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Did you know that our ancestors were nocturnal? They used to stay awake in the night to hunt without worrying about dangerous predators and sleep during the day. Now, our circadian rhythms are lined up with the sun. That's why as soon as the sun sets, our bodies start getting ready for rest, and we end up feeling sleepy.
Circadian rhythms are biological cycles that coordinate essential mental and physical functions, such as sleep and hunger. The circadian clock is regulated by a part of the brain called the Suprachiasmatic Nucleus (SCN).
The circadian clock is also influenced by temperature. When the body temperature drops around the afternoon and late evening, it induces drowsiness and sleep.
Sleep is induced by a hormone called melatonin, which is produced in low-light conditions. Bright light conditions during the day suppress melatonin production and promote wakefulness.
People who work the night shift have disrupted circadian rhythm and have an increased risk for the following conditions:
Working the night shift is carcinogenic to humans, according to multiple studies conducted the world over.
Several studies show that disruption in the night’s sleep can reduce melatonin levels and increase the risk of tumor growth.
Some animal studies have shown that exposure to light at night led to the growth of breast cancer.
The risk of breast cancer among nurses and other night-shift workers seems to be higher than their counterparts who worked day shifts.
A study published in the Journal of National Cancer Institute in 2001 reported that women who work in rotating night shifts for at least three nights per month, along with day shifts, have a moderately high risk of breast cancer.
Further, the risk seems to be higher when the night shifts per week increase!
This increased risk is attributed to the messed-up melatonin levels in the body.
In addition to promoting sleep, melatonin also stops tumor growth and protects against the spread of cancer cells.
When melatonin levels decrease in the body, it results in an imbalance of inflammatory cytokines, increased mutations in the cells, and oxidative damage (due to free radicals).
These events can all trigger cancer development.
A reduction in melatonin also affects estrogen levels, which further increases the risk of breast cancer.
A long duration of shift work throughout the years is associated with estrogen and progesterone-positive tumors.
When the circadian rhythm is altered, it changes the expression of the CLOCK genes. This also influences the production of reproductive hormones.
The Neuronal PAS Domain Protein 2 or NPAS2 gene is the largest circadian gene. It plays a vital role in sleep homeostasis and circadian rhythm regulation.
This gene also regulates the cell cycle and works with certain other genes for repairing DNA. The NPAS2 gene shows a strong association with breast cancer.
rs2305160 (Ala394Thr) is an SNP (Single Nucleotide Polymorphism) in the NPAS2 gene.
Among women with little or no exposure to shift work, the A allele (AA or AG) is associated with a significantly lower risk of breast cancer.
However, among women with AA genotype who had worked >2 years of rotating night shifts, the risk of breast cancer was nearly 3 fold compared to women with the same genotype with <2 years of night shift work.
| Genotype | Implication - > 2 years of rotating night shifts |
| AA (Thr/Thr) | ~3 fold increased risk of breast cancer |
| AG (Thr/Ala) | Slightly increased risk of breast cancer |
| GG (Ala/Ala) | Normal risk of breast cancer |
Use Xcode Life’s Free Gene Tool To Find Out If You Have The Risk Genotype!
RAR-Related Orphan Receptor A or the RORA gene is located on chromosome 15 and regulates genes involved in the body’s circadian rhythm.
rs1482057 is an SNP in the RORA gene. A study published in 2014 showed that SNP rs1482057 was associated with breast cancer in postmenopausal women.
Women who have at least one A allele and had a history of working night shifts in their lifetime had a higher risk of developing breast cancer.
Conversely, women having the CC genotype and working night shifts showed a decreased risk of breast cancer.
| Genotype | Implication |
| AA | Increased breast cancer risk on night shift work |
| AC | Increased breast cancer risk on night shift work |
| CC | Decreased breast cancer risk on night shift work |
Cryptochrome circadian regulator 2 or the CRY2 gene gives instructions to produce a protein involved in regulating the body’s circadian rhythm.
rs2292912 is an SNP in the CRY2 gene, located on chromosome 11. Night shift working increased the risk of breast cancer in women who carried the CG genotype of rs2292912 SNP.
| Genotype | Implication |
| CG | Increased breast cancer risk on night shift work |
| GG | Decreased breast cancer risk on night shift work |
| CC | Decreased breast cancer risk on night shift work |
Since working night shift hours increases the risk of breast cancer in women, one of the most effective ways to lessen this risk is to reduce working night shifts.
Switching with a colleague’s shift, alternating your night shifts with day shifts, or switching jobs can be a few ways by which you can reduce your night shift hours.
Apart from disrupting the sleep-wake cycle, disturbed sleep or poor quality of sleep in people who work night shifts can increase their risk for breast cancer.
So, if you are working a night shift, ensure you get your 7-8 hours of sleep every day. If you have trouble sleeping, consult your doctor about supplements that can help you catch up on your daily sleep.
People working the night shift must try and reduce other risk factors of breast cancer.
A healthy diet with lots of fruits, limited alcohol consumption and smoking, adequate physical activity, and reduced exposure to harmful chemicals can help reduce breast cancer risk.
Snoring is the loud or harsh sound from the nose or mouth that occurs when breathing is partially obstructed. The sound is produced when the soft palate and other soft tissues (such as uvula, tonsils, nasal turbinates, and others) in the upper airway vibrate.
Affecting nearly 90 million Americans, it can lead to disturbed, unrefreshing sleep, ultimately resulting in poor daytime function. Snoring is caused due to obstruction of air passage, resulting in the vibration of respiratory structures and the production of sound during breathing while asleep.
Snoring is more prevalent in males than in females. Certain risk factors such as genetic predisposition, throat weakness, obesity, mispositioned jaw, obstructive sleep apnea, sleep deprivation, alcohol consumption, and mouth breathing are associated with snoring.
Twin and family studies have identified the association between genetic factors and snoring risk, with heritability ranging between 18 to 28%.
A recent study published in 2019 leveraged data from a large U.K. Biobank study consisting of the Australian adult population to identify the molecular mechanisms associated with snoring.
MSRB3 is associated with protein and lipid metabolism pathways, which are related to hippocampal volume (a region in the brain) and lung function. Such genetic associations are consistent with the findings that severe bouts of snoring may be due to:
- Nocturnal oxygen desaturation (temporary drop in oxygen levels in hemoglobin)
- Lowered neuropsychological functions, with reduced ability to consolidate memory.
The rs10878269 is G>A polymorphism located in the MSRB3 gene. A study by Jones, Samuel E., et al.2016 showed that variant rs10878269 was significantly associated with reduced snoring risk.
Snoring is not often considered a serious health concern except in some conditions. Snoring can usually be cured through simple home remedies. Light and infrequent snoring is completely normal. Snoring that is linked to obstructive sleep apnea (OSA) is, however, worrisome and needs to be treated.
https://pubmed.ncbi.nlm.nih.gov/32060260/
Restless Leg Syndrome (also known as Willis-Ekbom Disease) is a neurologic and sleep-related movement disorder characterized by an irresistible urge to move in the legs, which typically occurs or worsens at rest. Affected people may experience abnormal, uncomfortable sensations ( paresthesia or dysesthesias ) that are often linked to cramping, crawling, burning, aching, itching, or prickling deep within the affected areas.
This condition has a 10% prevalence rate, with an increase in incidences as age advances. Since the symptoms occur during sleep and relaxation, it could disrupt a good night's sleep.
Restless leg syndrome causes an uncomfortable urge to move, which can be relieved by walking or moving the extremities. This interferes with sleep maintenance
How Does Genetics Influence the Risk of Restless Leg Syndrome (RLS)?
Restless leg syndrome shows an anticipation inheritance - with each generation, the age of onset of this condition advances.
A GWAS meta-analysis study of restless leg syndrome (RLS) in European ancestry has demonstrated the significant association of RLS with MEIS1, BTBD9, PTPRD, and other genes.
BTBD9 gene variants have been associated with RLS, with two experimental models providing better insights. The loss of this gene was associated with increased waking from sleep, motor activity, higher motor restlessness, and altered serum iron levels.
The MEIS1 gene is a transcription factor that plays a key role in hematopoiesis, endothelial cell development, and vascular patterning.
It also plays a role in neurodevelopment.
Research studies have shown that the reduced MEIS1 levels and function of the gene may contribute to the pathogenesis of sleep-related disorders.
rs113851554 And RLS
The rs113851554 is a G>T polymorphism located in the MEIS1 gene, which is found to be correlated with multiple sleep disorders.
A GWAS meta-analysis study of RLS in European ancestry has demonstrated that the rs113851554 T allele is associated with an increased risk of developing RLS susceptibility.
Non-genetic Influences on RLS Risk
Some nutritional deficiencies have been implicated in RLS. They include:
- Vitamin D deficiency
- Iron deficiency
Some medical conditions associated with RLS are:
- Depression
- Diabetes
- Fibromyalgia
- Rheumatoid arthritis
- Hypothyroidism
Effects of Restless Legs Syndrome on Health
Tips for Managing Restless Leg Syndrome (RLS)
Iron Supplements : Iron deficiency is one of the leading causes of RLS. If you test positive for iron deficiency, you may get started on iron supplements after consulting a qualified healthcare professional.
Baths and massages : Warm showers and massages can help relax muscles and prevent unnecessary leg movements.
Exercise : Restless Legs Syndrome foundation recommends moderate exercising to help manage RLS.
Avoid caffeine : High caffeine intake can worsen RLS. Either limit or avoid caffeine intake.
Summary
Reference
https://pubmed.ncbi.nlm.nih.gov/29029846/
Introduction: What is Sleep Bruxism?
Sleep Bruxism (also known as Teeth Grinding) is defined as repetitive jaw muscle activity during sleep. It is characterized by an unconscious act of grinding or clenching one's teeth tightly together. Over time, it could lead to damage of teeth, oral health conditions, facial muscle pain, sleep disturbances, difficulty while speaking or eating.
Sleep Bruxism is more common in children, adolescents, and young adults than middle-aged and older adults.
The prevalence of sleep bruxism is estimated to be around 15% in adolescents, around 8% of middle-aged adults, and only 3% in older adults.
According to statistical studies 6-50% of children experience nighttime teeth grinding.
How Does Genetics Influence Sleep Bruxism Risk?
Multiple studies have demonstrated that there may be a degree of inherited susceptibility to develop sleep bruxism. According to a study, around 21-50% of affected individuals have an immediate family member who had sleep bruxism during childhood.
Few studies have shown the significant associations of certain variants in neurotransmitters like dopamine, serotonin, and others ( DRD3, HTR2A, COMT, MMP9, and others) with sleep bruxism.
The DRD3 gene encodes the D3 subtype of the dopamine receptor, which is localized to the regions of the brain involved in cognitive, emotional, and endocrine functions.
Variations in DRD3 are implicated in the physiopathology of diseases affecting those functions.
The rs6280 is a T>C polymorphism located in the DRD3 gene, where the C allele may increase dopamine affinity and efficacy. Studies have shown that the Gly variant (C) is significantly associated with increased susceptibility to sleep bruxism.
Non-genetic Influences on Sleep Bruxism Risk
Sleep bruxism may be accelerated by lifestyle factors as well. Some of them include:
- Stress
- Alcohol consumption
- Anxiety
- Cigarette smoking
- Upper airway resistance
- Caffeine consumption
Effects of Bruxism on Health
Tips for Managing Bruxism
Mouth guards - Mouth guards help keep the teeth separated and hence prevent grinding.
Stress management - Stress is one of the major contributors to teeth grinding. So finding ways to alleviate stress can help prevent teeth grinding.
Avoid alcohol and caffeine - Teeth grinding tends to intensify upon alcohol and caffeine consumption.
Avoid chewing on pens and pencils - This practice gets your jaws used to grinding movement and may increase your tendency to grind your teeth.
Summary
References
https://pubmed.ncbi.nlm.nih.gov/32471213/
https://pubmed.ncbi.nlm.nih.gov/27611726/
https://pubmed.ncbi.nlm.nih.gov/28451935/
https://pubmed.ncbi.nlm.nih.gov/30092895/
https://pubmed.ncbi.nlm.nih.gov/25628080/
Sleep fragmentation is one of the symptoms of sleep disorders characterized by repeated, short sleep interruptions during the night, which leads to excessive tiredness during the day.
People with fragmented sleep tend to fall asleep quickly but wake up multiple times during the night for short periods. The other symptoms of fragmented sleep include morning headaches, daytime sleepiness, difficulty in concentrating, and memory lapses.
Fragmented sleep due to situational illness (like a cough or a sore back)is called short-term sleep fragmentation and goes away after some time.
Research studies have documented a greater impact on physical and emotional health when sleep quality and quantity are poor.
How Does Genetics Influence Sleep Fragmentation Risk?
A study reported the genetic and environmental variance in sleep complaints. The proportions were as follows:
1. At 8 years: 63% genetic, 32% non-shared environment
2. At 10 years: 66% genetic, 27% nonshared environment, 7% shared environment
The study also suggests that genetics affects sleep problems more strongly during the preschool/school age (63-69%) . Certain variants in HLA-DQB1, CRY1, and other genes might influence the risk of having fragmented sleep.
The CRY1 gene encodes a protein called flavin adenine dinucleotide-binding, a key component of circadian clock regulation.
Variations in the CRY1 gene are found to be associated with altered sleep patterns.
The rs184039278 is an A>C gain of function mutation located in the CRY1 gene, associated with a prolonged period of circadian molecular rhythms.
A study, Patke, Alina, et al.2017, demonstrated that both CC and AC carriers are strongly associated with late sleep times and sleep fragmentation.
Non-genetic Factors That Influence The Fragmented Sleep Risk
Some sleep-related disorders can result in fragmented sleep. A few examples are:
1. Snoring
2. Obstructive sleep apnea
3. Sleep-maintenance insomnia
4. Restless leg syndrome
Poor sleep is also caused by lifestyle habits such as:
1. Alcohol and caffeine consumption
2. Napping for a long time in the day
3. Exercising close to bedtime
Effects of Sleep Fragmentation on Health
Tips for Managing Sleep Fragmentation
You can follow these tips to have a peaceful night of sleep and avoid sleep fragmentation.
1. Tire yourself out: As fatigue accumulates throughout the day, it’ll be easier to fall asleep in the night.
2. Stay away from distractions: Switch off your phone, wear an eye mask, and shut the windows to prevent your sleep from being disturbed.
Summary
References
https://pubmed.ncbi.nlm.nih.gov/20975052/
https://pubmed.ncbi.nlm.nih.gov/28388406/
https://pubmed.ncbi.nlm.nih.gov/24179306/
Chronotype is influenced by differences in circadian rhythm, which refers to the fundamental 24-hour physiological cycle essential for various molecular and behavioral processes. It helps regulate sleep patterns.
The timing of circadian rhythms varies across individuals and is influenced by both environmental and genetic factors. People with earlier rhythms tend to rise early in the morning and feel sleepy earlier in the night. If your body sides with the “morning clock” then you are a “morning person.” The other end of this spectrum has people with delayed rhythms. They tend to sleep and wake up late and are often referred to as an “evening person” or a “night owl.”
Research has shown that morning people are more focused, persistent, agreeable, plan their future better, and are less likely to smoke and drink or get depressed. They may exhibit characteristics like:
- Waking up early
- Being more active during the morning hours
- Being more focused and happy
- Being more productive during the day
Similarly, night owls enjoy a burst of strength during the night and may exhibit characteristics like:
- Waking up late
- Being more active during the evening hours
- Being more creative and adventurous
- Being more productive during the night
A GWAS study of self-reported chronotype (morning/evening person) of UK Biobank data identified 22 regions in the circadian rhythm and photo-reception genes associated with morningness. This was also replicated in a 23andMe study.
One of the strongest associations was seen in the rs516134 SNP located near the RGS16 gene.
The RGS16 gene encodes a protein that belongs to the regulator of G protein signaling. This protein is responsible for turning off certain signal communications between cells in the body.
Microarray studies and gene expression analysis have demonstrated that the RGS16 gene exhibits circadian variations. According to a study, mice lacking this gene have a longer circadian period.
The rs516134 is a C>T polymorphism located in the RGS16 gene. The C allele is found to be strongly associated with morningness.
Non-genetic Influences On Circadian Rhythm
A study found that morningness is significantly associated with gender, with a prevalence of 39.7% in males and 48.4% in females.
Also, people over 60 were more likely to prefer mornings than people under 30 - meaning people’s sleep preferences may change over time.
Circadian rhythms affect day-to-day bodily functions such as sleep, eating habits, hormones release, and body temperature.
Many studies have documented that irregular rhythms are linked to various chronic conditions such as sleep disorders, obesity, depression, diabetes, hypertension, bipolar, and schizophrenia.
It is known that the vast majority of patients with depression have sleep abnormalities; either they sleep too much or have insomnia and can’t sleep at all.
Several genetic variants are correlated with how circadian rhythms function and their association with health conditions.
The interplay between genetics and non-genetic factors (such as sunlight, eating habits) with circadian rhythm is clear.
Maintaining a routine with a balanced lifestyle may help to stabilize the internal biological clock and health.
https://pubmed.ncbi.nlm.nih.gov/27494321/
https://pubmed.ncbi.nlm.nih.gov/26835600/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428740/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018537/
Sleep is a critical component of optimal health. A healthy sleep comprises various aspects, including adequate duration, good quality, and the absence of sleep disorders. Inadequate sleep at night is generally associated with:
- Daytime sleepiness
- Daytime fatigue
- Depressed mood
- Poor functioning
- Other health issues
Sleep duration refers to the total amount of sleep obtained either during the nighttime sleep event or across the 24-hr period.
Importance of An Adequate Sleep
Getting enough sleep at night is very important for several reasons. Sleep is linked to your mental and physical health and quality of life. When you get adequate sleep at night, you can be more productive and concentrate better during the day. It reduces your risk of heart disease and prevents depression. Your immune system becomes stronger as sleep helps the body to repair and recover. Your athletic performance can also be improved because of a good night’s sleep. Not getting enough sleep can make you gain weight faster.
RDA: What Is The “Ideal” Sleep Duration?
National Sleep Foundation guidelines recommend 7-9 hours of sleep per night for healthy adults. Babies, young children, and teens need even more sleep to enable their growth and development. People over 65 should also get 7 to 8 hours of sleep per night.
How Does Genetics Affect Sleep Duration?
Studies have shown that certain genetic variants influence habitual sleep duration, which explains why some individuals need more sleep than others.
Twin studies have shown that the heritability estimation of sleep duration is around 10 - 40%.
A GWAS study of self-reported chronotype and sleep duration of UK Biobank data identified several genetic regions associated with sleep duration. This study documented that people with genetic variants for longer sleep duration reported an average of 22 minutes more sleep.
The PAX8 gene encodes a member of the paired box (PAX) family of transcription factors involved in thyroid follicular cell development and the expression of thyroid-specific genes.
Variations in the PAX8 gene may affect different functions, including DNA binding, gene activation, and protein stability.
Research studies have found that the sleep-wake cycle may be influenced by regulating thyroid hormone levels. Individuals with hypothyroidism (a condition in which the thyroid gland does not produce enough thyroid hormones) are prone to excessive sleepiness. People with hyperthyroidism (in which the thyroid makes too much of the hormone), on the other hand, may have insomnia.
The rs62158211 is a G>T polymorphism located in the PAX8 gene. The T allele is associated with longer sleep duration.
A study documented that the rs62158211 was associated with an average 2.6-minute per-allele change in sleep duration.
Non-genetic Influences On Sleep Duration
Some risk factors that lead to shorter sleep duration include alcohol consumption, smoking, and physical inactivity.
Effects of Sleep Duration on Health
Few epidemiological and genetic studies have demonstrated a strong biological link between abnormal sleep duration, risk of schizophrenia, type 2 diabetes, fetal growth, and Crohn's disease.
Sleep duration is also associated with cardiovascular diseases, type 2 diabetes, depression, automobile and workplace accidents, learning and memory problems, and prospective mortality.
TipsTo Become An Early Riser
Summary
References:
https://www.sleepfoundation.org/articles/how-much-sleep-do-we-really-need
https://pubmed.ncbi.nlm.nih.gov/27992416/
https://pubmed.ncbi.nlm.nih.gov/27494321/
https://pubmed.ncbi.nlm.nih.gov/25469926/
Snoring is the loud or harsh sound from the nose or mouth that occurs when breathing is partially obstructed. The sound is produced when the soft palate and other soft tissues (such as uvula, tonsils, nasal turbinates, and others) in the upper airway vibrate.
Affecting nearly 90 million Americans, it can lead to disturbed, unrefreshing sleep, ultimately resulting in poor daytime function. Snoring is caused due to obstruction of air passage, resulting in the vibration of respiratory structures and the production of sound during breathing while asleep.
Snoring is more prevalent in males than in females. Certain risk factors such as genetic predisposition, throat weakness, obesity, mispositioned jaw, obstructive sleep apnea, sleep deprivation, alcohol consumption, and mouth breathing are associated with snoring.
How Does Genetics Influence Snoring Risk?
Twin and family studies have identified the association between genetic factors and snoring risk, with heritability ranging between 18 to 28%.
A recent study published in 2019 leveraged data from a large U.K. Biobank study consisting of the Australian adult population to identify the molecular mechanisms associated with snoring.
MSRB3 is associated with protein and lipid metabolism pathways, which are related to hippocampal volume (a region in the brain) and lung function. Such genetic associations are consistent with the findings that severe bouts of snoring may be due to:
- Nocturnal oxygen desaturation (temporary drop in oxygen levels in hemoglobin)
- Lowered neuropsychological functions, with reduced ability to consolidate memory.
The rs10878269 is G>A polymorphism located in the MSRB3 gene. A study by Jones, Samuel E., et al.2016 showed that variant rs10878269 was significantly associated with reduced snoring risk.
Non-genetic Influences On Snoring
Effects Of Snoring
Snoring is not often considered a serious health concern except in some conditions. Snoring can usually be cured through simple home remedies. Light and infrequent snoring is completely normal. Snoring that is linked to obstructive sleep apnea (OSA) is, however, worrisome and needs to be treated.
Tips For A Snore-free Sleep
Summary
References:
https://pubmed.ncbi.nlm.nih.gov/32060260/
Insomnia (also known as sleeplessness) is a common sleep disorder that is characterized by the inability to fall asleep or stay asleep at night, resulting in tired or unrefreshing sleep.
According to the American Psychiatric Association (APA), insomnia is the most common sleeping disorder.
Approximately 30% to 40% of adults in the United States report symptoms of insomnia.
A diagnosis of insomnia needs to meet the following two categories:
- Difficulties in sleep for at least three nights a week for a minimum of three months
- Difficulties in sleep that results in functional distress in the individual’s life
This can be caused by variations in biological, psychological, and social factors, which most often result in a reduced amount of sleep.
How Does Genetics Influence Insomnia Risk?
A research study published in 2019 found an association between certain variants in genes like DLG4, LRRK2, DNM1, CRH, GRIN1, DRD1, DRD2, SNCA, DRD4, NTSR1, CNTN2, and CALB1, and insomnia. DNM1 gene codes for the synaptic neuronal protein dynamin 1, which is associated with pre-sleep arousal, a characteristic feature among people with insomnia.
According to a research study, the heritability of insomnia is between 38 to 59%. This suggests a role of genetic factors in insomnia.
Tissue-specific gene-set analyses showed that insomnia might have higher genetic signals among genes that are usually expressed in the brain. The functions of these regions of the brain are of relevance to insomnia.
The genetic correlations between insomnia and psychiatric traits were stronger than the genetic correlations between insomnia and other sleep-based characteristics. According to the study, this suggests that genetically, insomnia resembles neuropsychiatric traits more closely than other sleep-related characteristics.
The MEIS1 gene is a transcription factor that plays a key role in hematopoiesis, endothelial cell development, and vascular patterning.
It also plays a role in neurodevelopment.
Research studies have shown that the reduced MEIS1 levels and function of the gene may contribute to the pathogenesis of sleep-related disorders.
The rs113851554 is a G>T polymorphism located in the MEIS1 gene, which is found to be correlated with multiple sleep disorders.
A study found that the T allele of rs113851554 is associated with [an increased risk of developing insomnia symptoms] (https://pubmed.ncbi.nlm.nih.gov/27992416/). Also, functional study analysis suggested that the rs113851554 in the MEIS1 locus is most strongly associated with insomnia disorder.
Non-genetic Influences On Insomnia Risk
Insomnia is more common in women than in men. In fact, women are twice as likely to fall asleep than men. One in four women has some insomnia symptoms.
Insomnia is more common in older people more than men and younger ones. As many as 50% of older adults complain about difficulty initiating or maintaining sleep.
Effects Of Insomnia On Health
TipsTo Prevent And Manage Insomnia
Summary
References
https://pubmed.ncbi.nlm.nih.gov/30804565/
https://pubmed.ncbi.nlm.nih.gov/26132482/
