As the name suggests, Allergic rhinitis (also known as hay fever) is an inflammatory disorder of the nasal mucosa, which occurs when the immune system overreacts to allergens in the air. This might sound small, but it affects 20% of the adult population and up to 40% of children.
Allergic rhinitis is biologically associated and equated with decreased learning, performance, productivity at work and school, and reduced life quality. It affects the quality of life, including fatigue, irritability, memory deficits, and depression. It is reflecting the social-economic costs and the negative impact on the quality of life.
If we talk about the current therapeutic options like allergen avoidance, medication, and immunotherapy, they are quite far from ideal. Light therapy has been treating immune-mediated dermatological conditions, e.g., psoriasis and atopic dermatitis.
It is one of the oldest treatments that has been practiced in ancient times. Red light therapy has profound immunosuppressive effects on the human body.
As per ARIA guidelines, Red light therapy has been recommended for patients with allergic rhinitis who do not respond to standard medical treatment.
Now, the questions arise what the benefits of red light therapy are? Why should you opt for it?
Well, there are many benefits to using red light therapy:
Light therapy treatment delivers light to pathological areas to promote tissue regeneration, reduce inflammation, and relieve pain. This treatment improves the nasal obstruction caused by Allergic rhinitis. The sessions involve illuminating the nasal cavity through specific wavelength log light ((660nm — 810nm) to the nose for a certain amount of time.
Most light therapy devices include one or two small LED light-emitting probes, which quickly stimulate the nasal cavity's blood capillaries.
Light therapy mechanisms reduce the number and function of dendritic cells and induce immunomodulatory cytokines like IL-10. Cytokines are a large group of proteins, peptides secreted by specific cells of our immune system. The Red Light therapy generates little heat, modulating mucosal blood supply and histamine release (organic nitrogenous compound involved in local immune responses). This heat alters mucosal blood supply.
The therapy shows improvement in the symptoms of nasal congestion and a decrease in nasal resistance. Studies showed that Phototherapy resulted in a significant improvement of clinical symptoms for nasal itching, rhinorrhea, sneezing, and total nasal score.
Red light therapy resulted in a remarkable improvement of clinical symptoms for nasal itching, rhinorrhea, sneezing, and total nasal score.
Adopt light therapy and give your life a better quality. Improve the shape of your life; let the negativity and obstructions be at bay!
References:
COVID-19 has created challenges for nearly every market, and the medical device manufacturing industry is no exception. As the virus sweeps the globe, it’s becoming increasingly difficult for leaders to overcome the arising challenges and prepare for the future.
While I firmly believe the key to navigating this evolving landscape is putting quality at the forefront of all activities, a function made seamless through best of breed quality management tools, I was curious what other industry leaders had to say.
The following are some of their best tips for effectively leading and managing teams during the COVID-19 pandemic and preparing your organization for what’s to come.
Keep in touch. Let your people know where things stand with the business. At home or in the office practicing social distancing, each of your workers will be dealing with different issues, both private and professional. The distributed workforce requires even more channels to help people stay connected.
“Leadership needs to provide regular communication, be transparent about the impact of the pandemic on your company, and set expectations with your team, investors, partners, and customers. There is a great deal of uncertainty in the world, and clarity from management is one of the keys to a healthy organization.” — Paul Grand, CEO, MedTech Innovator
Be sensitive to employees’ personal situations. Every member has their own worries and family needs during this crisis. Review goals and when needed realign expectations to match current circumstances.
Balance the content. Focus on efficiency in meetings to ensure your team still has time to do their work and manage their personal situation. The recommended time for meetings should be 15 minutes with no more than 4 people per meeting
Office time should be reduced. To avoid conflicts, make sure yo manage expectations. Be clear about your expectations and the expectation from your team during these challenging times. The last thing you want to do is have misunderstandings or conflicts with a good working team.
The key purpose of a leader is to continuously motivate and support the team. Talk about work-life structures, supporting flexible working arrangements, and vocalizing empathy towards your workmates. As a leader, you must empower them to deliver their best work while being absolutely empathetic towards challenges in their life.
Focus on the fact that COVID-19 is temporary. The natural instinct may be to slow down and withdraw resources. Instead, this is an excellent time to strategically plan and dedicate time, staff, and resources to ensuring that the post-pandemic time capitalizes on key changes.
Just because you can’t conduct research the way you always have doesn’t mean you can’t conduct research at all. It is important to stay flexible with the research methods you use. Understanding the pros and cons of each method and their overall ability to contribute to your research goal is critical to conducting meaningful and useful research.
All companies are working to lead their teams through today’s challenges with confidence. By taking care of your team and keeping quality you will improve the teamwork collaboration, communication, and transparency.
Having acne-prone skin can be incredibly frustrating, especially when your oral and topical treatments don’t seem to work well enough. Skincare ingredient junkies know actives that target acne problems such as salicylic acid and benzoyl peroxide can be a few of the most irritating ingredients that you can put on your skin- especially when used in hefty amounts.
If you’ve been wallowing into these-but to no avail, you might ease your frustrations by learning about what Blue Light Therapy can do to acne problems.
Blue Light therapy is a form of phototherapy that uses a visible light device that has been used by dermatologists for decades as a clinically proven treatment for acne.
The treatment is considered a generally safe, non-invasive, and pain-free procedure with no downtime. Besides being a popular anti-acne treatment, Blue Light therapy has also been shown to remove stubborn acne marks and sunspots. It eliminates free radicals caused by exposure to harsh environments that may oxidize and age your skin.
One significant impact of Blue light therapy is that it has been used to treat skin cancer in patients with actinic keratoses at University of Iowa Hospitals & Clinics. The American Academy of Dermatology considers Blue light therapy a promising treatment for numerous skin issues like acne.
Blue light has been shown to have an antimicrobial effect that penetrates deep into the skin’s pores to eliminate the acne-causing bacteria, otherwise known as Propionibacterium acnes, or P. acnes. Blue Light has been proven to have an antimicrobial effect, making it an ideal treatment to effectively kill several types of bacteria in your pores and oil glands responsible for causing breakouts.
A clinical study shows that 77% of people with acne-prone skin treated with blue light therapy for five weeks have seen significant changes in their skin. Another research suggests that at-home blue light therapy has reduced acne lesions on people who have used the therapy for 28 days.
Unlike other topical treatments that address inflammation, blue light therapy targets breakout-causing bacteria in your pores and by healing the skin from within. Blue Light Therapy is a form of defensive treatment to acne by eradicating bacteria that causes redness and inflammation and a proactive solution to preexisting acne.
Who is a good candidate for Blue Light Therapy?
Experts at the American Academy of Dermatologists agree that blue light therapy works best for people who have mild to moderate acne problems. It is also a great treatment to eliminate acne scars. Blue light therapy works by addressing the acne issue from its core. It works by removing preexisting mild to moderate acne while preventing sebum build-up that causes the inflammation. Severely too deep abdominal cystic acne may benefit from other prescriptive medications that target more serious skin problems. People who incorporate Retinols in their skincare routine may also want to avoid getting Blue Light treatments as such ingredients make the skin very sensitive.
Although many dermatologists use current clinical studies, there are available at-home blue light therapy devices that effectively treat acne problems.
The best Blue Light Devices should be FDA- cleared, just like our Blue Lights Therapy Beauty Skin Complexion Handheld Device and Aduro Mask, that is made with medical-grade quality. FDA-cleared at-home devices have innovated into using the same technology that delivers satisfactory results for acne-related problems.
Blue Light therapy works best as a treatment for acne when used consistently. A weekly maintenance appointment to your dermatologist’s clinic for a blue light treatment may cost you $100, which makes it a much more expensive endeavor than investing in at-home devices.
Portable blue light therapy devices can be more beneficial for you as they can be used more frequently as an addition to your skincare routine at a lower price point.
The best blue light therapy devices in the market provide a safer alternative to other harsh treatments for acne that may require risks such as scarring and irritation. If you want to know more about effective light therapy treatments, check this out.
Now you can add a cool, avant-garde addition to your skincare that can be a very convenient and effective treatment for your stubborn acne problems.
https://www.medicalnewstoday.com/articles/319254
https://uihc.org/health-topics/blue-light-therapy-warding-skin-cancer
https://www.healthline.com/health/blue-light-therapy
Today's customers expect nothing less than products of the highest quality, and it is incumbent on all manufacturers to assure this expectation is met. A proven technique for checking whether a manufacturing process is in control is a manufacturing audit.
A manufacturing audit is a comprehensive inspection of a process to determine whether it is performing satisfactorily. A manufacturing audit is usually limited to a small portion of units produced, but the manufacturing processes involved are reviewed thoroughly. An audit does not replace normal quality control efforts, but supplements them.
Medical audit is a systematic approach to peer review of medical care in order to identify opportunities for improvement and provide a mechanism for realizing them. Medical audit and clinical audit are often used interchangeably, but clinical audit might be considered to cover all aspects of clinical care-for example, nursing and the role of paramedical staff-whereas medical audit relates to practices initiated directly by doctors. It complements and may partly overlap financial audit, utilization review, and management of resources, but is primarily clinical, not managerial; its focus is the process and results of medical care rather than the use of resources and it is the responsibility of doctors rather than managers.
There are many reasons for conducting a manufacturing audit:
Kaiyan Medical got another audit supplier recognition by Made-in-China. We like to keep our audits and quality standards to the top in order to assure the best experience for our customers and clients
https://www.bmj.com/content/bmj/299/6697/498.full.pdf
You might have heard about hyperpigmentation from your dermatologist or a skincare company. But if you didn’t completely understand this skin condition — and you want to know how it develops, how to remove it, etc. — or if you have questions about this skin condition, this article can be of help.
Hyperpigmentation can be one or multiple skin patches or spots that appear much darker than your skin color. It is a cell mutation caused by changes in hormones, an injury like sunburn, acne, peeling from chemicals or any treatments, or inflammation. The darker areas of hyperpigmentation are excess deposits of melanin. And although it is harmless and common, having hyperpigmentation can make people more conscious about their looks. In fact, some people try to conceal it with cosmetic products, while some try to deal with it with professional help.
Age spots: As we age, brown, black or tan skin spots may develop on our hands, face, and/or head. These mostly affect light-skinned individuals and are caused by too much exposure from the sun.
Melasma: Usually caused by hormonal changes, melasma is common in women, especially those who are pregnant. It is composed of large patches of darkened skin that can appear on the face or stomach. Those with darker skin are more likely to have melasma.
Inflammation: This is caused by autoimmune reactions from skin conditions like acne and eczema or a skin injury. Post-inflammatory hyperpigmentation appears on the face and neck, and its appearance may vary depending on the skin tone. Inflammation can happen to anyone, regardless of skin color and origin.
There are different treatment options for hyperpigmentation, depending on your skin tone. Fair skin can be treated by most hyperpigmentation procedures, such as laser treatments and micro peeling. Medium skin usually reacts better with chemical peels and microdermabrasion therapy. Darker skin can benefit from using glycolic acid, kojic acid, microdermabrasion in a low setting, lower-strength chemical peels, and low-intensity laser treatments.
Some important things to watch out for when treating hyperpigmentation include:
Photobiomodulation is another name for red light therapy. It may help the body produce more energy and regenerate the skin by using natural light. This can also be used on hyperpigmentation and other skin injuries like acne, inflammation, burns, and scars. When used consistently, light therapy is highly effective in reducing and healing hyperpigmentation patches and helping them return to normal pigment levels.
Red light therapy is a powerful, advanced relief for skin inflammation. Skin cells heal and rejuvenate better when exposed to healthy wavelengths of light, which can help treat hyperpigmentation.
There’s a study that shows near-infrared light can help produce tyrosinase enzyme, which prevents melanin production. This helps patients with vitiligo stimulate melanocytes, the same compound in vitamin C that helps lighten hyperpigmentation. But the truth is, there is no clear clinical consensus among photomedicine researches about using near-infrared light for hyperpigmentation.
Red light wavelengths are considered to be safe as it does not stimulate the production of pigment. It creates healthy wavelengths of light to help the skin cells heal and rejuvenate naturally.
Results can be seen after several treatments done per week. The level of skin improvement depends on how consistently you use red light therapy. Also, the more consistent and the more careful you are in the process, the better the results you can see. Be sure not to pick or touch the treated areas to avoid infection or irritation.
Light therapy, especially when combined with other treatment options, can greatly help remove hyperpigmentation. To learn more benefits of red light therapy, you may reach out to us. We offer safe and easy-to-use light therapy devices that physicians use both for aesthetic and medical purposes. Meanwhile, if you have more questions about hyperpigmentation, please reach out to your dermatologist.
https://www.aocd.org/page/Hyperpigmentation#
https://www.healthline.com/health/hyperpigmentation
As the most accessible element in the globe, hydrogen plays a huge role in our biological processes. However, you may not know that hydrogen usually brings an uninvited guest in your body, and we call it deuterium. Having high deuterium levels may change the chemical reactions in your cells and affect your bodily functions and metabolism, leading to unwanted health consequences.
Deuterium is also known as a “heavy hydrogen” and is one of the two stable hydrogen isotopes. We commonly have it in our bodies — in fact, it helps children grow. However, adults may have too much deuterium because of dietary and environmental factors. As mentioned above, this may lead to chemical reactions at a cellular level and lead to health risks.
Hydrogen is necessary for our day-to-day bodily functions. Our biological processes require it, and we usually get it from what we eat or drink. Upon intake, hydrogen goes to the mitochondria, also known as the powerhouse of the cells.
Our mitochondria can be compared to thousands of engines that continually run to produce the ATP energy we need to survive daily. The majority of people eat only three to five pounds of food each day, but we usually make more than 170 pounds of ATP energy at the same time.
On the other hand, deuterium is like hydrogen’s “evil” sibling. And we repeat, excess deuterium is harmful to our bodies. Because it is twice as heavy and large as hydrogen, it may damage the nanomotors in your mitochondria and slow down ATP energy production. As time goes by, the wear and tear on your nanomotors caused by the heavy hydrogen atoms may completely break your nanomotors. This damage may cause muscle pain, dehydration, impaired memory, poor sleep, headaches, and lymph nodes.
Two “D-terminator” diagnostic tests can help measure the deuterium levels in your body. Advanced technology, such as magnetic resonance imaging (MRI), can also be used to visualize and track deuterium patterns in your body, whether it’s in your bodily fluids, DNA, or even your hair and nails. Based on these tests, your doctor will be able to determine your deuterium levels. And when it shows to be excessive, he/she may come up with a plan to deplete deuterium in your body.
We experience high deuterium levels because of what we eat or drink and some other environmental factors. For instance, carbohydrates, processed foods, and synthetic supplements contain high levels of deuterium. Tap, ocean, and river water also have high deuterium levels, so when you’re exposed to these things regularly, you may experience an overload of this hydrogen isotope.
Nutrition is the baseline of depleting deuterium. Based on your test results, your doctor may recommend consuming food groups that contain lower levels of deuterium, such as proteins, green vegetables, and healthy fats. You may also be advised to drink deuterium-depleted water to lower your deuterium levels.
Health experts say that a body that functions properly can naturally regulate deuterium levels and produce healthy amounts of ATP energy.
Red and near-infrared light can affect our body’s hydrogen bonds in a process quite similar to photosynthesis. The water inside our cells usually becomes less harmful when our bodies absorb wavelengths of red and near-infrared light between 600–950 nanometers. This helps with proper cellular respiration and helps increase ATP energy production in your body.
Changing the water's resistance in your body, red, and near-infrared light can help reduce the amount of friction at the cellular level, promote cellular longevity, and lead to higher outputs of good energy.
To learn more about the benefits of red light therapy or to see what kind of red and near light therapy devices you can use to lower your deuterium levels, click here.
Corrective and preventive action (CAPA or simply corrective action) consists of improvements to an organization's processes taken to eliminate causes of non-conformities or other undesirable situations.
The key thing about the CAPA process is that there are a lot of different processes that feed into it. You need to be diligent, but also apply scrutiny to what does and doesn’t require CAPA. Remember, it should be reserved for those systemic issues - every issue is not a CAPA!
Once you have something that’s worthy of a CAPA, here are the steps:
Like any other organ or part of the human body, the brain, too, is susceptible to injuries or declining functions, especially as we grow older. A healthy diet, physical exercise, and improving your blood pressure, blood sugar, or blood cholesterol levels are some of the ways through which you can maintain a healthier, younger brain.
The brain can suffer from numerous disorders that can be divided into:
Mentally stimulating activities are vital to keeping the brain young. Different brain activities, such as solving puzzles, math problems, or anything that may require at least some cognitive effort, contributes to the maintenance of the brain’s neural plasticity.
Neural plasticity is the ability of the central nervous system (CNS) to adapt to changes in the environment, aging, trauma, or injuries. It’s an important brain process in which neural networks work together to build a more resilient nervous system and maintain its proper functioning.
The first placebo-controlled study to demonstrate some of the benefits of Light Therapy treatments on the human brain was performed in 2013. Multiple improvements were observed among participants who received Light Therapy compared to the placebo group. Light therapy participants experienced:
In a more recent study effort, researchers treated older adults who were at risk of cognitive decline with Light Therapy. A positive neurocognitive effect was observed among the participants in this study, all of whom aged between 49 and 90. Some of the participants also struggled with cognitive decline due to vascular disease, however, Light Therapy was effective regardless of the nature of their cognitive decline.
As Light Therapy helped the elderly participants boost cognitive scores, researchers on the team were also able to observe their increased brain waves power (alpha, beta, and gamma brain waves in their resting state).
Combating age-related cognitive decline with Light Therapy has been in the focus of another recent study, published in February 2019. This study examined the frontal brain functions among elderly men. Frontal brain functions are key to directing behavior. The participants were divided into two groups, treatment, and placebo. Those who received treatment indeed showed improved cognitive performance following the treatment. These results demonstrate that Light Therapy can really work in a safe manner to treat age-related cognitive decline.
As of 2017, we also know that Light Therapy can improve the brain’s executive function. This is your ability to manage time, pay attention, change focus, plan, organize, multitask, remember details, or avoid saying the wrong thing at the wrong time3. In other words, the ability to create and meet goals.
As research further suggests, Light Therapy helped study participants to better perform in the Wisconsin Card Sorting Task (WCST)4. This is a neurophysiological test where the task-takers are asked to match a set of cards presented to them, in an attempt to assess their ability to demonstrate cognitive flexibility–a key process in cognitive ability. They are not told how to match the cards, but only if their particular match is correct or not. The WCST is a clinical way to measure the brain’s executive function. Those participants who received Light Therapy made fewer errors on the task and demonstrated improved set-shifting ability compared to the control group.
Such results suggest that Light Therapy improves the brain’s executive function and may have intriguing potentials for treating or preventing deficits resulting both from aging or neuropsychological disorders which include conditions such as epilepsy, stroke, migraines, brain tumors, dementia, multiple sclerosis, Parkinson’s and Alzheimer’s among others.
In 2017, scientists tested 118 people to see if Light Therapy can have a meaningful impact on their learning abilities. In a similar fashion to previous research, the participants were divided into treatment and placebo groups. Light Therapy showed that the treatment group improved their learning capabilities.
During the trial, the Light Therapy device was directed at the lateral prefrontal cortex of participants, and following treatments, they experienced faster and better rule-based learning5. So, imagine having all participants been bartenders demanded to know the exact ingredients of Mojito, Bloody Mary, Margarita, and other essential cocktails. This Light Therapy treatment would have aided their ability to remember all the ingredients needed for fashioning each drink, adding each ingredient in the desired sequence, or remember who on the table ordered a stronger Bloody Mary. We demonstrate this type of ability through our brain’s rule-based learning capacity.
Different life events may inhibit our brain’s ability to learn. Aging certainly is one of them. Other reasons may include extended exposures to pesticides or neurotoxins, which impair the mitochondria in brain cells. Since Light Therapy kind of “exercises” the mitochondria and prompts the brain to forge new neural networks, the process itself acts as a cognitive rehabilitation6. Which also leads us to the next section.
Cognitive decline may occur due to traumatic brain injuries, too. A person who suffers from one may face memory or concentration problems, mood swings, depression, anxiety, or speech problems among other TBI manifestations. What gives hope is another batch of studies that attests to the positive cognitive benefits among TBI patients from receiving Light Therapy.
Light Therapy has been shown to stimulate the growth of new nerve tissue and synapses in damaged brain cells, thus improving the cognitive brain functions of those patients who not only suffer from TBI but also from Chronic traumatic encephalopathy (CTE). The latter is a degenerative brain disease prevalent among athletes and military veterans or anyone who presents with a history of repetitive brain trauma.
https://www.webmd.com/add-adhd/executive-function#1
https://www.sciencedaily.com/releases/2015/04/150402161648.htm
https://www.cambridgecognition.com/cantab/cognitive-tests/memory/delayed-matching-to-sample-dms/
https://www.health.harvard.edu/mind-and-mood/12-ways-to-keep-your-brain-young
https://en.wikipedia.org/wiki/Psychomotor_vigilance_task
https://www.radiologyinfo.org/en/info.cfm?pg=carotid-intima
https://www.mayoclinic.org/diseases-conditions/traumatic-brain-injury/symptoms-causes/syc-20378557
https://brainworksneurotherapy.com/what-are-brainwaves
https://concussionfoundation.org/CTE-resources/what-is-CT
https://en.wikipedia.org/wiki/Wisconsin_Card_Sorting_Test.
Migraine is a neurological condition that can cause multiple symptoms. It’s frequently characterized by intense, debilitating headaches. Symptoms may include nausea, vomiting, difficulty speaking, numbness or tingling, and sensitivity to light and sound. Migraines often run in families and affect all ages.
People describe migraine pain as:
Migraine symptoms may begin one to two days before the headache itself. This is known as the prodrome stage. Symptoms during this stage can include:
The effects of green light on the brain have been researched and well-documented for years. The green light can reset the circadian rhythm through melatonin, the hormone that regulates our sleep-wake cycles. A special photoreceptor system in the human eye picks up light and elicits non-visual responses, sending signals to the brain to reset the body’s internal clock and altering melatonin production levels.
Long-time sufferers of migraines and other chronic pain conditions may benefit from exposure to LED green light. A new study, led by pharmacologist Mohab M. Ibrahim, M.D., Ph.D., found that the color green may be key to easing pain.
Ibrahim’s interest in studying the ameliorating effects of green light was inspired by his brother, who has dealt with severe headaches for several years. Instead of taking ibuprofen, his brother would sit in his garden and soak up the verdure of nature to ease the pain from his headaches.
“I wanted to see what is in his garden or in a garden, in general, that would make headaches better,” said Ibrahim, director of the Chronic Pain Management Clinic at Banner — University Medical Center Tucson.
In his clinical practice, Ibrahim also saw that his patients suffering from migraines and fibromyalgia had limited treatment options, and wanted to find a novel, non-invasive, nonpharmacological therapy.
In his study, which has yet to be published, Ibrahim exposed 25 migraine volunteers first to white lights for two hours as a control, then to green LED lights. He measured multiple parameters, including pain reduction, frequency of migraines or headaches, frequency of fibromyalgia flare-ups, pain intensity and duration, and quality of life.
On a scale of 0 to 10, with 0 indicating no pain and 10 the highest level of pain, migraine volunteers had an initial average baseline pain score of 8. After completing the green light therapy, their score dropped down to an average of 2.8. The frequency of headaches dropped from 19 to 6.5 per month, and the overall quality of life climbed from 48 percent to 78 percent.
“The best part about it … is the simplicity, the affordability and, most importantly, the lack of side effects,” Ibrahim said. “It’s a normal light. We’re not using a high-energy laser or anything like that.”
But if pain works through the nervous system, how exactly can green light, which works through the visual system, make people feel better?
New studies show that there are neuronal connections that span from the retina all the way to the spinal cord, passing through the parts of the brain that control and modulate pain. Green light changes the levels of serotonin and alters the endogenous opioid system, an innate pain-relieving system found throughout the central and peripheral nervous system, gastrointestinal tract, and immune system, said Bing Liao, M.D., a neurologist at Houston Methodist Hospital.
“The endogenous opioid system … allows the body to generate something similar to opioids and gives us a sensation of pain relief and happy feeling,” Liao said. “Research has found that, with green light, the receptors of the endogenous opioid system can increase production in the brain and body, and the hormone by itself can increase in production, as well. … It might be an explanation for why people feel good when they’re in a green environment.”
While more studies must be done to test the efficacy of green light therapy as a treatment for chronic pain, Ibrahim said he is trying to advance this therapy as a complement to current therapies.
“What this green light therapy offers is a non-invasive, non-pharmacological additional tool, so it might help reduce opioids,” he said. “I don’t think it will eliminate opioids, but at least it may reduce it enough. It may provide people just with extra help or extra relief so that they may not need the number of opioids that they’re on.”
https://www.ncbi.nlm.nih.gov/pubmed/28001756
https://www.ncbi.nlm.nih.gov/pubmed/21182447
https://www.ncbi.nlm.nih.gov/pubmed/23964217
https://www.ncbi.nlm.nih.gov/pubmed/7769534
https://www.ncbi.nlm.nih.gov/pubmed/26989758
