Teething
Encyclopedia
Teething is the process by which an infant
's first teeth (the deciduous teeth
, often called "baby teeth" or "milk teeth") sequentially appear by emerging through the gums. Teething may start as early as three months or as late, in some cases, as twelve months. The typical time frame for the first teeth to appear is somewhere between six and nine months. It can take up to several years for all 20 teeth to complete the tooth eruption
; they typically arrive in pairs. Though the process of teething is sometimes referred to as "cutting teeth", when teeth emerge through the gums they do not cut through the flesh. Instead, special chemicals are released within the body that cause some cells in the gums to die and separate, allowing the teeth to come through.
It is a widespread misconception that teething causes fever
. Teething may cause a slightly elevated temperature, but not rising into the febrile range (above 100-101F, or above 38-38.2C). Higher temperatures during teething are due to some form of infection, such as a herpes virus, initial infection of which is extremely widespread among children of teething age.
Ironically, whilst teething is a natural process which creates little more than discomfort, some methods for relieving teething pain have caused serious harm and even death. Old remedies for teething include "blistering, bleeding, placing leeches on the gums, and applying cautery to the back of the head". In the sixteenth century the French surgeon Ambroise Paré
introduced the lancing of gums using a lancet, in the belief that teeth were failing to emerge from the gums due to lack of a pathway, and that this failure was a cause of death. This belief and practice persisted for centuries, with some exceptions, until towards the end of the nineteenth century lancing became increasingly controversial and was then abandoned, although as late as 1938 an Anglo-American dental textbook advised in favour of lancing, and described the procedure. In the first half of the twentieth century, teething powders in the English-speaking world often contained calomel, a form of mercury. It was removed from most powders in 1954 when it was shown to cause "pink disease" (acrodynia), a form of mercury poisoning
.
Teething toys have a long history. In England in the 17th–19th centuries, a coral meant a teething toy made of coral, ivory or bone, often mounted in silver as the handle of a rattle. A museum curator has suggested that these substances were used as "sympathetic magic" and that the animal bone could symbolize animal strength to help the child cope with pain.
Milk teeth
tend to emerge sooner in females than in males. The exact pattern and initial starting times of teething appear to be hereditary. When and how teeth appear in an infant has no bearing on the health of the child.
of the gums
before a tooth comes through is the cause for the pain and fussiness a baby experiences during this change. These symptoms usually begin about three to five days before the tooth shows, and they disappear as soon as the tooth breaks the skin. Some babies are not even bothered by teething.
Common symptoms include drooling
or dribbling, mood changes and feelings of irritability or crankiness and swollen gums. Crying, sleeplessness
, restless sleep at night, and mild fever are also associated with teething. Teething can begin as early as 3 months and continue until a child's third birthday. In rare cases, an area can be filled with fluid and appears over where a tooth is erupting and cause the gums to be even more sensitive. Pain is often associated more with large molars since they cannot penetrate through the gums as easily as the other teeth.
Some of the signs or symptoms that a baby has entered the teething stage will be actions that are noticeable. They may chew on their fingers or toys to help relieve pressure on their gums. Babies might refuse to eat or drink due to the pain. Symptoms will generally fade on their own, but a doctor should be notified if they worsen or are persistent. Teething may cause signs and symptoms in the mouth and gums, but it doesn't cause problems elsewhere in the body.
Pulling on the ears is another sign of pain; the pain in the mouth throbs throughout the baby's head so they pull their ears believing that it will provide relief. Mild rash
can develop around the mouth due to skin irritation that is caused because of excessive drooling or dribbling.
There is a risk that fever around the age of teething is dismissed as due to teething when it is actually due to illness, particularly infection by herpes viruses. "Coincidentally, primary tooth eruption begins at about the time that infants are losing maternal antibody protection against the herpes virus. Also, reports on teething difficulties have recorded symptoms which are remarkably consistent with primary oral herpetic infection such as fever, irritability, sleeplessness, and difficulty with eating." "Younger infants with higher residual levels of antibodies would experience milder infections and these would be more likely to go unrecognized or be dismissed as teething difficulty." Herpes virus infection may take the form of primary herpetic gingivostomatitis (HSV-1) or of infection by human herpesvirus 6, which infects 90% of children by age 2. "The symptoms of elevated temperature and facial rash could be explainable by infection with the Human Herpes Virus 6 (HHV-6) agent, which is ubiquitous among infants of teething age." Other viruses may also cause fevers which may be misattributed to teething, but the oral involvement that may occur with herpes viruses makes misdiagnosis a particular risk for such infections.
before treatment is administered.
A teething ring is generally a soft plastic device that can be chewed on and allows the baby to break down some of the gum tissue which promotes the growth of the teeth out of the gum. Some teething rings can easily be broken or damaged, so other types of teething devices can be made from household items. Placing a wet washcloth in the freezer for a few minutes and then applying it gently to the gums can be effective, but care must be taken not to expose a baby's gums to coldness for too long.
Infants chew on objects to aid in the teething process. This can be dangerous if the baby is allowed to chew on objects which are small enough to be swallowed or which could break while being chewed and cause choking
. Teething rings and other toys, called teether
s, are often designed with textures that will appeal to an infant during teething. Drawing water into a pacifier and freezing it as another way to offer a teething child relief. The cold pressure on the gums gives relief without making the child’s fingers cold.
Some infants gain relief from chewing on cold objects. Some children respond well to chilled foods. Suggestions for chilled foods that might appeal to a baby include applesauce, yogurt, and pureed fruits.
Dentist
s recommend brushing infants' teeth as soon as they appear. It is not advisable to wait for the teething process to be complete. Dentists may recommend against the use of fluoride toothpaste
during teething.
Not all parents are comfortable with the idea of using medications, and the U.S. Food and Drug Administration
advises against it because of the risk of methemoglobinemia
http://www.fda.gov/Drugs/DrugSafety/ucm250024.htm. Instead to treat the pain, parents should use teething rings and gum massage.
, lidocaine
, or choline salicylate. Benzocaine must be used cautiously because it can cause methemoglobinemia
; choline salicylate is related to aspirin
and "may cause Reye's syndrome
in susceptible children, especially those with or recovering from viral infections, or when used in combination with other NSAIDs". 5% lidocaine gel produces anaesthesia (numbing) within 2-5 minutes, lasting for 10-20 minutes. However, one author concludes that "Overall, the risks and adverse effects from inappropriate or prolonged use of pharmacological agents outweigh their potential benefits." She points out that "the psychological trauma involved in administering medications or applying topical preparations to infants must be considered", and argues that "the placebo effect must not be overlooked. For example, applying a gel of 20% benzocaine in polyethelene glycol may give only a modest benefit over applying the placebo, which gives an efficacy of 60% compared with 90% for the active preparation."
Medicines are often applied to the babies' gums to relieve swelling and pain. These gels are similar to the toothache gel that is used by adults for sore gums and toothaches, but is administered in much smaller doses. Teething gels work as a numbing agent to dull the nerves in the gums so that the pain is less noticeable. It is important to follow the directions on the package to ensure that the correct amount of medication is administered and that proper techniques are used to reduce the risk for infection. It is important not to let the medicine numb the throat as it may interfere with the normal gag reflex and may make it possible for food to enter the lungs. Similar medicines are also available in powder form, as "teething powder".
Acetaminophen
and ibuprofen
are also recommended to treat the pain and swelling that babies experience, but should not be administered to babies under six months of age. It should only be used a few times a day so that it does not mask symptoms that are being experienced due to other medical conditions and not because of teething. Products that contain aspirin
should never be given to a child unless directed by a pediatrician, due to the risk of Reye's syndrome
.
Some traditional medicine used to treat teething pain has been found to be harmful due high lead content, with effects including toxic encephalopathy
. "Surma" or "kohl
" has traditionally been used in the Middle East and Indian subcontinent as a teething powder, as have the Middle Eastern "saoott"/"cebagin". "Santrinj" - a 98% lead oxide
product otherwise used as a paint primer - is also used in the Middle East as a home remedy for teething.
Infant
A newborn or baby is the very young offspring of a human or other mammal. A newborn is an infant who is within hours, days, or up to a few weeks from birth. In medical contexts, newborn or neonate refers to an infant in the first 28 days after birth...
's first teeth (the deciduous teeth
Deciduous teeth
Deciduous teeth, otherwise known as reborner teeth, baby teeth, temporary teeth and primary teeth, are the first set of teeth in the growth development of humans and many other mammals. In some Asian countries they are referred to as fall teeth as they will eventually fall out, while in almost all...
, often called "baby teeth" or "milk teeth") sequentially appear by emerging through the gums. Teething may start as early as three months or as late, in some cases, as twelve months. The typical time frame for the first teeth to appear is somewhere between six and nine months. It can take up to several years for all 20 teeth to complete the tooth eruption
Tooth eruption
Tooth eruption is a process in tooth development in which the teeth enter the mouth and become visible. It is currently believed that the periodontal ligaments play an important role in tooth eruption...
; they typically arrive in pairs. Though the process of teething is sometimes referred to as "cutting teeth", when teeth emerge through the gums they do not cut through the flesh. Instead, special chemicals are released within the body that cause some cells in the gums to die and separate, allowing the teeth to come through.
It is a widespread misconception that teething causes fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
. Teething may cause a slightly elevated temperature, but not rising into the febrile range (above 100-101F, or above 38-38.2C). Higher temperatures during teething are due to some form of infection, such as a herpes virus, initial infection of which is extremely widespread among children of teething age.
History
Teething used to be considered (wrongly) a cause of death, as many children died in the first years of life, at the same time as teething occurs. "The tendency in the past to attribute serious disease to teething was so prevalent that in 1842 teething was the registered cause of death in 4.8% of all infants who died in London under the age of 1 year and 7.3% of those between the ages of 1 to 3 years according to the Registrar General's report."Ironically, whilst teething is a natural process which creates little more than discomfort, some methods for relieving teething pain have caused serious harm and even death. Old remedies for teething include "blistering, bleeding, placing leeches on the gums, and applying cautery to the back of the head". In the sixteenth century the French surgeon Ambroise Paré
Ambroise Paré
Ambroise Paré was a French surgeon. He was the great official royal surgeon for kings Henry II, Francis II, Charles IX and Henry III and is considered as one of the fathers of surgery and modern forensic pathology. He was a leader in surgical techniques and battlefield medicine, especially the...
introduced the lancing of gums using a lancet, in the belief that teeth were failing to emerge from the gums due to lack of a pathway, and that this failure was a cause of death. This belief and practice persisted for centuries, with some exceptions, until towards the end of the nineteenth century lancing became increasingly controversial and was then abandoned, although as late as 1938 an Anglo-American dental textbook advised in favour of lancing, and described the procedure. In the first half of the twentieth century, teething powders in the English-speaking world often contained calomel, a form of mercury. It was removed from most powders in 1954 when it was shown to cause "pink disease" (acrodynia), a form of mercury poisoning
Mercury poisoning
Mercury poisoning is a disease caused by exposure to mercury or its compounds. Mercury is a heavy metal occurring in several forms, all of which can produce toxic effects in high enough doses...
.
Teething toys have a long history. In England in the 17th–19th centuries, a coral meant a teething toy made of coral, ivory or bone, often mounted in silver as the handle of a rattle. A museum curator has suggested that these substances were used as "sympathetic magic" and that the animal bone could symbolize animal strength to help the child cope with pain.
Sequence of appearance
The infant teeth tend to emerge in pairs - first one lower incisor emerges then the other lower incisor emerges before the next set begin to emerge. The general pattern of emergence is:- Lower central incisorIncisorIncisors are the first kind of tooth in heterodont mammals. They are located in the premaxilla above and mandible below.-Function:...
s (2) at approximately 6 months - Upper central incisors (2) at approximately 8 months
- Upper lateral incisors (2) at approximately 10 months
- Lower lateral incisors (2) at approximately 10 months
- First molarMolar (tooth)Molars are the rearmost and most complicated kind of tooth in most mammals. In many mammals they grind food; hence the Latin name mola, "millstone"....
s (4) at approximately 14 months - Canines (4) at approximately 18 months
- Second molars (4) at approximately 2-3 years
Milk teeth
Deciduous teeth
Deciduous teeth, otherwise known as reborner teeth, baby teeth, temporary teeth and primary teeth, are the first set of teeth in the growth development of humans and many other mammals. In some Asian countries they are referred to as fall teeth as they will eventually fall out, while in almost all...
tend to emerge sooner in females than in males. The exact pattern and initial starting times of teething appear to be hereditary. When and how teeth appear in an infant has no bearing on the health of the child.
Teething symptoms
The level of pain that a baby can handle will be different for each child. Some may be a lot fussier than others while they are teething. The soreness and swellingSwelling (medical)
In medical parlance, swelling is the transient enlargement or protuberance in the body and may include tumors. According to cause, it may be congenital, traumatic, inflammatory, neoplastic or miscellaneous....
of the gums
Gingiva
The gingiva , or gums, consists of the mucosal tissue that lies over the mandible and maxilla inside the mouth.-General description:...
before a tooth comes through is the cause for the pain and fussiness a baby experiences during this change. These symptoms usually begin about three to five days before the tooth shows, and they disappear as soon as the tooth breaks the skin. Some babies are not even bothered by teething.
Common symptoms include drooling
Drooling
Drooling is when saliva flows outside the mouth...
or dribbling, mood changes and feelings of irritability or crankiness and swollen gums. Crying, sleeplessness
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, restless sleep at night, and mild fever are also associated with teething. Teething can begin as early as 3 months and continue until a child's third birthday. In rare cases, an area can be filled with fluid and appears over where a tooth is erupting and cause the gums to be even more sensitive. Pain is often associated more with large molars since they cannot penetrate through the gums as easily as the other teeth.
Some of the signs or symptoms that a baby has entered the teething stage will be actions that are noticeable. They may chew on their fingers or toys to help relieve pressure on their gums. Babies might refuse to eat or drink due to the pain. Symptoms will generally fade on their own, but a doctor should be notified if they worsen or are persistent. Teething may cause signs and symptoms in the mouth and gums, but it doesn't cause problems elsewhere in the body.
Pulling on the ears is another sign of pain; the pain in the mouth throbs throughout the baby's head so they pull their ears believing that it will provide relief. Mild rash
Rash
A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
can develop around the mouth due to skin irritation that is caused because of excessive drooling or dribbling.
Misdiagnosis as teething
Teething has not been shown to cause fever or diarrhea; however the belief that teething causes fever is extremely common among parents. Whilst there is some evidence that teething can cause an elevated temperature, it does not cause fever (temperature over 100-101F, or over 38-38.2C). One small 1992 study found a significant rise in temperature on the day of eruption of the first tooth. Another study in 2000 found "mild temperature elevation" (but not fever over 102F).There is a risk that fever around the age of teething is dismissed as due to teething when it is actually due to illness, particularly infection by herpes viruses. "Coincidentally, primary tooth eruption begins at about the time that infants are losing maternal antibody protection against the herpes virus. Also, reports on teething difficulties have recorded symptoms which are remarkably consistent with primary oral herpetic infection such as fever, irritability, sleeplessness, and difficulty with eating." "Younger infants with higher residual levels of antibodies would experience milder infections and these would be more likely to go unrecognized or be dismissed as teething difficulty." Herpes virus infection may take the form of primary herpetic gingivostomatitis (HSV-1) or of infection by human herpesvirus 6, which infects 90% of children by age 2. "The symptoms of elevated temperature and facial rash could be explainable by infection with the Human Herpes Virus 6 (HHV-6) agent, which is ubiquitous among infants of teething age." Other viruses may also cause fevers which may be misattributed to teething, but the oral involvement that may occur with herpes viruses makes misdiagnosis a particular risk for such infections.
Treatment
Before treating a baby for teething, it is important to know what is causing the baby to be upset. Rubbing a finger gently along the gums in search for swollen ridges or the feel of a tooth below the gums is one way to be certain. If unsure, it is recommended that the child be seen by a pediatricianPediatrics
Pediatrics or paediatrics is the branch of medicine that deals with the medical care of infants, children, and adolescents. A medical practitioner who specializes in this area is known as a pediatrician or paediatrician...
before treatment is administered.
A teething ring is generally a soft plastic device that can be chewed on and allows the baby to break down some of the gum tissue which promotes the growth of the teeth out of the gum. Some teething rings can easily be broken or damaged, so other types of teething devices can be made from household items. Placing a wet washcloth in the freezer for a few minutes and then applying it gently to the gums can be effective, but care must be taken not to expose a baby's gums to coldness for too long.
Infants chew on objects to aid in the teething process. This can be dangerous if the baby is allowed to chew on objects which are small enough to be swallowed or which could break while being chewed and cause choking
Choking
Choking is the mechanical obstruction of the flow of air from the environment into the lungs. Choking prevents breathing, and can be partial or complete, with partial choking allowing some, although inadequate, flow of air into the lungs. Prolonged or complete choking results in asphyxia which...
. Teething rings and other toys, called teether
Teether
A teether is a soothing tool for infants that are going through the phase of teething.The European Commission's Scientific Committee announced that they are banning phthalate softeners in baby toys, because of toxic residue in six phthalate that were used in the manufacture of baby toys such as...
s, are often designed with textures that will appeal to an infant during teething. Drawing water into a pacifier and freezing it as another way to offer a teething child relief. The cold pressure on the gums gives relief without making the child’s fingers cold.
Some infants gain relief from chewing on cold objects. Some children respond well to chilled foods. Suggestions for chilled foods that might appeal to a baby include applesauce, yogurt, and pureed fruits.
Dentist
Dentist
A dentist, also known as a 'dental surgeon', is a doctor that specializes in the diagnosis, prevention, and treatment of diseases and conditions of the oral cavity. The dentist's supporting team aides in providing oral health services...
s recommend brushing infants' teeth as soon as they appear. It is not advisable to wait for the teething process to be complete. Dentists may recommend against the use of fluoride toothpaste
Toothpaste
Toothpaste is a paste or gel dentifrice used with a toothbrush as an accessory to clean and maintain the aesthetics and health of teeth. Toothpaste is used to promote oral hygiene: it serves as an abrasive that aids in removing the dental plaque and food from the teeth, assists in suppressing...
during teething.
Not all parents are comfortable with the idea of using medications, and the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
advises against it because of the risk of methemoglobinemia
Methemoglobinemia
Methemoglobinemia is a disorder characterized by the presence of a higher than normal level of methemoglobin in the blood. Methemoglobin is an oxidized form of hemoglobin that has an increased affinity for oxygen, resulting in a reduced ability to release oxygen to tissues. The oxygen–hemoglobin...
http://www.fda.gov/Drugs/DrugSafety/ucm250024.htm. Instead to treat the pain, parents should use teething rings and gum massage.
Medication
In cases where the infant is in obvious pain, some doctors recommend the use of non-steroidal anti-inflammatories (NSAIDs) or child-safe pain-relief treatments containing benzocaineBenzocaine
Benzocaine is a local anesthetic commonly used as a topical pain reliever, or in cough drops. It is the active ingredient in many over-the-counter anesthetic ointments...
, lidocaine
Lidocaine
Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...
, or choline salicylate. Benzocaine must be used cautiously because it can cause methemoglobinemia
Methemoglobinemia
Methemoglobinemia is a disorder characterized by the presence of a higher than normal level of methemoglobin in the blood. Methemoglobin is an oxidized form of hemoglobin that has an increased affinity for oxygen, resulting in a reduced ability to release oxygen to tissues. The oxygen–hemoglobin...
; choline salicylate is related to aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
and "may cause Reye's syndrome
Reye's syndrome
Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar . The classic features are liver damage, aspirin use and a viral infection...
in susceptible children, especially those with or recovering from viral infections, or when used in combination with other NSAIDs". 5% lidocaine gel produces anaesthesia (numbing) within 2-5 minutes, lasting for 10-20 minutes. However, one author concludes that "Overall, the risks and adverse effects from inappropriate or prolonged use of pharmacological agents outweigh their potential benefits." She points out that "the psychological trauma involved in administering medications or applying topical preparations to infants must be considered", and argues that "the placebo effect must not be overlooked. For example, applying a gel of 20% benzocaine in polyethelene glycol may give only a modest benefit over applying the placebo, which gives an efficacy of 60% compared with 90% for the active preparation."
Medicines are often applied to the babies' gums to relieve swelling and pain. These gels are similar to the toothache gel that is used by adults for sore gums and toothaches, but is administered in much smaller doses. Teething gels work as a numbing agent to dull the nerves in the gums so that the pain is less noticeable. It is important to follow the directions on the package to ensure that the correct amount of medication is administered and that proper techniques are used to reduce the risk for infection. It is important not to let the medicine numb the throat as it may interfere with the normal gag reflex and may make it possible for food to enter the lungs. Similar medicines are also available in powder form, as "teething powder".
Acetaminophen
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
and ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....
are also recommended to treat the pain and swelling that babies experience, but should not be administered to babies under six months of age. It should only be used a few times a day so that it does not mask symptoms that are being experienced due to other medical conditions and not because of teething. Products that contain aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
should never be given to a child unless directed by a pediatrician, due to the risk of Reye's syndrome
Reye's syndrome
Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar . The classic features are liver damage, aspirin use and a viral infection...
.
Some traditional medicine used to treat teething pain has been found to be harmful due high lead content, with effects including toxic encephalopathy
Toxic encephalopathy
* Baker, E. . Chronic toxic encephalopathy caused by occupational solvent exposure. Annals of Neurology. 63: 545-547- External links :*****...
. "Surma" or "kohl
Kohl (cosmetics)
Kohl is an ancient eye cosmetic. It was made by grinding galena and other ingredients. It is widely used in South Asia, the Middle East, North Africa, the Horn of Africa, and parts of West Africa to darken the eyelids and as mascara for the eyelashes...
" has traditionally been used in the Middle East and Indian subcontinent as a teething powder, as have the Middle Eastern "saoott"/"cebagin". "Santrinj" - a 98% lead oxide
Lead oxide
Lead oxide may refer to:* Lead oxide, PbO, litharge, massicot* Lead oxide, Pb3O4, minium, red lead* Lead dioxide , PbO2Less common lead oxides are:* Lead oxide, Pb2O3, lead sesquioxide...
product otherwise used as a paint primer - is also used in the Middle East as a home remedy for teething.
External links
- NHS Choices Birth to Five Planner: Teething
- NHS Choices Health A-Z: Teething
- "Personal View: It's only teething... A report of the myths and modern approaches to teething", M P Ashley, British Dental Journal 191, 4 - 8 (2001) Published online: 14 July 2001 | doi:10.1038/sj.bdj.4801078. http://www.nature.com/bdj/journal/v191/n1/full/4801078a.html