alcoholics Anonymous, reports that A.A. co-founder Bill Wilson was treated by hydrotherapy for his alcoholism in the early 1930s.
=== Recent techniques ===
A subset of cryotherapy involves cold water immersion or ice baths, used by physical therapists, sports medicine facilities, and rehab clinics. Proponents assert that it results in improved return of blood flow and byproducts of cellular breakdown to the lymphatic system and more efficient recycling.
Alternating the temperatures, either in a shower or complementary tanks, combines hot and cold in the same session. Proponents claim improvement in the circulatory system and lymphatic drainage. Experimental evidence suggests that contrast hydrotherapy helps to reduce injury in the acute stages by stimulating blood flow and reducing swelling.
== Society and culture ==
The growth of hydrotherapy and various forms of hydropathic establishments resulted in a form of tourism, both in the UK, and in Europe. At least one book listed English, Scottish, Irish and European establishments suitable for each specific malady, while another focused primarily on German spas and hydropathic establishments, but including other areas. While many bathing establishments were open all year round, doctors advised patients not to go before May, "nor to remain after October. English visitors rather prefer cold weather, and they often arrive for the baths in May and return in September. Americans come during the whole season, but prefer summer. The most fashionable and crowded time is during July and August". In Europe, interest in various forms of hydrotherapy and spa tourism continued unabated through the 19th century and into the 20th century, where "in France, Italy and Germany, several million people spend time each year at a spa." In 1891, when Mark Twain toured Europe and discovered that a bath of spring water at Aix-les-Bains soothed his rheumatism, he described the experience as "so enjoyable that if I hadn't had a disease I would have borrowed one just to have a pretext for going on".
This was not the first time such forms of spa tourism had been popular in Europe and the U.K. Indeed,
in Europe, the application of water in the treatment of fevers and other maladies had, since the seventeenth century, been consistently promoted by a number of medical writers. In the eighteenth century, taking to the waters became a fashionable pastime for the wealthy classes who decamped to resorts around Britain and Europe to cure the ills of over-consumption. In the main, treatment in the heyday of the British spa consisted of sense and sociability: promenading, bathing, and the repetitive quaffing of foul-tasting mineral waters.
A hydropathic establishment is a place where people receive hydropathic treatment. They are commonly built in spa towns, where mineral-rich or hot water occurs naturally.
Several hydropathic institutions wholly transferred their operations away from therapeutic purposes to become tourist hotels in the late 20th century while retaining the name 'Hydro'. There are several prominent examples in Scotland at Crieff, Peebles and Seamill amongst others.
== Animal hydrotherapy ==
Canine hydrotherapy is a form of hydrotherapy directed at the treatment of chronic conditions, post-operative recovery, and pre-operative or general fitness in dogs.
== See also ==
== Notes ==
== References ==
== Further reading ==
Abbott, George Knapp (2007). Elements of Hydrotherapy for Nurses. Brushton, New York: Teach Services. ISBN 978-1-57258-521-8.
Campion, Margaret Reid, ed. (2001). Hydrotherapy: Principles and Practice. Woburn, Massachusetts: Butterworth-Heineman. ISBN 0-7506-2261-X.
Cayleff, Susan E (1991). Wash and Be Healed: The Water-Cure Movement and Women's Health. Philadelphia: Temple University Press. ISBN 0-87722-859-0.
Dail, Clarence; Thomas, Charles (1989). Hydrotherapy: Simple Treatments for Common Ailments. Brushton, New York: Teach Services. ISBN 0-945383-08-8.
Grüber, C; Riesberg, A; et al. (March 2003). "The effect of hydrotherapy on the incidence of common cold episodes in children: A randomised clinical trial". European Journal of Pediatrics. 162 (3): 168–76. doi:10.1007/s00431-002-1138-y. PMID 12655421. S2CID 20497073.
Landewé, Rb; Peeters, R; et al. (January 1992). "No difference in effectiveness measured between treatment in a thermal bath and in an exercise bath in patients with rheumatoid arthritis". Nederlands Tijdschrift voor Geneeskunde. 136 (4): 173–6. PMID 1736128.{{cite journal}}: CS1 maint: multiple names: authors list (link)
Sinclair, Marybetts (2008). Modern Hydrotherapy for the Massage Therapist. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. ISBN 978-0-7817-9209-7.
Thrash, Agatha; Thrash, Calvin (1981). Home Remedies: Hydrotherapy, Massage, Charcoal and Other Simple Treatments. Seale, Alabama: Thrash Publications. ISBN 0-942658-02-7. | Wikipedia/Water_cure_(therapy) |
Hormone therapy or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also be referred to as hormonal therapy or antihormone therapy. The most general classes of hormone therapy are oncologic hormone therapy, hormone replacement therapy (for menopause), androgen replacement therapy (ART), oral contraceptive pills, and Gender-affirming hormone therapy.
== Types ==
Hormone replacement therapy (HRT), also known as menopausal hormone therapy (MHT), is for women with menopausal symptoms. It is based on the idea that the treatment may prevent discomfort caused by diminished circulating estrogen and progesterone hormones, or in the case of the surgically or prematurely menopausal, that it may prolong life and may reduce incidence of dementia. It involves the use of one or more of a group of medications designed to artificially boost hormone levels. The main types of hormones involved are estrogen, progesterone, or progestins, and sometimes, testosterone. It is often referred to as "treatment" rather than therapy.
Hormone replacement therapy for people with hypogonadism and intersex conditions (e.g., Klinefelter syndrome, Turner syndrome)
Androgen replacement therapy (ART) in males with low levels of testosterone due to disease or aging. It is a hormone treatment often prescribed to counter the effects of male hypogonadism or for men who have lost their testicular function to disease, cancer, or other causes. It is sometimes used for late-onset hypogonadism (so-called "andropause"), but the significance of a decrease in testosterone levels is debated and its treatment with replacement is controversial. The Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone have been established in older men with low testosterone levels.
Gender-affirming hormone therapy for transgender people introduces sex steroids associated with the gender that the patient identifies with (notably testosterone for transgender men and estrogen for transgender women). Some intersex and non-binary people may also undergo hormone therapy. Cross-sex hormone treatment for transgender individuals is divided into two main types: feminizing and masculinizing.
Feminizing hormone therapy for transgender women
Masculinizing hormone therapy for transgender men
Hormonal therapy for cancer
Androgen deprivation therapy for men with prostate cancer
Estrogen deprivation therapy for women with estrogen receptor-positive breast cancer
High-dose estrogen therapy for women with estrogen receptor-positive breast cancer
Chemical castration of men or sex offenders with paraphilias or hypersexuality
Growth hormone therapy for growth hormone deficiency
Thyroid hormone replacement in hypothyroidism
Antithyroid therapy in hyperthyroidism
Glucocorticoid and/or mineralocorticoid replacement in conditions such as Addison's disease
Antiglucocorticoid therapy in Cushing's syndrome
Insulin therapy in type 1 diabetes
Oral contraceptive pills for various purposes including birth control
Menstrual suppression
Bioidentical Hormone Replacement Therapy is a bioidentical hormone replacement therapy uses hormones that are chemically identical to those the human body produces. One effective form of BHRT is hormone pellet therapy, which involves implanting tiny pellets under the skin that release hormones over time to balance hormonal levels, potentially alleviating symptoms such as chronic fatigue, irritability, and sexual dysfunction.
== See also ==
Life extension
Hormone replacement therapy
Feminizing hormone therapy
== References == | Wikipedia/Hormone_therapy |
Epigenetic therapy refers to the use of drugs or other interventions to modify gene expression patterns, potentially treating diseases by targeting epigenetic mechanisms such as DNA methylation and histone modifications.
Epigenetics is the study of changes in gene expression that do not arise from alterations in the DNA sequence, resulting in the heritable silencing of genes without changing the coding sequence. Epigenetic therapy involves using drugs or other techniques to influence these epigenetic mechanisms in addressing specific medical conditions. Various diseases, such as diabetes, cancer, heart disease, and mental illnesses, are influenced by epigenetic mechanisms. Emerging areas of epigenetic therapy include its application in heart disease, primarily focusing on tissue regeneration, and in schizophrenia, where the focus lies on alleviating symptoms. Overall, epigenetic therapies aim to target the underlying epigenetic molecular pathways responsible for disease manifestation.
== Epigenetics ==
Epigenetics refers to the study of changes in gene expressions that do not result from alterations in the DNA sequence'. Altered gene expression patterns can result from chemical modifications in DNA and chromatin, to changes in several regulatory mechanisms. Epigenetic markings can be inherited in some cases, and can change in response to environmental stimuli over the course of an organism's life.
Many diseases are known to have a genetic component, but the epigenetic mechanisms underlying many conditions are still being discovered. A significant number of diseases are known to change the expression of genes within the body, and epigenetic involvement is a plausible hypothesis for how they do this. These changes can be the cause of symptoms to the disease. Several diseases, especially cancer, have been suspected of selectively turning genes on or off, thereby resulting in a capability for the tumorous tissues to escape the host's immune reaction.
Known epigenetic mechanisms typically cluster into three categories. The first is DNA methylation, where a cytosine residue that is followed by a guanine residue (CpG) is methylated. In general, DNA methylation attracts proteins which fold that section of the chromatin and repress the related genes. The second category is histone modifications. Histones are proteins which are involved in the folding and compaction of the chromatin. There are several different types of histones, and they can be chemically modified in a number of ways. Acetylation of histone tails typically leads to weaker interactions between the histones and the DNA, which is associated with gene expression. Histones can be modified in many positions, with many different types of chemical modifications, but the precise details of the histone code are currently unknown. The final category of epigenetic mechanism is regulatory RNA. MicroRNAs are small, noncoding sequences that are involved in gene expression. Thousands of miRNAs are known, and the extent of their involvement in epigenetic regulation is an area of ongoing research. Epigenetic therapies are reversible, unlike gene therapy. This means that they are druggable for targeted therapies.
== Potential applications ==
=== Cancer ===
Epigenetic alterations can play a major role in the development and progression of cancer. This can be seen as a result of the changes made by various epigenetic mechanisms (i.e. DNA methylation, histone modification, non-coding RNAs) which may work to silence or activate cancer-related genes (i.e. tumor-suppressor genes or oncogenes), therefore invoking changes in gene expression patterns that are responsible for the initiation, progression, and metastasis of cancer. One example includes DNA hypermethylation of tumor-suppressor genes which can cause transcriptional inactivation of genes (i.e. CDKN2A) encoding for other regulatory proteins (i.e. p14 and p16) that play a vital role in the cell cycle. However, there are numerous avenues in which cancer can arise epigenetically given the various hallmarks of cancer. Because of this, epigenetic drugs are utilized to target and combat the internal dysregulation caused by these epigenetic alterations.
DNA methyltransferase inhibitors (DNMTis) are used as a treatment option against various forms of cancer. Some of these drugs, including 5-azacytidine, Decitabine, and Zebularine, have been shown to reactivate the cellular anti-tumor systems repressed by cancer, enabling the body to weaken and kill off the tumor. This can specifically result due to DNMTis ability to block overly active DNMTs, resulting in the hypomethylation of CpG regions which can allow for normal cell growth. Other treatment options including histone deacetylase inhibitors (HDACis), such as vorinostat, have also shown promising epigenetic therapeutic effects through the reactivation of apoptosis, cell death of undesirable cells, and the inhibition of angiogenesis, the formation of new blood vessels that can be utilized by cancerous cells as an extra source of nutrients. HDACis are an example of a chromatin-modifying drug, which specifically targets the acetylation portion of cancerous cells, and like DMNTis, is able to reactivate the cellular anti-tumor systems within a cell. Now because of their wide-ranging effects throughout the entire body, many of these drugs may have major side effects, making dosage regulation important; however, the survival rates are increased significantly when they are used for treatment, whether independently or in congruence with chemotherapy or other cancer-related forms of medication.
Phytochemical interventions have also gained traction in serving as an epigenetic treatment option against cancer. Phytochemicals, which are compounds produced by plants that act as a protectant to aid in their survival, can have an impact on the function of DNMTs. Polyphenols, a type of phytochemical that can be found in everyday foods and ingredients like tea, apples, and various forms of berries, have been shown to have anticancer effects. For example, epigallocatechin gallate (EGCG), the most prevalent polyphenol found in green tea, can work to inhibit cell proliferation by inducing apoptosis, preventing angiogenesis, and disrupting regulatory pathways, such as MAPK pathways.
Although various mechanisms have been utilized to mitigate the negative effects of cancer development and progression, drug resistance does still occur. Drug resistance can emerge as a result of continued and repetitive usage of a drug, giving pathogens time to develop defenses against drugs designed to kill them. In cancer, overexpression, for instance in DNA methylation and histone deactylase, can cause deleterious effects which can enhance drug resistance behaviors such as drug efflux. Drug efflux is regulatory process in which toxic compounds (i.e. drugs for cancer) get removed from a cell to reduce its cytotoxic effects. However, research suggests there are ways to overcome this type of drug resistance, with one being through the use of epigenetic factor inhibitors.
=== Cardiovascular disease ===
Cardiovascular disease is one of the leading cause of death. Factors such as age, smoking, obesity, diabetes, and hypertension increase the likelihood of developing cardiovascular diseases. As of now, initial investigations have established links between DNA methylation, histone modifications, RNA-based mechanisms, and the onset of cardiovascular diseases such as atherosclerosis, cardiac hypertrophy, myocardial infarction, and heart failure. Epigenetic alterations like DNA methylation enzymes can reverse abnormal DNA methylation, histone modifications, and non-coding RNA regulation play critical roles in cardiovascular disease. A number of cardiac dysfunctions have been linked to cytosine methylation patterns. DNA methylation is an important epigenetic mechanism, it is able to transfer to offspring DNA through the regulation of DNMT. DNA demethylation can happen through either an active or passive process. Passive demethylation refers to the failure of maintenance DNA methyltransferases (DNMTs) to methylate the newly synthesized DNA strand during mitosis. DNMT deficient mice show upregulation of inflammatory mediators, which cause increased atherosclerosis and inflammation. Atherosclerotic tissue has increased methylation in the promoter region for the estrogen gene, although any connection between the two is unknown. Hypermethylation of the HSD11B2 gene, which catalyzes conversions between cortisone and cortisol, and is therefore influential in the stress response in mammals, has been correlated with hypertension. Decreased LINE-1 methylation is a strong predictive indicator of ischemic heart disease and stroke, although the mechanism is unknown. Various impairments in lipid metabolism, leading to clogging of arteries, has been associated with the hypermethylation of GNASAS, IL-10, MEG3, ABCA1, and the hypomethylation of INSIGF and IGF2. Additionally, upregulation of a number of miRNAs has been shown to be associated with acute myocardial infarction, coronary artery disease, and heart failure. Strong research efforts into this area are very recent, with all of the aforementioned discoveries being made since 2009. Mechanisms are entirely speculative at this point, and an area of future research. It has been demonstrated that miRNAs regulate gene expression by suppressing messenger RNA (mRNA) translation and increasing mRNA degradation. Studies have shown that miRNAs can influence myocardial angiogenesis and the survival and proliferation of cardiomyocytes by regulating target gene expression.
Epigenetic treatment methods for cardiac dysfunction are still highly speculative. SiRNA therapy targeting the miRNAs mentioned above is being investigated. The primary area of research in this field is on using epigenetic methods to increase the regeneration of cardiac tissues damaged by various diseases. By comprehending the roles these mechanisms play in disease pathology, researchers can devise precise treatments to regulate gene expression, potentially halting or alleviating the progression of cardiovascular diseases.
=== Diabetic retinopathy ===
Diabetes is a disease where an affected individual is unable to convert food into energy. When left untreated, the condition can lead to other, more severe complications. A common sign of diabetes is the degradation of blood vessels in various tissues throughout the body. Retinopathy refers to damage from this process in the retina, the part of the eye that senses light. Diabetic retinopathy is known to be associated with a number of epigenetic markers, including methylation of the Sod2 and MMP-9 genes, an increase in transcription of LSD1, a H3K4 and H3K9 demethylase, and various DNA Methyl-Transferases (DNMTs), and increased presence of miRNAs for transcription factors and VEGF.
It is believed that much of the retinal vascular degeneration characteristic of diabetic retinopathy is due to impaired mitochondrial activity in the retina. Sod2 codes for a superoxide disputes enzyme, which scavenges free radicals and prevents oxidative damage to cells. LSD1 may play a major role in diabetic retinopathy through the downregulation of Sod2 in retinal vascular tissue, leading to oxidative damage in those cells. MMP-9 is believed to be involved in cellular apoptosis, and is similarly downregulated, which may help to propagate the effects of diabetic retinopathy.
Several avenues to epigenetic treatment of diabetic retinopathy have been studied. One approach is to inhibit the methylation of the Sod2 and MMP-9. The DNMT inhibitors 5-azacytidine and 5-aza-20-deoxycytidine have both been approved by the FDA for the treatment of other conditions, and studies have examined the effects of those compounds on diabetic retinopathy, where they seem to inhibit these methylation patterns with some success at reducing symptoms. The DNA methylation inhibitor Zebularine has also been studied, although results are currently inconclusive. A second approach is to attempt to reduce the miRNAs observed at elevated levels in retinopathic patients, although the exact role of those miRNAs is still unclear. The Histone Acetyltransferase (HAT) inhibitors Epigallocatechin-3-gallate, Vorinostat, and Romidepsin have also been the subject of experimentation for this purpose, with some limited success. The possibility of using Small Interfering RNAs, or siRNAs, to target the miRNAs mentioned above has been discussed, but there are currently no known methods to do so. This method is somewhat hindered by the difficulty involved in delivering the siRNAs to the affected tissues.
Type 2 diabetes mellitus (T2DM) has many variations and factors that influence how it affects the body. DNA methylation is a process by which methyl groups attach to DNA structure causing the gene to not be expressed. This is thought to be an epigenetic cause of T2DM by causing the body to develop an insulin resistance and inhibit the production of beta cells in the pancreas. Because of the repressed genes the body does not regulate blood sugar transport to cells, causing a high concentration of glucose in the blood stream.
Another variation of T2DM is mitochondrial reactive oxygen species (ROS) which causes a lack of antioxidants in the blood. This leads to oxidation stress of cells leading to the release of free radicals inhibiting blood glucose regulation and hyperglycemic conditions. This leads to persistent vascular complications that can inhibit blood flow to limbs and the eyes. This persistent hyperglycemic environment leads to DNA methylation as well because the chemistry within chromatin in the nucleus is affected.
Current medicine used by T2DM sufferers includes Metformin hydrochloride which stimulates production in the pancreas and promotes insulin sensitivity. A number of preclinical studies have suggested that adding a treatment to metformin that would inhibit acetylation and methylation of DNA and histone complexes. DNA methylation occurs throughout the human genome and is believed to be a natural method of suppressing genes during development. Treatments targeting specific genes with methylation and acetylation inhibitors is being studied and debated.
=== Autism spectrum disorder ===
Autism or autism spectrum disorder (ASD) is a neurodevelopmental disorder discovered in 1943. It is part of a growing group of disorders called pervasive developmental disorders (PDDs), which are becoming increasingly common up to 1 in 110 in the United States and 1 in 64 in the United Kingdom.
While there are many causes for Autism spectrum disorder to manifest (viral infection, encephalitis, or an auto immune reaction, but the primary reasons are genetic or epigenetic. in the 1970s karyotyping allowed for the understanding of chromosomes, over time techniques such as fluorescence in situ hybridization (FISH)) we began to be able to analyze chromosomes with more resolution. Chromosome microarray and single nucleotide genotyping, and even whole genotype sequencing allow resolution at the gene level. One issue that possibly leads to autism is copy number variation in a gene the most studied of which is the 15q multiplication from the maternal chromosome. A database of genes (AutDB) has over 800 potential targets for study as a cause for autism. While not an exhaustive list a few examples are NLGN4X, PAH, PEX7,and SYNE1.
The heterogeneity of autism causes and symptoms has led to research in epigenetic factors. Maternal health during pregnancy, including taking folic acid, has been shown to affect the chances of not having ASD through epigenetic means. DNA methylation and histone modification are the two leading causes for epigenetic causes for autism. Targets for research for DNA methylation in relation to autism are oxytocin receptor, SHANK3, and BCL-2. Oxytocin is a hormone that partially controls social interactions, this has been epigenetically linked to autism. Methylation controls SHANK3 levels, which in turn activate CpG- island genes, which can lead to autism. BCL-2 is involved in cell death, and an event that misfires could contribute to brain development in that region. Histone modification also potentially leads to autism. Histone modification contributes to brain development. Modification of lysine residues on the H3 histone effect brain development. histone deacetylase inhibitors sodium butyrate and trichostatin A are regulators of oxytocin and vasopressin which are linked to autism symptoms.
Epigenetic therapies are a new emerging medical field. There are a number of potential therapies to treat ASD, using various methods. While the research into potential therapies is still in its infancy one of the positives of epigenetic therapy is it is reversible, this leads to many less potential side effects. While there are no current therapeutics approved for epigenetic use in autism there are a number of potential categories, histone deacetylase inhibitors (HDACis), and DNA methyltransferases. While there is great hope for epigenetic therapy for autism and some powerful research, there is currently no available drugs in clinical trials.
Histone acetlytion is a standard way to measure gene activity, HDACS remove histones thereby lowering the gene activity at that site. HDACi drugs are being tested and used as cancer theraputics, but are showing potential for neurodevelopmental disorders such as ASD. Valproic acid, commonly called Vorinostat, is an HDACi that helps with mood stabilization, this shows that it has potential for other neuro applications. MGCD0103 is a drug that is in preclinical trials as a cancer drug. Is mechanism is to affect HDAC1. HDAC1 has a large impact on many functions in the body, including many neuro regions, this makes it a good candidate for a potential Autism therapy.
DNA Methyltransferases (DNMT) have the potential to silence specific genes. As we learn more about genes related to ASD such as PAH (see above) these compounds become more relevant as therapies. There are three types of DNMT's. DNMT1 is a maintenance DNMT whereas DNMT3a and DNMT 3b are a de novo factor. There are currently two therapeutics being tested for this process, azacitidine and decitabine.
=== Fear, anxiety, and trauma ===
Traumatic experiences can lead to several mental illnesses including post-traumatic stress disorder. It was previously thought that PTSD could be treated with advances in cognitive behavioral therapy methods like Exposure therapy. In exposure therapy, patients are exposed to stimuli that provoke fear and anxiety. In theory, repeated exposure can lead to a decreased connection between the stimuli and the anxiety. While exposure therapy helps many patients, many patients do not experience improvement in their symptoms while others may experience more symptoms.
The biochemical mechanisms underlying these systems are not completely understood. However, brain-derived neurotrophic factor (BDNF) and the N-methyl-D-aspartate receptors (NMDA) have been identified as crucial in the exposure therapy process. Successful exposure therapy is associated with increased acetylation of these two genes. Acetylation is a biochemical modification that affects how tightly DNA is wound around histone proteins, thereby influencing gene expression. When the genes encoding BDNF and NMDA receptors experience increased acetylation, they become more "accessible" for transcription, the first step in protein production. So, enhanced expression of BDNF and NMDA receptors seems to bolster neural plasticity, facilitating the brain's capacity to form new connections and adjust its responses to anxiety-provoking stimuli. For these reasons, increasing the acetylation of these two genes has been a major area of recent research into the treatment of anxiety disorders.
N-methyl-D-aspartate receptors (NMDA receptors) play a crucial role in synaptic plasticity and learning, including fear extinction, which is a core mechanism targeted in exposure therapy. These receptors are involved in the consolidation of new memories and the extinction of fear responses by regulating the strength of synaptic connections. Exposure therapy aims to reduce the fear response to specific stimuli by repeated exposure to those stimuli in a safe environment. During exposure therapy, the process of fear extinction occurs, where individuals learn that the feared stimuli no longer predict harm. NMDA receptors are implicated in this fear extinction learning process through their involvement in synaptic plasticity mechanisms, such as long-term potentiation (LTP) and long-term depression (LTD), which underlie the formation and extinction of fear memories. Research has shown that pharmacological manipulation of NMDA receptors can influence fear extinction learning and enhance the efficacy of exposure therapy. For example, drugs that enhance NMDA receptor function, such as D-cycloserine, have been used as adjuncts to exposure therapy to facilitate fear extinction in individuals with anxiety disorders. The article "Effects of D-cycloserine on extinction: translation from preclinical to clinical work" (Davis et al., 2006) discusses the preclinical and clinical studies investigating the effects of D-cycloserine, a partial agonist at the glycine site of the NMDA receptor, on fear extinction and its translation to clinical applications in exposure therapy for anxiety disorders.
In relation to epigenetic therapy, modulating NMDA receptor-related pathways and enhancing fear extinction learning. By targeting epigenetic modifications of NMDA receptor genes, such as promoting DNA demethylation or histone acetylation, it may be possible to enhance NMDA receptor function and facilitate fear extinction processes. This could involve adjunctive treatments with epigenetic-modifying agents, tailored to individual genetic and epigenetic profiles, to optimize exposure therapy outcomes in individuals with anxiety disorders.
Going deeper into BDNF as well, utilizing BDNF as more than a mere marker in exposure therapy and integrating it into epigenetic therapy to target BDNF-related pathways could serve as a valuable addition to complement exposure therapy. The relationship between BDNF, exposure therapy, and epigenetic therapy can be illuminated by considering the role of BDNF in fear extinction learning, which is a core mechanism targeted in exposure therapy, and the potential for epigenetic mechanisms to modulate BDNF expression and function.
BDNF plays a pivotal role in fear extinction learning, crucial for exposure therapy, by facilitating synaptic plasticity and consolidating safety memories. Individuals with BDNF dysfunction, like those with the Val66Met SNP (The Val66Met single nucleotide polymorphism (SNP) of BDNF), may exhibit impaired fear extinction, potentially leading to treatment resistance in exposure therapy. Consequently, strategies aimed at enhancing BDNF function or expression could enhance the efficacy of exposure therapy interventions. Moreover, epigenetic mechanisms, such as DNA methylation and histone modifications, dynamically regulate BDNF expression and function. Environmental factors and genetic variants like the Val66Met SNP can influence BDNF epigenetic marks, impacting its transcriptional activity. Targeting epigenetic modifications of BDNF presents a novel approach to modulating fear extinction processes, potentially improving exposure therapy outcomes. Epigenetic therapy could complement exposure therapy by targeting BDNF-related pathways, such as demethylating the BDNF gene promoter or altering histone acetylation patterns to facilitate BDNF transcription. Integrating genetic information, such as BDNF polymorphisms, with epigenetic profiles and clinical data allows for personalized treatment approaches. Identifying individuals likely to benefit from targeted epigenetic interventions could enhance fear extinction learning and improve treatment outcomes in exposure therapy. This interplay between BDNF, exposure therapy, and epigenetic regulation holds promise for optimizing treatment outcomes and advancing personalized medicine approaches for anxiety disorders.
HDAC inhibitors are also a topic that can be discussed in this area. Exposure therapy's effectiveness in rodents is increased by the administration of Vorinostat, Entinostat, TSA, sodium butyrate, and VPA, all known histone deacetylase inhibitors. Several studies in the past two years have shown that in humans, Vorinostat and Entinostat increase the clinical effectiveness of exposure therapy as well, and human trials using the drugs successfully in rodents are planned. In addition to research on the effectiveness of HDAC inhibitors, some researchers have suggested that histone acetyltransferase activators might have a similar effect, although not enough research has been completed to draw any conclusions. However, none of these drugs are likely to be able to replace exposure therapy or other cognitive behavioral therapy methods. Rodent studies have indicated that administration of HDAC inhibitors without successful exposure therapy worsens anxiety disorders significantly, although the mechanism for this trend is unknown. The most likely explanation is that exposure therapy works by a learning process, and can be enhanced by processes that increase neural plasticity and learning. However, if a subject is exposed to a stimulus that causes anxiety in such a way that their fear does not decrease, compounds that increase learning may also increase re-consolidation, ultimately strengthening the memory.
Psychotherapy can be linked to alterations in epigenetic markers. An example of the growing evidence that indicates that successful psychotherapy can be linked to alterations in epigenetic markers, particularly DNA methylation, and could serve as a potential indicator of treatment efficacy is a research paper titled "Epigenetics of traumatic stress: The association of NR3C1 methylation and posttraumatic stress disorder symptom changes in response to narrative exposure therapy". This study explored the relationship between DNA methylation at the glucocorticoid receptor gene (NR3C1) and the success of psychotherapy in treating Posttraumatic Stress Disorder (PTSD) among conflict survivors in Northern Uganda. The researchers used Narrative Exposure Therapy (NET) on a sample of 153 individuals with PTSD and conducted diagnostic interviews and saliva sampling before treatment and at 4 and 10 months after treatment completion. They found that changes in methylation at a specific CpG site (cg25535999) were associated with PTSD symptom development. Treatment responders showed an increase in methylation at this site after therapy, while lower methylation levels before treatment predicted greater symptom improvement. These findings suggest that epigenetic changes at NR3C1 may play a role in the success of trauma-focused therapy, highlighting the importance of glucocorticoid signaling in PTSD treatment.
=== Schizophrenia ===
Research findings have demonstrated that schizophrenia is linked to numerous epigenetic alterations, including DNA methylation and histone modifications. For example, the therapeutic efficacy of schizophrenic drugs such as antipsychotics are limited by epigenetic alterations and future studies are looking into the related biochemical mechanisms to improve the efficacy of such therapies. Even if epigenetic therapy wouldn't allow to fully reverse the disease, it can significantly improve the quality of life.
== See also ==
Pharmacoepigenetics
== References == | Wikipedia/Epigenetic_therapy |
Salvage therapy, also known as rescue therapy, is a form of therapy given after an ailment does not respond to standard therapy. The most common diseases that require salvage therapy are HIV and various cancers. The term is not clearly defined; it is used both to mean a second attempt and a final attempt. Salvage therapy drugs or drug combinations have, in general, much more severe side effects than the standard line of therapy. This is often true of a drug of last resort.
== Uses ==
=== HIV ===
Antiretroviral drugs (ARVs) are given to slow down the HIV reproduction, which in turn increases quality of life and survival. If the patient's viral load (the amount of HIV in the blood) rebounds after being suppressed by ARVs, the virus has likely developed resistance to the ARVs. As more and more mutations conferring drug resistance develop in the HIV's genome, it becomes difficult to select an ARV that will meaningfully suppress HIV replication and keep the patient's viral load low. Salvage therapy, in this context, is the attempt to contain the replicating HIV once the usual line of treatments have been exhausted. When at least one regimen containing protease inhibitors has failed in a patient, the subsequent attempts to treat the HIV infection may be referred to as salvage therapy.
=== Cancers ===
Salvage chemotherapy is a treatment that is given after the cancer has not responded to other chemotherapy regimens.
== See also ==
Heroic measure
== References == | Wikipedia/Salvage_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/Grief_therapy_dog |
Duct tape occlusion therapy (DTOT) is a method of treating warts by covering them with duct tape for prolonged periods.
The manner in which duct tape appears to work is unclear. The tape might create a macerating and keratolytic environment, stimulating an immune response. The type of adhesive in the duct tape is likely to be important as leeching of the adhesive into the skin may be causing the immune system response. Side effects can include skin irritation and peeling.
There is mixed evidence that occlusive treatment with various types of duct tape is effective. Clinical trials in 2012 concluded that no statistically significant difference between clear duct tape and placebo could be determined within the sample. No such trial was conducted for the more-common, grey duct tape, which uses a different type of adhesive. On health information websites, duct tape is referred to as a treatment with mixed evidence of efficacy, no good evidence or described as alternative medicine.
Despite the mixed evidence for efficacy, the simplicity of the method and its limited side-effects leads some researchers to be reluctant to dismiss it.
== Evidence ==
In 1978, Jerome Z Litt was the first to suggest that adhesive tape could be used to treat warts on the fingers. He claimed: "My method is safe, easy, simple, painless, inexpensive, and highly effective. It leaves no scarring or deformed nails. The mystery remains: How and why does this method work? I cannot offer any reasonable or logical explanation. It cannot be all 'hypnotic' or 'suggestive.' Could it be that the airtight occlusion and a chemical reaction set up by the adhesive in the tape might combine to release a chemical or 'toxin' causing the formation of antibodies? Whatever it may be, it works. I recommend that you try it."
A 2002 study involved 51 individuals (aged 3–22) treated with either "standard duct tape" (not otherwise specified in the study) or cryotherapy. A piece of duct tape was cut as close to the size of the wart as possible, and applied to the area. The tape was left on for 6 days and replaced with new duct tape if it fell off. After 6 days, the tape was removed, the area soaked in water, and the wart debrided with an emery board or pumice stone. The tape was left off overnight and reapplied on the following morning. This process continued for up to 2 months or until the wart was resolved, whichever occurred first. Progress was monitored every 4 weeks. The researchers found the duct tape treatment significantly more effective than the cryotherapy (P=0.05) with 85% in the duct tape treatment group having a complete resolution of their wart, compared to 60% in the cryotherapy group. The study was criticized due to lack of a placebo control group, and because a number of outcome assessments were done by phone. There was also no reported long term follow up to ensure no recurrence of the warts.
Two later studies failed to repeat the results of the 2002 study. One compared duct tape with moleskin, finding no statistically significant difference in results reported between the two groups. Both studies used 3M clear duct tape, again concluding no statistically significant effect on wart resolution. The statistical power of the latter trial has been questioned, and it has been suggested that duct tape occlusion therapy only works with rubber-based adhesives, whereas these studies utilized acrylic-based adhesive.
== References == | Wikipedia/Duct_tape_occlusion_therapy |
Fluoride therapy is the use of fluoride for medical purposes. Fluoride supplements are recommended to prevent tooth decay in children older than six months in areas where the drinking water is low in fluoride. It is typically used as a liquid, pill, or paste by mouth. Fluoride has also been used to treat a number of bone diseases.
Relatively high ingestion of fluoride by babies and children may result in white marks on the teeth known as fluorosis. Excessive ingestion by babies and children can result in severe dental fluorosis, indicated by a brown or yellow coloring, weakening and brittleness of the teeth, or in severe cases, acute toxicity. Fluoride therapy typically uses the sodium fluoride form, though stannous fluoride may also be used. Fluoride decreases breakdown of teeth by acids, promotes remineralisation, and decreases the activity of bacteria. Fluoride works primarily through direct contact with teeth.
Fluoride came into use to prevent tooth decay in the 1940s. Fluoride is on the World Health Organization's List of Essential Medicines. In 2021, it was the 291st most commonly prescribed medication in the United States, with more than 600,000 prescriptions.
== Medical uses ==
=== Dental caries ===
Fluoride therapy has a beneficial effect on the prevention of dental caries. Fluoride toothpaste, with concentrations of 1000 ppm and above, reduces the risk of dental caries in school-aged children and adolescents. As primary teeth are being developed, the ingestion of fluoride causes the teeth to form stronger and more resistant to cavities, although this increases the risk of dental fluorosis. Water and milk fluoridation are two forms of systemic fluoride therapy that are effective at preventing dental cavities.
=== Osteoporosis ===
Fluoride supplementation has been studied for the treatment of postmenopausal osteoporosis, for which it does not appear to be effective. Even though sodium fluoride increases bone density, it does not decrease the risk of fractures.
== Side effects ==
=== Fluorosis ===
The use of fluoride toothpaste (with concentrations of 1000 ppm and above) and fluoride supplements in children below the age of six years, especially within the first three years of life, is associated with a greater risk of dental fluorosis. The use of fluoride supplements during the last six months of pregnancy has no significant impact on the incidence of fluorosis in children. Optimal water fluoridation for the prevention of dental caries increases the prevalence of dental fluorosis by 4 to 5%. The observed effects are mild to moderate, usually of minimal aesthetic concern.
=== Other risks ===
Water fluoridation is not linked to the development of osteoporosis or cancer.
== Overdose ==
Consumption of large amounts of fluoride can lead to fluoride poisoning and death. The lethal dose for most adult humans is estimated at 5 to 10 grams, equivalent to 32 to 64 mg elemental fluoride per kg of body weight. Ingestion of fluoride can produce gastrointestinal discomfort at doses as low as 0.2 mg/kg, 20 times lower than lethal doses. Chronic intake and topical exposure may cause dental fluorosis, and excess systematic exposure can lead to skeletal fluorosis. The American Dental Association (ADA) recommends infants primarily consume human milk to reduce fluoride intake and prevent infants developing fluorosis.
In 1974, a three-year-old child swallowed 45 milliliters of 2% fluoride solution, triple the fatal amount, and died. The fluoride was administered during his first visit to the dentist, and the dental office was later found liable for the death.
== Mechanism ==
Strictly speaking, fluoride therapy repairs rather than prevents damage to the teeth, causing the mineral fluorapatite to be incorporated into damaged tooth enamel. Fluorapatite is not a natural component of human teeth, although it is found in the teeth of sharks. The main mineral found in natural tooth enamel is hydroxyapatite rather than the fluorapatite created in the presence of fluoride. Even without fluoride, teeth experience alternating increases and decreases in mineral content, depending upon how acidic or alkaline the mouth is, and depending upon the concentration of other substances in the mouth, such as phosphate and calcium.
Fluoride reduces the decay of tooth enamel by the formation of fluorapatite and its incorporation into the dental enamel. The fluoride ions reduce the rate of tooth enamel demineralization and increase the rate of remineralization of teeth at the early stages of cavities. Fluoride exerts these effects by the demineralization and remineralization cycle. The remineralization cycle, critical to decay prevention, occurs when fluoride is present in the oral cavity. After fluoride is swallowed it has a minimal effect.
Fluoride ions are involved in three principal reactions of remineralization:
Iso-ionic exchange of F− for OH− in apatite: Ca10(PO4)6(OH)2 + 2F− → Ca10(PO4)6F2 + 2OH−
Crystal growth of fluorapatite from a supersaturated solution: 10 Ca2+ + 6PO43− + 2F− → Ca10(PO4)6F2
Apatite dissolution with CaF2 formation: Ca10(PO4)6(OH)2 + 2F− → 10 CaF2 + 6PO43− + 2OH−
Iso-ionic exchange by the replacement of F− for OH¯ in apatite and crystal growth of fluorapatite from supersaturated solutions are able to occur during exposure to low levels of fluoride (0.01–10 ppm F) over long periods of time. Reaction of apatite dissolution with CaF2 formation occurs in higher levels of fluoride (100–10,000 ppm F) and the addition of CaF2 or a CaF2 containing compound.
Fluoride's effect on oral microflora and the significance of this effect on fluoride's overall effectiveness against cavities does not currently have a consensus. Many studies on bacterial cells in laboratories have shown the fluoride has many effects on them as an antimicrobial agent. The antimicrobial effects require concentrations of fluoride at least 10 ppm F, which only occurs briefly in the mouth with oral fluoride-containing products. A study looked at fluoride's effects on oral microflora and concluded that fluoride may not solely interact as an antimicrobial agent, acting additionally to reduce bacterial adhesion to teeth, along with the primary action of decreasing demineralization. Further investigation will need to be done to verify these claims.
Fluoride can be delivered by many chemical methods (sodium fluoride, stannous fluoride, amine fluoride, monofluorophosphate, and more). The anti-caries performance differences between them have been shown to have less effect than variations in behavior shown by individuals in brushing, using fluoride products and post use behavior. Often the chemical form of fluoride is driven by compatibility with the other elements mixed with, price, and such.
All fluoridation methods provide low concentrations of fluoride ions in saliva, thus exerting a topical effect on the plaque fluid. Fluoride does not prevent cavities but rather controls the rate at which they develop, and so repeated exposure throughout the day is essential for its effective function. The more constant the supply the more beneficial fluoride will be in cavity prevention.
== Delivery ==
=== Water fluoridation ===
Water fluoridation is the controlled addition of fluoride to a public water supply in order to reduce tooth decay. Its use in the U.S. began in the 1940s, following studies of children in a region where water is naturally fluoridated. In 1945, Grand Rapids, Michigan became the first city in the world to fluoridate its drinking water. The Grand Rapids water fluoridation study was originally sponsored by the U.S. Surgeon General, but was taken over by the NIDR shortly after the institute's inception in 1948. Fluoridation is now used for about two-thirds of the U.S. population on public water systems and for about 5.7% of people worldwide. Although the best available evidence shows no association with adverse effects other than fluorosis, most of which is mild, water fluoridation has been contentious and opposition to water fluoridation exists despite its support by public health organizations. Water fluoridation is the most cost-effective way to induce fluoride, with an estimated cost between US$0.50 and $3.00 per person per year, depending on the size of the community involved. A dollar spent on fluoridating water is estimated to save $7–42 on dental treatment.
=== Toothpaste ===
Most toothpastes contains between 0.22% (1,000 ppm) and 0.312% (1,450 ppm) fluoride, usually in the form of sodium fluoride, stannous fluoride, or sodium monofluorophosphate (MFP).
Frequent use of toothpaste with 1,100 ppm fluoride content enhances the remineralization of enamel and inhibits the demineralization of enamel and root surfaces.
Most toothpastes with fluoride contain mild abrasives in order to remove heavier debris and light surface staining. These abrasives include calcium carbonate, silica gels, magnesium carbonates and phosphate salts.
Fluoride is available in three forms during toothbrushing. First, it is available as a free ionic fluoride which can react with the tooth structure, interfere with the metabolism of bacteria in plaque, or absorb to the oral mucosa. Second, it is available as profluoride compounds which can precipitate in the mouth during toothbrushing and release ionic fluoride. Lastly, fluoride in toothpaste can exist as unavailable fluoride compounds which do not release fluoride ions. This is due to the fluoride ions being swallowed or expelled when spitting.
High-fluoride content toothpaste generally contains 1.1% (5,000 ppm) sodium fluoride toothpaste. This type of toothpaste is used in the same manner as regular toothpaste. The application of high-fluoride content toothpaste in adults twice daily improves the surface hardness of untreated root decay when compared to toothpaste with regular fluoride content.
Fluoridated toothpaste is also available in the form of 0.454% stannous fluoride (SnF2 with fluoride concentration 1,100 ppm). When combined with the stannous ion (Sn2+), fluoride in toothpaste appears to have a wide range of benefits to oral health.
Toothpastes containing stannous fluoride have been shown to be more effective than other fluoride toothpastes for reducing dental decay, dental erosion, gingivitis, tooth hypersensitivity, dental plaque, calculus (tartar) and stains. A systematic review revealed stabilised stannous fluoride-containing toothpastes caused a reduction of plaque, gingivitis and staining in clinical trials, with a significant reduction in calculus and halitosis compared to other toothpastes.
Anti-sensitivity toothpastes with fluoride are also available for those who have sensitive teeth. Some anti-sensitivity toothpastes with fluoride on the market contain the ingredients called strontium chloride or potassium nitrate which help to alleviate tooth sensitivity.
=== Mouth rinses ===
Fluoride mouth rinses can be professionally applied by a dental professional or used at home. The most common fluoride compound used in mouth rinse is neutral sodium fluoride. Fluoride mouth rinses range from 0.05% to 0.2% (225–1,000 ppm) in concentration. The fluoride rinse with a 0.05% fluoride content is used for daily rinsing, while the rinse with 0.2% fluoride content is used for weekly rinsing and in school-based weekly rinsing programs. Fluoride at these concentrations is not strong enough for people at high risk for tooth decay. Regular use of a daily (230 ppm) or weekly (900 ppm) fluoride mouth rinse under supervision results into a reduction of tooth decay in children's permanent teeth. After a fluoride mouthrinse treatment, the fluoride in the mouthrinse is retained in the saliva which helps prevent tooth decay.
Fluoride mouth rinses are recommended for use in conjunction with other fluoride therapies, but is usually contraindicated for children under six years old as they may swallow the rinse and increase their risk of dental fluorosis. In areas without fluoridated drinking water, these rinses are recommended for children.
Many brands of topical fluoride exist. They are not recommended if a person is drinking water that already contains sufficient fluoride.
=== Gels/foams ===
There are several types of professionally applied fluoride gels and foams on the market. The types of professionally applied fluoride gels include 2.0% neutral sodium fluoride and 1.23% acidulated phosphate fluoride. Acidulated phosphate fluoride (APF) gel or foam comprises a sodium fluoride solution, paste, or powder that has been acidulated with hydrofluoric acid to pH 3 to 4, buffered with a phosphate, and mixed with a gel or foam vehicle such as carboxymethyl cellulose. 1.23% acidulated phosphate fluoride gel or foam is used for patients without tooth-colored restorations, while 2.0% neutral sodium fluoride is used for patients with composites, porcelain, titanium, sealants or sensitivity.
Professionally applied fluoride gel or foam is applied through the use of a foam mouth tray which is held in the mouth by gently biting down. The application usually lasts for approximately four minutes, and patients should not rinse, eat, smoke, or drink for 30 minutes after application. The reason for this is to allow the teeth to absorb the fluoride into the tooth structure when it is at its highest concentration, without being interrupted. This aids in the repair of microscopic dental decay. There is no clinical evidence on the effectiveness of one-minute fluoride gel/foam applications. A specific benefit when using foam is that less product is required during application, which results in a lower fluoride dose and lessens the risk of accidental ingestion. Additionally, more research regarding the efficacy of fluoride foam is needed as the evidence for its effectiveness is not as strong compared to those of fluoride gels and varnish.
Some gels are made for home application with the use of a custom tray. A model of a person's teeth can be made by a dental professional, who then uses that to make trays, similar to a sport guard tray, which is put over their teeth. The patient can then use this to hold a fluoride treatment against their teeth overnight or several minutes during the day. The concentration of fluoride in these gels is much lower than in professional products. The self-applied sodium fluoride gel/foam typically contains 0.5% fluoride and stannous fluoride gel/foam contains 0.15%.
Head and neck radiation treatment may destroy the cells of the salivary gland which can result in dry mouth. Patients with reduced salivary flow are at an increased risk of tooth decay. The home application of 1.1% fluoride gel with a custom tray is recommended for patients undergoing or are finished with head and neck radiation treatment and patients with decreased salivary flow.
More research is required regarding the efficacy of fluoride gels in treating initial dental decay lesions.
=== Varnish ===
Fluoride varnish has practical advantages over gels in ease of application and use of smaller volume of fluoride than required for gel applications. The principle of fluoride varnish is to apply fluoride salt in a very high concentration (approximately 50,000 ppm) onto the surface of the teeth. Fluoride varnish is a resin-based application that is designed to stay on the surface of the teeth for several hours. As this varnish rests on the tooth's surface, saliva dissolves the fluoride salt, which in turn allows fluoride ions to be released and absorbed by the teeth and soft tissues. Later, the fluoride is re-released into the oral cavity from these reservoirs which acts as protection for the teeth against cavities. Currently, there is also no published evidence that indicates that professionally applied fluoride varnish is a risk factor for enamel fluorosis. The varnish is applied with a brush and sets within seconds.
Fluoride varnish has shown to be effective in reducing initial dental decay lesions in both primary and permanent dentition. Application of fluoride varnish every six months is effective in preventing dental decay in primary and permanent teeth of children and adolescents.
=== Slow-release devices ===
Devices that slowly release fluoride can be implanted on the surface of a tooth, typically on the side of a molar where it is not visible and does not interfere with eating. The two main types are copolymer membrane and glass bead. These devices are effective in raising fluoride concentrations and in preventing cavities, but they have problems with retention rates, that is, the devices fall off too often. A 2018 Cochrane review found insufficient evidence to determine the effect of slow-release fluoride glass beads in caries-inhibiting when compared to other types of fluoride therapy.
=== Lozenges ===
Fluoridated lozenges may contain about 1 mg fluoride each, and are meant to be held in the mouth and sucked. The dissolved lozenge is swallowed slowly, so the use of lozenges is both a topical and a systemic therapy. A 1955 study comparing the effects of fluoride lozenges and fluoride pills provided clear evidence early that fluoride acts topically.
=== Medical supplements ===
Medical fluoride supplements in the form of tablets, lozenges, or liquids (including fluoride-vitamin preparations) are used primarily for children in areas without fluoridated drinking water. The evidence supporting the effectiveness of this treatment for primary teeth is weak. The supplements prevent cavities in permanent teeth. A significant side effect is mild to moderate dental fluorosis. A Cochrane review also found no evidence that daily fluoride supplementation in pregnant women was effective in preventing tooth decay or causing fluorosis in their children.
== See also ==
Silver diammine fluoride
== References ==
== Further reading ==
Committee on Fluoride in Drinking Water, National Research Council. (2006). Fluoride in Drinking Water: A Scientific Review of EPA's Standards. National Academies Press.
Government guidelines
Fluoride History – History of fluoride therapy including early patents | Wikipedia/Fluoride_therapy |
The expressive therapies are the use of the creative arts as a form of therapy, including the distinct disciplines expressive arts therapy and the creative arts therapies (art therapy, dance/movement therapy, drama therapy, music therapy, writing therapy, poetry therapy, and psychodrama). The expressive therapies are based on the assumption that people can heal through the various forms of creative expression. Expressive therapists share the belief that through creative expression and the tapping of the imagination, people can examine their body, feelings, emotions, and thought process.
== Definition and credentialing ==
Expressive arts therapy is the practice of using imagery, storytelling, dance, music, drama, poetry, movement, horticulture, dreamwork, and visual arts together, in an integrated way, to foster human growth, development, and healing. Expressive arts therapy is its own distinct therapeutic discipline, an inter-modal discipline where the therapist and client move freely between drawing, dancing, music, drama, and poetry.
According to the National Organization for Arts in Health (NOAH), what distinguishes the six creative arts therapies—art, dance/movement, drama, music and poetry therapy as well as psychodrama—from expressive arts therapy is that expressive arts therapy interventions are designed to include more than one of the "expressive" art forms (art, dance, drama, music, poetry), whereas creative arts therapists, such as art, dance/movement, drama, music, poetry and psychodrama therapists, are often intensively trained and educated to use only one modality in their practice.: 6–7 But NOAH also acknowledged that the terms "are often used interchangeably in the field", and that in any case all such professionals should collaborate closely.: 10, 18, 22
The International Expressive Arts Therapy Association (IEATA) is the responsible organization handling the credentialing of expressive arts therapists.
The National Coalition of Creative Arts Therapies Association (NCCATA) connects all six modalities of the creative arts therapies. However, each modality of the creative arts therapies has its own national association that regulates professional credentials, establishes educational standards and hosts annual conferences for the purpose of exchanging new ideas and research.
== History ==
=== Early years ===
Margaret Naumburg, Edith Kramer, Hanna Kwiatkowska and Elinor Ulman have been credited with being the pioneers of the field of sensory art therapy. While all of these scientists made significant contributions, Margaret Naumburg has been hailed the "Mother of Art Therapy". Her work focused on the use of art, mainly as a psychoanalytic diagnostic tool. It followed closely other psychoanalytic practices of the time, and was viewed as the communication of unconscious ideas and emotions that were being expressed by the patient.
== Modern approaches ==
Today's art therapy is broken down into three different approaches: psychodynamic, humanistic, and learning and developmental. The psychodynamic approach uses terms such as "transference" and defense mechanism to describe why individuals express the art in the way they do, and why this is an expression of the subconscious. The humanistic approach is more of a positive psychology approach, and is defined by an optimistic view of humans, and how expression through their art allows them to take control over these emotions. The learning and developmental approach focuses on the art therapy as a method to assist children who have emotional and developmental disabilities.
== Education ==
Each national association of the different modalities of expressive therapies sets its own educational standards. In the United States, there are a fair number of colleges that offer approved programs in compliance with the national associations' credentialing requirements.
There are 37 universities for music therapy, 34 universities for art therapy, seven universities for dance/movement therapy, and five universities for drama therapy, as well as 5 universities for expressive arts therapy, that have approved master's degree programs in the United States. In addition, the American Music Therapy Association (AMTA) has 75 undergraduate music therapy programs approved. Once finished with an academic degree, potential therapists have to apply for credentialing at the responsible national association.
== Creative arts therapies modalities ==
There are six creative arts therapy modalities, recognized by the NCCATA, including art therapy, dance therapy, drama therapy, music therapy, poetry therapy and psychodrama. In some areas, the terms Creative Arts Therapy and Creative Arts Therapist may only be used by those who are properly licensed, as is the case in the State of New York.
=== Art therapy ===
Created in the 1940s, Art therapy consists of the combination of psychotherapy and art. The creative process as well as the created art piece serves as a foundation for self-exploration, understanding, acceptance and eventually healing and personal growth. The creative act in therapy therefore can be seen as a means of re-experiencing inner conflict connected to resolution. The four main types are expression, imagination, active participation, and mind-body connection. Assisting in those with depression, breast cancer, and asthma, art therapy can be done at any age and does not require and skill set. Art Therapy has undergone extensive research which revealed that it decreases anxiety, increases self-concept and quality of life, and reduces negative thoughts. With two main goals in mind, Art Therapy strives to enhance personal and relational goals for those in need. Self-esteem, social skills, and cognitive functions are also said to be an area of importance. A certified art therapist is essential in order for the therapy to ensure improvement, however common art therapy using even a friend to discuss trauma can be enough to help someone.
=== Dance/movement therapy ===
Like other creative arts therapy modalities, dance/movement therapy is based on the assumption that "mind, body and spirit are inseparable and interconnected" (ADTA). Movement is the primary tool of intervention in a therapy session, but dance/movement therapy also uses the art of play in therapy. Like other creative art therapies it uses primarily nonverbal communication. Dance and movement therapy has shown to be the most beneficial in those who enjoy exercises that involve less talking an expression through movements.
=== Drama therapy ===
Drama therapy refers to the combination of the two disciplines drama/theatre and psychotherapy. Drama Therapy, as a hybrid of both disciplines, uses theater techniques to treat individuals with mental health, cognitive, and developmental disorders. Through the art of play and pretend, patients gain perspective in therapy to their life experiences, which in the field is referred to as "aesthetic distance".
=== Music therapy ===
Music Therapy is the use of music, music-making, or other music-related interventions within a therapeutic relationship. Music therapy is a broad field with many areas and populations to specialize in. A holistic practice, music therapy can address emotional/psychological, cognitive, communication, motor, sensory, pain, social, behavioral, end of life, and even spiritual needs. This is due in part to music being processed in many areas of the brain. Music therapy helps patients "communicate, process difficult experiences, and improve motor or cognitive functioning" (Jenni Rook, MT-BC, LCPC, 2016). When used as psychotherapy, at its core, music therapy may use music as a symbolic representation and expression of the psychological world of the individual.
Townsend's study in the "Journal of Child Psychology and Psychiatry and Allied Disciplines" has shown that 1 in 5 children who lost their parent are most likely to develop a psychiatric disorder. This finding underscored the significance of instructors to initiate writing on the subjects of "death" and "loss" in academic writing. One of the few ways to bring this into practice is through music-making or songwriting.
Songwriting allows individual to process the trauma they experience in their life in three ways: By telling stories that have been passed down to them; by connecting their songs to cultural traditions; and by sharing their feelings with each other and their community. Songwriting is a way to organize a narrative. Through forming a coherent story, an unpleasant or chaotic situation can be made more approachable.
Deroo's research focuses on the Black teenage girl, Noriah, who wrote the song named "Air I Breathe" in remembrance of her passing mother and sister. Through Noriah's story, Deroo tries to find the answer to how can youths tackle the nuanced implications of loss using creative expression. Noriah's experience shows that there can be many therapeutic possibilities with songwriting. By using eulogies in her songs, Noriah is able to communicate her bond with her lost ones through lyrics. As demonstrated with the composition of "Air I Breathe", while the memories of Noriah and her departed would eventually fade, "Air I Breathe" serves as a permanent reminder for Noriah to keep in mind the memories. During a speech in the university classroom, Noriah expressed her purpose in writing the song. “I wrote a song about the loss of my little sister and biological mother, back to back, and so much love I had for them, and what I couldn't get out. It was a way to get out the rest of the feeling that I had—telling that story to you directly, but I could sing it instantly. It was like a form of therapy” (Deroo).
In addition, writing and sharing about lost can benefit the community who then can learn from the experiences that were previously private. As Ryden argues, audiences embrace the story as if they are their own, making meaning of the experience in their own ways. This idea was further demonstrated through the interaction between Noriah and Wendy. Being inspired by Noriah's song, Wendy entered the room with her own experience of loss.
Music Therapy also benefits a variety of disorders, like cardiac and mental disorders. It aids those who suffer from depression, anxiety, autism, substance abuse, and Alzheimer's. In cases where a person is suffering from mental disorders, music relieves stress, improves self-esteem, etc. Evidence has shown that people who have used Music Therapy in the past have improved in several aspects of life that do not concern just those suffering from mental illness. In music therapy, people may improve their singing which may then impact their ability to speak. Therefore, it can change several aspects of life, not just those of helping mental illness.
=== Poetry therapy ===
Poetry therapy (also referred to using the broader term bibliotherapy) stands out from other creative arts therapies, which are all based on the assumption of the existence of a language that functions without words. Poetry therapy, however, is the use of the written word to bring healing and personal growth. For instance, To, The Bravest Person I Know is one of the classic illustrations of how to use poetry to overcome anxiety, depression (mood), and other sorts of insecurity.
In Manning's research about high school poetry classes, he found that through poetry classes, students are able to reimagine their struggles as a source of strength, develop a sense of possibility, and build bonds that empower them to speak through the silence that surrounded their life struggles. Manning advocated the need for opportunities for creative expression in classroom spaces. Not only would this practice encourage youth to express themselves authentically using their own words in an environment where their voice is constrained by school literacy, but it would also contribute to positive changes to the current school environment by honoring students' voices and life experiences.
=== Psychodrama ===
Psychodrama is a distinct form of psychotherapy developed by Jacob L. Moreno in the early 20th century. Moreno, a trained psychiatrist himself, had the goal of creating a more effective, action-based form of psychotherapy. Later it was modified by other authors according to Sigmund Freud and C.G. Jung. He developed a clear three phase structure (warm up, action, sharing) to his therapy as well as multiple intervention-methods that are still used by psychodrama therapists today.
Although related, psychodrama and drama therapy describe different modalities within the field of creative arts therapies. Whereas psychodrama uses real-life experience of the patients in therapy to "practice new and more effective roles and behaviors" (ASGPP), drama therapy lets the patients explore more fictional stories, such as improvised scenes, myths or fairy tales.
== Benefits ==
=== Self-discovery ===
This discovery often leads to a relief of emotional tension caused by past events, and can be used as a coping mechanism.
Given the ability to claim your own story, which helps with personal affirmation.
=== Empowerment ===
Expressive therapy gives individuals the ability to articulate their fears and stresses in a non-conventional way, and often leads to sense of control over these emotions.
Particularly beneficial for vulnerable populations such as youth experiencing homelessness, as it helps them process trauma, regulate emotions, and rebuild a sense of identity and self-worth.
=== Stress relief ===
Effective for stress relief by itself, but can provide even better results if paired with other relaxation devices such as guided imagery.
Expressive therapy provides individuals with a foundation on which they can recognize and confront pain.
=== Physical pain relief and rehabilitation ===
Expressive therapy has been shown to help decrease pain in patients who are recovering from illness and injury. It has also been used in patients who are chronically or terminally ill, to provide relief and pain control.
== Empirical evidence ==
=== Ball (2002) ===
Ball conducted long-term research on five children who were considered to be severely emotionally disturbed. These children participated in 50 art therapy sessions, and the results suggested that the art therapy was successful, and the children showed marked progress in their treatment over the course of the 50 sessions.
=== Pifalo (2006) ===
In this study, 41 girls or young women who had been sexually abused were given structured group art therapy for eight weeks, and were measured before treatment using the Briere's Trauma Symptom Checklist for Children (TSCC). They were given the test again after the treatment, and for 9 out of 10 of the girls, a statistically significant reduction in scores on the test was observed.
=== Bar-Sela, Atid, Danos, Gabay & Epelbaum (2007) ===
This study worked with 60 adults who had cancer. These adults attended weekly individual art therapy, in addition to watercolor painting classes. After just four sessions, the experimental group saw marked and significant improvement in depression and fatigue, as measured by the Hospital Anxiety and Depression Scale and a brief fatigue inventory. While they showed a decrease in depression, there was no significant difference in the levels of anxiety of the patients.
=== Gusak (2006) ===
In this study, the researcher worked with 29 incarcerated men. The men attended eight sessions of group art therapy, and were tested before and after the treatment using the Beck Depression Inventory Short Form. After the eight sessions, all of the men showed significant improvement in the symptoms of depression and their score on the Beck Depression Inventory reflected these improvements.
=== Bulfone et al. (2009) ===
In this study Bulfone et al. utilized music therapy as their treatment. 60 women who had been diagnosed with stage 1 or 2 breast cancer were randomly assigned to a control or experimental group. The control group received standard assistance before chemotherapy, while the experimental group had the chance to listen to music before the chemotherapy began. The results showed that the anxiety levels of the experimental group were significantly lower than those of the control group, and also showed a significantly lower level of depression.
== Applications ==
=== Expressive writing therapy in virtual setting (2024) ===
Virtual settings have expanded the reach of expressive writing therapy. A study on intimate partner violence (IPV) survivors demonstrated that online writing sessions in a structured environment significantly reduced trauma symptoms, providing a safe and accessible space for emotional processing.
== See also ==
Cinema therapy
Clinical psychology
Counseling psychology
Expressive therapies continuum
Freedom of speech
Psychotherapy
== References ==
== External links ==
International Expressive Arts Therapy Association (Worldwide)
National Coalition of Creative Arts Therapies Associations (United States)
American Art Therapy Association
American Dance Therapy Association Archived 2020-02-10 at the Wayback Machine
North American Drama Therapy Association
American Music Therapy Association
National Association for Poetry Therapy
American Society for Group Psychotherapy and Psychodrama
Expressive Arts Therapy Association of Hong Kong (Hong Kong and Mainland China) | Wikipedia/Sensory_art_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/Hormone_replacement_therapy |
Comic book therapy is a form of art therapy in which those undergoing rehabilitation or those who have already completed rehabilitation express their experiences through personal narratives within a comics format. The combination of text and image enables patients to process their memories and emotions through two different, yet compatible mediums. Comic book therapy can also be used in a psychotherapeutic setting, whereby clients are encouraged to read specific comic books, often surrounding topics similar to their own diagnoses. Clients are encouraged to present their thoughts and feelings they experienced while reading as well as to draw parallels with their own lived experiences based on the events that occur within the books. This is done in an effort to reach a cathartic moment of clarity and understanding of one's own life.
Both forms of therapy can be used throughout a patient's treatment process: immediately after diagnosis, throughout rehabilitation, and during the events that follow, including readjustment and general coping.
Comic book therapy is currently being applied to a variety of populations, including patients diagnosed with life-altering diagnoses (i.e. cancer, Dementia, Parkinson's Disease, diabetes, etc.), patients and family members experiencing severe illness or death, families undergoing therapy, sexual assault survivors, and soldiers returning from war. One such therapy, originally conceptualized by Captain Russel Shilling, is currently being developed by The United States Defense Advanced Research Projects Agency (DARPA).
== Comic book therapy and graphic medicine ==
Graphic medicine, originally coined by Ian Williams, is a literary genre that combines the medium of comics and the discourse of medicine. Within the last ten years, graphic stories, which are also referred to as adult themed comics, have slowly become a rising pop-culture trend. It owes its success in part to the rise of medical humanities, an interdisciplinary study of medicine and healthcare related topics. While medical humanities incorporate a variety of language-based subjects (i.e. philosophy, ethics, religion, etc.), graphic medicine strives to analyze the same healthcare-related topics using an artistic lens. The genre combines the conventionality of text with the eccentricity of images to present intimate narratives related to healthcare or medical experiences. These narratives are also sometimes referred to as "graphic pathologies", as they commonly discuss diagnoses of injury, illness, or disease.
Current professionals within the field are striving to develop a collection of novels that can act not only as a therapeutic tool for patients and their loved ones, but that serve as an educational tool for medical students as well.
The general concepts of graphic medicine and comic book therapy are often used interchangeably as they both strive to develop healthcare-related stories using both text and graphics. There is however a distinction that should be made. Graphic medicine acts as an umbrella term that encompasses a host of therapeutic techniques. Therefore, comic book therapy comfortably fits under its heading as just one of many therapies that the field of graphic medicine investigates.
== History ==
The foundations of the comics industry began in the early 1920s just after the culmination of the First World War. Initially starting out as small black-and-white strips, comics predominantly acted as entertaining filler space within national and local magazines and newspapers around the country. It was not until 1929 with the publication of The Funnies #1 that the first collection of comics material came about. The years following witnessed a spurt of comics publication that lasted up until present day with children and adults alike still knowing names like Batman, Superman, Peanuts, and Calvin and Hobbes.
Professionals within the graphic medicine field trace the history of comics back further than the early 1920s, however. Instead, they claim the origin of their academic field can be traced back to prehistoric cave drawings and man's desire to express himself with pictures. In this light, professors of graphic medicine and clinicians of comic book therapy include Egyptian hieroglyphics, Mayan and Aztecs drawings, and the great art of the Greeks, the Persians, and the Romans within the history of comic books as well. They do, of course, begin the story of comics specifically in 1938 with the publication of Action Comics #1, the first to detail the adventures and heroic efforts of Superman. The development of radio, television, and film only heightened the popularity of comic books and comic book characters; and by 1980, the merchandising of comic books hit an all-time peak. Today, comic books have slowly begun to matriculate within select topics of academia, now regarded as significant contributions to literary expression, covering topics of medicine, politics, economy, and social change.
== Current uses ==
Since its beginning, graphic medicine as a field of study has steadily become more relevant. As such, the use of comic book therapy as well as its functions have expanded as well. Today, comic books and graphic novels alike are being implemented in a variety of clinical and educational settings, likely due to its efforts in serving a variety of needs for a diverse target audience. Comic book therapies can serve multiple purposes. Some authors hope to relay information, creating a graphic encyclopedia of sorts. Therapists often collaborate with patients in comic book therapy to develop a closer relationship based on the tenets of empathy and understanding. Patients, more often than not, are encouraged to process difficult emotions and memories in the attempt to process, readjust, and engage in healthier coping strategies. Because of its multiple functions, graphic medicine and comic book therapy have been implemented both therapeutically and educationally in the medical field.
=== Therapeutic tool ===
==== Creating a comic book ====
One form of comic book therapy involves the creation of a comic strip, a comic book, or a graphic novel. The process by which a patient, family member, caregiver, or practitioner creates a comic book is complex and involves extensive research. In essence, the process of developing a comic book serves as a therapeutic coping mechanism that goes beyond text-based storytelling. Instead, patients are pushed to think through multiple media. The process can sometimes, hopefully frequently, lead to significant cognitive and emotion breakthroughs. These effects are likely due to the sheer versatility of the comic book medium, as they allow for the simultaneous expression of body image, verbal expression, physical action, and emotion.
Therapists often encourage patients to develop characters first, as this first step situates the patient in relation to their environment, past and present. Most often, the characters of comic book therapy novels imitate those within the author's own life, developing an autobiography of sorts. Occasionally, their experiences are identical to those of reality; often, an author chooses to reshape the narrative altogether, providing the reader an augmented reality of some kind. Patients take this opportunity to rewrite their story, making choices they didn't or couldn't during their own experiences. The comic book aspect acts as a safe avenue of release, in which a patient can comfortably create a world in which the consequences of actions are limited to panels in which they develop.
==== Reading a comic book ====
Another form of comic book therapy encourages patients, their support systems, and their healthcare providers to read already published graphic novels and comic books. As the field of graphic medicine has grown, so too have the collection of comic books and novels. As such, current graphic novels and comic books cover a wide range of topics, including cancer, Parkinson's disease, Schizophrenia, Alzheimer's disease, eating disorders, and so on. Popular novels include Cancer Vixen: a True Story by Marisa Acocella Marchetto, Tangles: A Story About Alzheimer's, My Mother, and Me by Sarah Leavitt, and Marbles: Mania, Depression, Michelangelo and Me by Ellen Forney. Therapists recommend novels that discuss similar experiences, similar diagnoses, similar personal histories to those of their own patients. Patients are encouraged to read them critically in the efforts of finding some kind of parallel between their own experiences and those described within the panels. This method of therapy goes beyond just reading a recommended autobiography. The images and graphics within each panel add to the narrative, bridging a gap between words and meaning. The way in which an author chooses to depict their characters, the environment, and the text are all important and contribute largely the reading experience.
==== Group therapy ====
Comic books have often been used as a source of therapy by providing the reader a way to associate themselves with the characters. The readers then can draw correlations between their own struggles parallel to the characters. In recent years this has been especially helpful, as comic books have continued to grow more inclusive to portray age, race, sex, and sexual orientation.
The way comic books are utilized in counseling is to provide the reader with self-awareness, thus a connection to their self through characters they identify with. According to Lauren Calhoun, this type of therapy is implemented by individual therapy, group therapy, and bibliotherapy.
The group approach is a newer take on comic book therapy and provides a way for clients to explore their values and beliefs. A study done with a group of 18-year-olds provided insight on how each one of them studied themselves through the lens of a shared character. After the session they were each asked to create their own comic book, and the results showed that each individual had found a way to empower themselves through the experience. Using comic books as a tool for therapy, especially in group settings is a potentially rich resource that should be further explored.
=== Educational tool ===
Current professionals within the field are striving to develop a field of study that can act not only as a therapeutic tool for patients and healthcare providers alike, but that can serve as an educational tool for medical students as well. With the advancement of technology and the diversification of the patient population, medical practices have undergone significant change within the last century. On the other hand, the education process prior to medical practice has remained arguably stagnant. Present day medical school programs cover material in three broad categories, including the scientific basis of medicine, patient care, and physicianship. The methods of teaching vary across universities, but the basic curricula remain the same across the board. With the evolution of medical practice arriving so quickly, some argue that medical training should follow in suit. According to the scholars of Graphic Medicine, there are multiple parallels between comic book therapy, when used as educational tool, and the everyday practice of medicine. In this way, having medical students engage in comic book therapy during their medical training could prove significant later on. The hustle and bustle of medical practice can prove stressful, especially for a new doctor fresh out of medical school. In order to prove oneself within the medical field, many believe an individual must possess characteristics like 'competency', 'professionalism', and 'brilliance'; rarely are physicians referred to as 'artistically creative' or 'creative' at all.
== See also ==
Graphic medicine
Art therapy
Psychotherapy
Bibliotherapy
Expressive therapy
== References == | Wikipedia/Comic_book_therapy |
Dehydration can occur as a result of diarrhea, vomiting, water scarcity, physical activity, and alcohol consumption. Management of dehydration (or rehydration) seeks to reverse dehydration by replenishing the lost water and electrolytes. Water and electrolytes can be given through a number of routes, including oral, intravenous, and rectal.
== In diarrhea ==
When diarrhea occurs, hydration should increase to prevent dehydration.
The WHO recommends using the oral rehydration solution (ORS) if available, but homemade solutions such as salted rice water, salted yogurt drinks, vegetable and chicken soups with salt can also be given. The goal is to provide both water and salt: drinks can be mixed with half a teaspoon to full teaspoon of salt (from one-and-a-half to three grams) added per liter. Clean plain water can also be one of several fluids given.
ORS is mass-produced as commercial solutions such as Pedialyte, and relief agencies such as UNICEF widely distribute packets of pre-mixed salts and sugar. The World Health Organization (WHO) describes a homemade ORS with one liter water with one teaspoon salt (or 3 grams) and six teaspoons sugar (or 18 grams) added (approximately the "taste of tears"). However, the WHO does not generally recommend homemade solutions as how to make them is easily forgotten. Rehydration Project recommends adding the same amount of sugar but only one-half a teaspoon of salt, stating that this more dilute approach is less risky with very little loss of effectiveness. Both agree that drinks with too much sugar or salt can make dehydration worse.
=== Medium dehydration ===
In what the World Health Organization (WHO) terms "some dehydration," the child or adult is restless and irritable, is thirsty, and will drink eagerly.
WHO recommends that if there is vomiting, don't stop, but do pause for 5–10 minutes and then restart at a slower pace. (Vomiting seldom prevents successful rehydration since most of the fluid is still absorbed. Plus, vomiting usually stops after the first one to four hours of rehydration.) With the older WHO solution, also give some clean water during rehydration. With the newer reduced-osmolarity, more dilute solution, this is not necessary.
Begin to offer food after the initial four-hour rehydration period with children and adults. With infants, continue to breastfeed even during rehydration as long as the infant will breastfeed. Begin zinc supplementation after initial four-hour rehydration to reduce severity and duration of episode. If available, zinc supplementation should be continued for 10 to 14 days. During the initial period of rehydration, the patient should be re-assessed at least every four hours.
The family should be provided with at least two days worth of ORS packets. WHO recommends, in addition to infants continued to be breastfed, that children older than six months be given some food before being sent home, which helps to emphasize to parents the importance of continuing to feed the child during diarrhea.
=== Severe dehydration ===
In severe dehydration, the person may be lethargic or unconscious, drinks poorly, or may not be able to drink.
In malnourished persons, rehydration should be performed relatively slowly by drinking or by nasogastric tube unless the person is also experiencing shock, in which case it should be performed quicker. Malnourished patients should receive a modified ORS which has less sodium, more potassium, and modestly more sugar. For patients not malnourished, rehydration should be performed relatively rapidly by means of intravenous (IV) solution. For infants under one year of age, WHO recommends giving, within the first hour, 30 milliliters of Ringer's Lactate Solution for each kilogram of body weight, and then, within the next five hours, 70 milliliters of Ringer's Lactate per kilogram of body weight. For children over one year and for adults, WHO recommends, within the first half hour, 30 milliliters of Ringer's Lactate per kilogram of body weight, and then, within the next two-and-a-half hours, 70 milliliters per kilogram. For example, if a child weighs fifteen kilograms (who is obviously over one year of age), he or she should receive 450 ml of Ringer's Lactate Solution within the first half hour, and then 1,050 ml of Ringer's Lactate within the next two-and-a-half hours. Patients who can drink, even poorly, should be given Oral Rehydration Solution (ORS) by mouth until the IV drip is running. In addition, all patients should start to receive some ORS when they are able to drink without difficulty, which is usually three to four hours for infants and one to two hours for older persons. ORS provides additional base and potassium which may not be adequately supplied by IV fluid. Ideally, patients should be reassessed every fifteen to thirty minutes until a strong radial pulse is present, and thereafter, assessed at least hourly to confirm that hydration is improving. Hopefully, patients will graduate to the medium dehydration or "some" dehydration category and receive continued treatment as above.
Inadequate replacement of potassium losses during diarrhea can lead to potassium depletion and hypokalaemia (low serum potassium) especially in children with malnutrition. This can potentially cause muscle weakness, impaired kidney function, and cardiac arrhythmia. Hypokalaemia is worsened when base is given to treat acidosis without simultaneously providing potassium, as happens in standard IVs including Ringer's Lactate Solution. ORS can help correct potassium deficit, as can giving foods rich in potassium during diarrhea and after it has stopped.
As in above sections, for all patients, supplemental zinc can help to reduce the severity and duration of diarrhea. In addition, supplemental vitamin A is often recommended, particular for children who have diarrhea during or shortly after measles, or in children who are already malnourished, although ideally for all patients.
=== In children ===
WHO recommends a child with diarrhea continue to be fed. Continued feeding speeds the recovery of normal intestinal function. In contrast, children whose food is restricted, have diarrhea of longer duration and recover intestinal function more slowly. A child should also continue to be breastfed. And in the example of the treatment of cholera, CDC also recommends that persons continue to eat and children continue to be breastfed.
If IV treatment is not available at the facility, WHO recommends sending the child to a nearby facility if it can be reached within 30 minutes and providing the mother with ORS to administer to the child during the trip. If another facility is not available, ORS can be given by mouth as the child can drink and/or by nasogastric tube.
WHO states that knowing the levels of serum electrolytes rarely changes the recommended treatment of children with diarrhea and dehydration, and furthermore, that these values are often misinterpreted. Most electrolyte imbalances are adequately treated by ORS. For example, a child who has been given an excess of sugar or salt like that which is in commercial soft drinks, sugared fruit drinks, or over-concentrated infant formula, may develop hypernatraemic dehydration. This occurs when these over-concentrated solutions sit in the gut and draw water from the rest of the body, and the reduced fluids in the body's tissues then have a higher proportion of salt to fluid. Children with serum sodium greater 150 mmol/liter have thirst out of proportion to other signs of dehydration. There is a danger of convulsions which usually occur when serum sodium concentrations are greater than 165 mmol/liter. Less commonly, convulsions can also occur when serum sodium is less than 130 mmol/liter. Treatment with ORS can usually bring serum sodium concentrations back to normal within twenty-four hours.
Children with diarrhea who drink mostly water or overly dilute drinks with too little salt may develop hyponatraemia (serum sodium less than 130 mmol/liter). This is especially common in children with shigellosis and in severely malnourished children with edema. ORS is safe and effective for nearly all children with hyponatraemia, an exception being children with edema for whom ORS provides too much sodium.
== Contraindications ==
Drinks especially high in simple sugars, such as soft drinks and fruit juices, are not recommended as the main source of hydration, or for children under 5 years of age as they may increase diarrhea. Plain water may be used if more specific and effective ORT preparations of hydrational fluids are unavailable or are not palatable. A nasogastric tube can be used in young children to administer fluids if warranted.
== Preparation ==
Appropriate amounts of supplemental zinc and potassium should be added if available. But the availability of these should not delay rehydration. As WHO points out, the most important thing is to begin preventing dehydration as early as possible. In another example of prompt ORS hopefully preventing dehydration, CDC recommends for the treatment of cholera continuing to give Oral Rehydration Solution during travel to medical treatment.
The approximate amount of oral rehydration solution (ORS) to be given over four hours can be obtained by multiplying 75 milliliters of solution by the child's weight in kilograms. For example, a child who weighs 15 kilograms should be given approximately 1,125 ml of ORS over four hours. Of course, the exact amount depends on how dehydrated the child is. And in general, let the person drink as much as they wish. The person can drink a little faster at first and then relatively slowly. For babies, a dropper or syringe without the needle may be used. Toddlers under two should be offered a teaspoonful every 1–2 minutes. Older children and adults may take frequent sips.
== Procedure ==
Vomiting often occurs during the first hour or two of treatment with ORS, especially if a child drinks the solution too quickly, but this seldom prevents successful rehydration since most of the fluid is still absorbed. WHO recommends that if a child vomits, to wait five or ten minutes and then start to give the solution again more slowly.
== References == | Wikipedia/Rehydration_therapy |
Journal therapy is a writing therapy focusing on the writer's internal experiences, thoughts and feelings. This kind of therapy uses reflective writing enabling the writer to gain mental and emotional clarity, validate experiences and come to a deeper understanding of themself. Journal therapy can also be used to express difficult material or access previously inaccessible materials.
Like other forms of therapy, journal therapy can be used to heal a writer's emotional or physical problems or work through a trauma, such as an illness, addiction, or relationship problems, among others. Journal therapy can supplement an on-going therapy, or can take place in group therapy or self-directed therapy.
== Brief history ==
Ira Progoff created the intensive journal writing program in 1966 in New York. The intensive journal method is a structured way of writing about nature that allows the writer to achieve spiritual and personal growth. This method consists of a three-ring, loose-leaf binder with four color-coded sections: lifetime dimension, dialogue dimension, depth dimension and meaning dimension. These sections are divided into several subsections. Some of these subsections include topics like career, dreams, body and health, interests, events and meaning in life. Progoff created the intensive journal so that working in one part of the journal would in turn stimulate one to work on another part of the journal, leading to different viewpoints, awareness and connections between subjects. The intensive journal method began with recording the session in a daily log.
The field of journal therapy reached a wider audience in the 1970s with the publication of three books, namely, Progoff's At a Journal Workshop (1978), Christina Baldwin's One to One: Self-Understanding Through Journal Writing (1977) and Tristine Rainer's The New Diary (1978).
In 1985, psychotherapist and journal therapy pioneer, Kathleen Adams, started providing journal workshops, designed as a self-discovery process.
In the 1990s, James W. Pennebaker published multiple studies which affirmed that writing about emotional problems or traumas led to both physical and mental health benefits. These studies drew more attention to the benefits of writing as a therapy.
In the 2000s, journal therapy workshops were conducted at the Progoff's Dialogue House, Adams' Center for Journal Therapy and certificates were given through educational institutions. Generally, journal therapists obtain an advanced degree in psychology, counseling, social work, or another field and then enter a credentialing program or independent-study program.
== Effects ==
Journal therapy is a form of expressive therapy used to help writers better understand life's issues and how they can cope with these issues or fix them. The benefits of expressive writing include long-term health benefits such as better self-reported physical and emotional health, improved immune system, liver and lung functioning, improved memory, reduced blood pressure, fewer days in hospital, fewer stress-related doctor visits, improved mood and greater psychological well-being. Other therapeutic effects of journal therapy include the expression of feelings, which can lead to greater self-awareness and acceptance and can in turn allow the writer to create a relationship with his or herself. The short-term effects of expressive writing include increased distress and psychological arousal.
== Practice ==
Many psychotherapists incorporate journal "homework" in their therapy but few specialize in journal therapy. Journal therapy often begins with the client writing a paragraph or two at the beginning of a session. These paragraphs would reflect how the client is feeling or what is happening in his or her life and would set the direction of the session. Journal therapy then works to guide the client through different writing exercises. Subsequently, the therapist and the client then discuss the information revealed in the journal. In this method, the therapist often assigns journal "homework" that is to be completed by the next session. Journal therapy can also be provided to groups.
== Techniques ==
Journal therapy consists of many techniques or writing exercises. In all journal therapy techniques, the writer is encouraged to date everything, write quickly, keep writings and always tell the complete truth. Some of the journal therapy techniques are as follows:
Sprint
Catharsis is encouraged by allowing a writer to write about anything for a designated period, such as for five minutes or for ten minutes.
Lists
The writer writes any number of connected items in order to help prioritize and organize.
Captured moments
Writer attempts to completely describe the essence and emotional experience of a memory.
Unsent letters
This attempts to silence a writer's internal censor; it can be used in a grieving process or to get over traumas, such as sexual abuse.
Dialogue
The writer creates both sides to a conversation involving anything, including but not limited to, people, the body, events, situations, time etc.
Feedback
Important to journal therapy as feedback makes the writer be aware of his or her feelings; it also allows the writer to acknowledge, accept and reflect on what they he/she has written before (thoughts, feelings, etc.).
== Setting ==
A quiet and private environment must be created and provided throughout the entire journal writing process. This environment should contain features or elements that can make the writer feel good such as music, candles, a hot drink etc. This environment works to empower the writer and to associate good feelings with journal writing. To transition into writing, a journal writing session can be started with a drawing or sketch. After journal writing, something active should be done, such as running, walking, stretching, breathing etc. or something that is enjoyable like taking a bubble bath, baking cookies, listening to music, talking to someone, etc.
== Notes ==
== Further reading == | Wikipedia/Journal_therapy |
Therapy is the attempted remediation of a health problem.
Therapy may also refer to:
Psychotherapy
== Music ==
Therapy?, a rock band from Northern Ireland
=== Albums ===
Therapy (Anne-Marie album) or the title song, 2021
Therapy (James Whild Lea album), 2007
Therapy (Loudon Wainwright III album) or the title song, 1989
Therapy (MiChi album) or the title song, 2012
Therapy (Diatribe EP) or the title song, 1991
Therapy (Tech N9ne EP), 2013
Therapy (Zoe Wees album), 2023
=== Songs ===
"Therapy" (Armin van Buuren song), 2018
"Therapy" (The Damned song), 1980
"Therapy" (T-Pain song), 2008
"Therapy" (Mary J. Blige song), 2014
"Therapy" (Budjerah song), 2023
"Therapy", by the Alchemist from Chemical Warfare, 2009
"Therapy", by All Time Low from Nothing Personal, 2009
"Therapy", by Axium from Blindsided, 2003
"Therapy", by Brooke Fraser, 2016
"Therapy", by Conro, 2020
"Therapy", by Duke Dumont, 2020
"Therapy", by Heltah Skeltah from Nocturnal, 1996
"Therapy", by India.Arie from Testimony: Vol. 2, Love & Politics, 2009
"Therapy", by Infectious Grooves from The Plague That Makes Your Booty Move... It's the Infectious Grooves, 1991
"Therapy", by Khalid from American Teen, 2017
"Therapy", by Kim Cesarion, 2016
"Therapy", by Maisie Peters from The Good Witch, 2023
"Therapy", by Relient K from Forget and Not Slow Down, 2009
== Literature ==
Therapy (Fitzek novel), a 2006 novel by Sebastian Fitzek
Therapy (Kellerman novel), a 2004 novel by Jonathan Kellerman
Therapy (Lodge novel), a 1995 novel by David Lodge
Therapy (journal), now Clinical Practice, a medical journal
== Other uses ==
Therapy (New York City), a gay bar and nightclub in Manhattan
Therapy (film), a 2021 Cameroonian film
"Therapy" (Roseanne), a 1992 television episode
== See also ==
List of therapies
List of psychotherapies | Wikipedia/Therapy_(disambiguation) |
Bridge therapy is therapy intended, in transportation metaphor, to serve as a figurative bridge to another stage of therapy or health, helping a patient past a challenging period caused by particular severe illness. There are various types of bridge therapy, such as bridge to transplant, bridge to candidacy, bridge to decision, bridge to recovery, and anticoagulation bridge (such as heparin bridge). Bridge therapy exists in contrast to destination therapy, which is the figurative destination rather than a bridge to something else.
Bridge to transplant: Such therapy can provide an opportunity for optimization of their clinical condition to successfully reach organ transplant, still being eligible for transplant after spending time waiting for an organ to become available. In patients with decompensated end-stage heart failure it can provide hemodynamic stabilization and potential end-organ function recovery allowing "bridging" to transplantation. For example, a left ventricular assist device (LVAD) often serves as a bridge to heart transplant, locoregional therapy (such as radiofrequency ablation) for hepatocellular carcinoma can serve as a bridge to liver transplant, and extracorporeal membrane oxygenation (ECMO) or lung volume reduction surgery (LVRS) can serve as a bridge to lung transplant.
Bridge to candidacy: A patient was too critically ill to be a candidate for a certain therapy or transplantation, but the bridge therapy can carry them to a state of being eligible for transplantation; for example, ECMO as a bridge to nontransplant cardiac surgery.
Bridge to decision: A decision will soon be made about what to do next (that is, which definitive therapy will come soon), but first the patient needs a bridge to support them until that decision; for example, short-term mechanical circulatory support as a bridge to durable left ventricular assist device implant in refractory cardiogenic shock.
Bridge to recovery: A recovery is likely, but first support is needed to carry someone through a tough time; for example, ECMO in methamphetamine toxicity, which can be viewed as both rescue therapy and bridge to recovery.
Anticoagulation bridge: Temporary anticoagulation, such as with heparin, is used during a perioperative period when a patient's regular anticoagulant therapy, such as with warfarin, is suspended; the goal is to prevent excess risk of severe bleeding during or after surgery. The heparin bridge provides some anticoagulant effect (to prevent thrombosis from warfarin withdrawal) but not as much as would make severe bleeding likely.
A related concept is linkage to care, which is a bridge to therapy, such as when community screening events (for conditions such as high blood pressure or high blood sugar) find new cases of hypertension or diabetes; recipients are helped to find appropriate care (for example, some have not been to a doctor for many years and can use help finding a new doctor).
== References == | Wikipedia/Bridge_therapy |
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