Refractive error

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Refractive error
Other namesRefraction error
Refractive Errors of the Eye.jpg
A correctly-focused eye (top), and two showing refractive error: In the middle image, the light is focused too far forward; in the bottom image, the focal point is behind the eye.
Specialty Ophthalmology, optometry
Symptoms Blurry vision, double vision, headaches, eye strain
Complications Blindness, amblyopia [1] [2]
Types Near-sightedness, far-sightedness, astigmatism, presbyopia
Causes Eyeball length, problems with cornea shape, aging of the lens
Diagnostic method Eye examination
Treatment Eyeglasses, contact lenses, refractive surgery
Frequency~1.5 billion

Refractive error is a problem with focusing light accurately on the retina due to the shape of the eye and/or cornea. [3] The most common types of refractive error are near-sightedness, far-sightedness, astigmatism, and presbyopia. Near-sightedness results in far away objects being blurry, far-sightedness and presbyopia result in close objects being blurry, and astigmatism causes objects to appear stretched out or blurry. Other symptoms may include double vision, headaches, and eye strain. [3]

Contents

Near-sightedness is due to the length of the eyeball being too long; far-sightedness the eyeball too short; astigmatism the cornea being the wrong shape, while presbyopia results from aging of the lens of the eye such that it cannot change shape sufficiently. [3] Some refractive errors occur more often among those whose parents are affected. Diagnosis is by eye examination.

Refractive errors are corrected with eyeglasses, contact lenses, or surgery. [3] Eyeglasses are the easiest and safest method of correction. Contact lenses can provide a wider field of vision; however they are associated with a risk of infection. Refractive surgery may consist of either permanently changing the shape of the cornea or, alternatively, implanting intraocular lenses. [3] [4]

The number of people globally with refractive errors has been estimated at one to two billion. [5] Rates vary between regions of the world with about 25% of Europeans and 80% of Asians affected. [5] Near-sightedness is the most common disorder. [6] Rates among adults are between 15 and 49% while rates among children are between 1.2 and 42%. [7] Far-sightedness more commonly affects young children and the elderly. [8] [9] Presbyopia affects most people over the age of 35. [3]

The number of people with refractive errors that have not been corrected was estimated at 660 million (10 per 100 people) in 2013. [10] Of these 9.5 million were blind due to the refractive error. [10] It is one of the most common causes of vision loss along with cataracts, macular degeneration, and vitamin A deficiency. [11]

Classification

Top: farsighted corrected using convex lens. Bottom: nearsighted corrected using concave lens. Refractive error.jpg
Top: farsighted corrected using convex lens. Bottom: nearsighted corrected using concave lens.

Refractive error – sometimes called "ametropia" – refers to a condition in which the refractive power of an eye does not match the length of the eye, so the image is focused away from the central retina, instead of directly on it. [12]

Types of refractive error include myopia, hyperopia, presbyopia, and astigmatism.

Children are typically born hyperopic and shift toward emmetropia or myopia as their eyes lengthen through childhood. [17]

Other terminology include anisometropia, when the two eyes have unequal refractive power, [18] and aniseikonia, when the magnification power between the eyes differ. [19]

Refractive errors are typically measured using three numbers: sphere, cylinder, and axis. [20]

An eye that has no refractive error when viewing distant objects is said to have emmetropia or be emmetropic meaning the eye is in a state in which it can focus parallel rays of light (light from distant objects) on the retina, without using any accommodation. A distant object, in this case, is defined as an object located beyond 6 meters, or 20 feet, from the eye, since the light from those objects arrives as essentially parallel rays when considering the limitations of human perception. [21]

Risk factors

Genetics

Fundus of person with retinitis pigmentosa, early stage Fundus of patient with retinitis pigmentosa, early stage.jpg
Fundus of person with retinitis pigmentosa, early stage

There is evidence to suggest genetic predilection for refractive error. Individuals that have parents with certain refractive errors are more likely to have similar refractive errors. [3]

The Online Mendelian Inheritance in Man (OMIM) database has listed 261 genetic disorders in which myopia is one of the symptoms. [22] Myopia may be present in heritable connective tissue disorders such as: Knobloch syndrome (OMIM 267750); Marfan syndrome (OMIM 154700); and Stickler syndrome (type 1, OMIM 108300; type 2, OMIM 604841). [23] Myopia has also been reported in X-linked disorders caused by mutations in loci involved in retinal photoreceptor function (NYX, RP2, MYP1) such as: autosomal recessive congenital stationary night blindness (CSNB; OMIM 310500); retinitis pigmentosa 2 (RP2; OMIM 312600); and Bornholm eye disease (OMIM 310460). [23] Many genes that have been associated with refractive error are clustered into common biological networks involved in connective tissue growth and extracellular matrix organization. [23] Although a large number of chromosomal localisations have been associated with myopia (MYP1-MYP17), few specific genes have been identified. [22]

Environmental

In studies of the genetic predisposition of refractive error, there is a correlation between environmental factors and the risk of developing myopia. [24] Myopia has been observed in individuals with visually intensive occupations. [23] Reading has also been found to be a predictor of myopia in children. It has been reported that children with myopia spent significantly more time reading than non-myopic children who spent more time playing outdoors. [23] Additionally, focusing on near objects for long periods of time - such as when reading, looking at close screens, or writing - has been associated with myopia. [25] [26] Socioeconomic status and higher levels of education have also been reported to be a risk factor for myopia. [27] Blepharoptosis can also induce refractive errors. [28]

Normal refraction

In order to see a clear image, the eye must focus rays of light on to the light-sensing part of the eye – the retina, which is located in the back of the eye. This focusing – called refraction – is performed mainly by the cornea and the lens, which are located at the front of the eye, the anterior segment. [29]

When an eye focuses light correctly on to the retina when viewing distant objects, this is called emmetropia or being emmetropic. This means that the refractive power of the eye matches what is needed to focus parallel rays of light onto the retina. A distant object is defined as an object located beyond 6 meters (20 feet) from the eye.[ citation needed ]

When an object is located close to the eye, the rays of light from this object no longer approach the eye parallel to each other. Consequently, the eye must increase its refractive power to bring those rays of light together on the retina. This is called accommodation, and is accomplished by the eye thickening the lens. [29]

Diagnosis

A doctor uses a trial frame and trial lenses to measure the person's refractive error. Refrarction error test.JPG
A doctor uses a trial frame and trial lenses to measure the person's refractive error.

Blurry vision may result from any number of conditions not necessarily related to refractive errors. The diagnosis of a refractive error is usually confirmed by an eye care professional during an eye examination using a large number of lenses of different optical powers, and often a retinoscope (a procedure entitled retinoscopy ) to measure objectively in which the person views a distant spot while the clinician changes the lenses held before the person's eye and watches the pattern of reflection of a small light shone on the eye. Following that "objective refraction" the clinician typically shows the person lenses of progressively higher or weaker powers in a process known as subjective refraction . Cycloplegic agents are frequently used to more accurately determine the amount of refractive error, particularly in children [24]

An automated refractor is an instrument that is sometimes used in place of retinoscopy to objectively estimate a person's refractive error. [30] Shack–Hartmann wavefront sensor and its inverse [31] can also be used to characterize eye aberrations in a higher level of resolution and accuracy.

Vision defects caused by refractive error can be distinguished from other problems using a pinhole occluder, which will improve vision only in the case of refractive error. [32]

Screening

When refractive errors in children are not treated, the child may be at risk of developing ambylopia, where vision may remain permanently blurry. [33] Because young children typically do not complain of blurry vision, the American Academy of Pediatrics recommends that children have yearly vision screening starting at three years old so that unknown refractive errors or other ophthalmic conditions can be found and treated if deemed necessary by healthcare professionals. [33] [34]

Management

The management of refractive error is done post-diagnosis of the condition by either optometrists, ophthalmologists, refractionists, or ophthalmic medical practitioners. [35]

How refractive errors are treated or managed depends upon the amount and severity of the condition. Those who possess mild amounts of refractive error may elect to leave the condition uncorrected, particularly if the person is asymptomatic. For those who are symptomatic, glasses, contact lenses, refractive surgery, or a combination are typically used. [29] [20] [22]

Glasses

These are the most effective ways of correcting the refractive error. However, the availability and affordability of eyeglasses can present a difficulty for people in many low income settings of the world. Glasses also pose a challenge to children to whom they are prescribed to, due to children's tendency to not wear them as consistently as recommended. [36]

As mentioned earlier refractive errors are because of the improper focusing of the light in the retina. Eyeglasses work as an added lens of the eye serving to bend the light to bring it to focus on the retina. Depending on the eyeglasses, they serve many functions.

Reading glasses
These are general over-the-counter glasses which can be worn for easier reading, especially for defective vision due to aging called presbyopia.
Single vision prescription lenses
They can correct only one form of defective vision, either far-sightedness or near-sightedness.
Multifocal lenses
The multifocal lenses can correct defective vision in multiple focus, for example: near-vision as well as far-vision. This are particularly beneficial for presbyobia. [37]

Contact lenses

Alternatively, many people choose to wear contact lenses. One style is hard contact lenses, which can distort the shape of the cornea to a desired shape. Another style, soft contact lenses, are made of silicone or hydrogel. Depending on the duration they are designed for, they may be worn daily or may be worn for an extended period of time, such as for weeks. [35]

There are a number of complication associated with contact lenses. Typically the ones that are used daily.[ citation needed ]

Complications of contact lens wearDescription
Conjunctivitis (giant papillary form)Caused in response to the allergen present in the material from which the contact lens is made from. There is often discomfort in the eye after wearing and vision may be affected. Choosing the right lens material and changing it regularly might prevent conjunctivitis.
Corneal abrasionCaused by a foreign body, dust, sand, or grit trapped under the lens.
Corneal edemaCaused by decreased oxygen delivery to the tissue compressed by the lens. Usually resolved after the removal of the lenses. Discomfort upon lens removal may be seen.
NeovascularizationNew blood vessels may form in the iris region and the limbus. This may impair vision.
InfectionsVarious viral, bacterial, and fungal infection may be seen in the eye post-contact-lens wear, if proper lens hygiene is not maintained. Acanthamoeba are the most common infections in the people using contact lenses.

If redness, itching, and difficulty in vision develops, the use of the lenses should be stopped immediately and the consultation of ophthalmologists may be sought.

Surgery

Laser in situ keratomileusis (LASIK) and photo-refractive keratectomy (PRK) are popular procedures; while use of laser epithelial keratomileusis (LASEK) is increasing. Other surgical treatments for severe myopia include insertion of implants after clear lens extraction (refractive lens exchange). Full thickness corneal graft may be a final option for patients with advanced kerataconus although currently there is interest in new techniques that involve collagen crosslinking. As with any surgical procedure complications may arise post-operatively Post-operative monitoring is normally undertaken by the specialist ophthalmic surgical clinic and optometry services. Patients are usually informed pre-operatively about what to expect and where to go if they suspect complications. Any patient reporting pain and redness after surgery should be referred urgently to their ophthalmic surgeon. [38] [39]

Medical treatment

Atropine has believed to slow the progression of near-sightedness and is administered in combination with multifocal lenses. These, however, need further research. [40] [41]

Prevention

Strategies being studied to slow worsening include adjusting working conditions, increasing the time children spend outdoors, [23] and special types of contact lenses. [42] In children special contact lenses appear to slow worsening of nearsightedness. [42] [43]

A number of questionnaires exist to determine quality of life impact of refractive errors and their correction. [44] [45]

Epidemiology

DALYs per 100,000 people due to refractive errors in 2004. .mw-parser-output .div-col{margin-top:0.3em;column-width:30em}.mw-parser-output .div-col-small{font-size:90%}.mw-parser-output .div-col-rules{column-rule:1px solid #aaa}.mw-parser-output .div-col dl,.mw-parser-output .div-col ol,.mw-parser-output .div-col ul{margin-top:0}.mw-parser-output .div-col li,.mw-parser-output .div-col dd{page-break-inside:avoid;break-inside:avoid-column} .mw-parser-output .legend{page-break-inside:avoid;break-inside:avoid-column}.mw-parser-output .legend-color{display:inline-block;min-width:1.25em;height:1.25em;line-height:1.25;margin:1px 0;text-align:center;border:1px solid black;background-color:transparent;color:black}.mw-parser-output .legend-text{} No data Less than 100 100-170 170-240 240-310 310-380 380-450 450-520 520-590 590-660 660-730 730-800 More than 800 Refractive errors world map - DALY - WHO2004.svg
DALYs per 100,000 people due to refractive errors in 2004.
  No data
  Less than 100
  100–170
  170–240
  240–310
  310–380
  380–450
  450–520
  520–590
  590–660
  660–730
  730–800
  More than 800

It is estimated that at least 2 billion people in the world have refractive errors. [5] The number of people globally with refractive errors that have not been corrected was estimated at 660 million (10 per 100 people) in 2013. [10]

Refractive errors are the first common cause of visual impairment and second most common cause of visual loss . [47] The assessment of refractive error is now done in DALY (Disability Adjusted Life Years) which showed an 8% increase from 1990 to 2019. [48] [ unreliable source ]

The number of people globally with significant refractive errors has been estimated at one to two billion. [5] Rates vary between regions of the world with about 25% of Europeans and 80% of Asians affected. [5] Near-sightedness is one of the most prevalent disorders of the eye. [6] Rates among adults are between 15 and 49% while rates among children are between 1.2 and 42%. [7] Far-sightedness more commonly affects young children, whose eyes have yet to grow to their full length, and the elderly, who have lost the ability to compensate with their accommodation system. [8] [9] Presbyopia affects most people over the age of 35, and nearly 100% of people by the ages of 55–65. [3] Uncorrected refractive error is responsible for visual impairment and disability for many people worldwide. [10] It is one of the most common causes of vision loss along with cataracts, macular degeneration, and vitamin A deficiency. [11]

Cost

The yearly cost of correcting refractive errors is estimated at 3.9 to 7.2 billion dollars in the United States. [49]

See also

References

  1. ↑ "Care of the Patient with Amblyopia" (PDF). American Optometric Association. Archived from the original (PDF) on 19 August 2016. Retrieved 17 February 2020.
  2. ↑ Dandona, R; Dandona, L (2001). "Refractive error blindness". Bulletin of the World Health Organization. 79 (3): 237–43. PMC   2566380 . PMID   11285669.
  3. 1 2 3 4 5 6 7 8 "Facts About Refractive Errors". nei.nih.gov. National Eye Institute. October 2010. Archived from the original on 28 July 2016. Retrieved 29 July 2016.
  4. ↑ Kook, Daniel; Kohnen, Thomas (2012). "31 - Refractive lens exchange". In Spaeth, George L.; Danesh-Meyer, Helen V.; Goldberg, Ivan; Kampik, Anselm (eds.). Ophthalmic Surgery: Principles and Practice (Fourth ed.). W.B. Saunders. pp. 187–191. doi:10.1016/B978-1-4377-2250-5.00031-X. ISBN   978-1-4377-2250-5.
  5. 1 2 3 4 5 Denniston, Alastair; Murray, Philip (2018). Oxford Handbook of Ophthalmology (4 ed.). OUP Oxford. p. 926. ISBN   978-0-19-881675-1.
  6. 1 2 Foster, PJ; Jiang, Y (February 2014). "Epidemiology of myopia". Eye. 28 (2): 202–8. doi:10.1038/eye.2013.280. PMC   3930282 . PMID   24406412.
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  9. 1 2 Grosvenor, Theodore (2007). Primary care optometry (5 ed.). St. Louis (Miss.): Butterworth Heinemann, Elsevier. p. 70. ISBN   978-0-7506-7575-8. Archived from the original on 15 August 2016.
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  12. ↑ Lawrenson, John G.; Huntjens, Byki; Virgili, Gianni; Ng, Sueko; Dhakal, Rohit; Downie, Laura E.; Verkicharla, Pavan K.; Kernohan, Ashleigh; Li, Tianjing; Walline, Jeffrey J. (13 February 2025). "Interventions for myopia control in children: a living systematic review and network meta-analysis". The Cochrane Database of Systematic Reviews. 2025 (2): CD014758. doi:10.1002/14651858.CD014758.pub3. ISSN   1469-493X. PMC   11822883 . PMID   39945354.
  13. ↑ Urone, PP; Hinrichs, R; Dirks, K; Sharma, M (2016). "Vision and Optical Instruments: Vision Correction". College Physics. OpenStax. 26.2.
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  15. ↑ Khurana, AK (September 2008). "Asthenopia, anomalies of accommodation and convergence". Theory and practice of optics and refraction (2nd ed.). Elsevier. pp. 100–103. ISBN   978-81-312-1132-8.
  16. ↑ Grosvenor, Theodore (2007). Primary care optometry (5 ed.). St. Louis (Miss.): Butterworth Heinemann, Elsevier. pp. 17–19. ISBN   978-0-7506-7575-8.
  17. ↑ Saluja, Gunjan; Kaur, Kirandeep (2023), "Childhood Myopia and Ocular Development", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   36508524 , retrieved 31 October 2023
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  19. ↑ "Aniseikonia". EyeWiki. American Academy of Ophthalmology . Retrieved 10 February 2020.
  20. 1 2 Porter, Daniel (18 April 2023). "How to Read an Eyeglasses Prescription". American Academy of Ophthalmology . Retrieved 31 October 2023.
  21. ↑ Bope, Edward T.; Kellerman, Rick D. (2015). Conn's Current Therapy 2016. Elsevier Health Sciences. p. 354. ISBN   978-0-323-35535-3.
  22. 1 2 3 Morgan, Ian G.; Ohno-Matsui, Kyoko; Saw, Seang-Mei (May 2012). "Myopia". The Lancet. 379 (9827): 1739–1748. doi:10.1016/S0140-6736(12)60272-4. PMID   22559900.
  23. 1 2 3 4 5 6 Wojciechowski, Robert (April 2011). "Nature and Nurture: the complex genetics of myopia and refractive error". Clinical Genetics. 79 (4): 301–320. doi:10.1111/j.1399-0004.2010.01592.x. PMC   3058260 . PMID   21155761.
  24. 1 2 Barnes, Katherine (February 2013). "Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia". Clinical Genetics. 45 (3): 314–8. doi:10.1111/j.1399-0004.2010.01592.x. PMC   3740568 . PMID   23396134.
  25. ↑ Huang, Hsiu-Mei; Chang, Dolly Shuo-Teh; Wu, Pei-Chang (20 October 2015). Jhanji, Vishal (ed.). "The Association between Near Work Activities and Myopia in Children—A Systematic Review and Meta-Analysis". PLOS ONE. 10 (10): e0140419. Bibcode:2015PLoSO..1040419H. doi: 10.1371/journal.pone.0140419 . ISSN   1932-6203. PMC   4618477 . PMID   26485393.
  26. ↑ Dutheil, Frédéric; Oueslati, Tharwa; Delamarre, Louis; Castanon, Joris; Maurin, Caroline; Chiambaretta, Frédéric; Baker, Julien S.; Ugbolue, Ukadike C.; Zak, Marek; Lakbar, Ines; Pereira, Bruno; Navel, Valentin (3 January 2023). "Myopia and Near Work: A Systematic Review and Meta-Analysis". International Journal of Environmental Research and Public Health. 20 (1): 875. doi: 10.3390/ijerph20010875 . ISSN   1660-4601. PMC   9820324 . PMID   36613196.
  27. ↑ Foster, P J; Jiang, Y (February 2014). "Epidemiology of myopia". Eye. 28 (2): 202–208. doi: 10.1038/eye.2013.280 . ISSN   0950-222X. PMC   3930282 . PMID   24406412.
  28. ↑ Owji, N; Khalili, MR; Bazrafkan, H; Heydari, M (September 2022). "Long-term outcome of refractive errors in patients with congenital blepharoptosis who have undergone ptosis surgery". Clinical & Experimental Optometry. 105 (7): 715–720. doi:10.1080/08164622.2021.1973344. PMID   34538220. S2CID   237573319.
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  33. 1 2 "Refractive Errors in Children". aapos.org. American Association for Pediatric Ophthalmology and Strabismus. Retrieved 30 October 2023.
  34. ↑ Adam, Henry (2 April 2020). "Vision Screening" . Pediatric Care Online. doi:10.1542/aap.ppcqr.396022. ISSN   2767-6617. S2CID   263605231.
  35. 1 2 Cochrane, Gillian M.; du Toit, Rènée; Le Mesurier, Richard T. Le (12 April 2010). "Management of refractive errors" . BMJ. 340: c1711. doi:10.1136/bmj.c1711. ISSN   0959-8138. PMID   20385718. S2CID   8240093.
  36. ↑ Wedner, S.; Masanja, H.; Bowman, R.; Todd, J.; Bowman, R.; Gilbert, C. (1 January 2008). "Two strategies for correcting refractive errors in school students in Tanzania: randomised comparison, with implications for screening programmes" . British Journal of Ophthalmology. 92 (1): 19–24. doi:10.1136/bjo.2007.119198. ISSN   0007-1161. PMID   18156372. S2CID   2157969.
  37. ↑ "Eyeglasses for Refractive Errors | National Eye Institute". www.nei.nih.gov. Archived from the original on 8 January 2020. Retrieved 29 June 2021.
  38. ↑ Mukamal, Reena (3 May 2023). "10 Cataract Surgery Side Effects, and How to Cope". American Academy of Ophthalmology . Retrieved 6 November 2023.
  39. ↑ "LASIK — Laser Eye Surgery". American Academy of Ophthalmology. 26 July 2023. Retrieved 6 November 2023.
  40. ↑ Shih, Yung-Feng; Hsiao, C. Kate; Chen, Chien-Jen; Chang, Ching-Wei; Hung, Por T.; Lin, Luke L.-K. (June 2001). "An intervention trial on efficacy of atropine and multi-focal glasses in controlling myopic progression". Acta Ophthalmologica Scandinavica. 79 (3): 233–236. doi: 10.1034/j.1600-0420.2001.790304.x . ISSN   1395-3907. PMID   11401629.
  41. ↑ Lee, Jong-Jer; Fang, Po-Chiung; Yang, I-Hui; Chen, Chih-Hsin; Lin, Pei-Wen; Lin, Sue-Ann; Kuo, Hsi-Kung; Wu, Pei-Chang (February 2006). "Prevention of Myopia Progression with 0.05% Atropine Solution" . Journal of Ocular Pharmacology and Therapeutics. 22 (1): 41–46. doi:10.1089/jop.2006.22.41. ISSN   1080-7683. PMID   16503774.
  42. 1 2 Li, X; Friedman, IB; Medow, NB; Zhang, C (1 May 2017). "Update on Orthokeratology in Managing Progressive Myopia in Children: Efficacy, Mechanisms, and Concerns". Journal of Pediatric Ophthalmology and Strabismus. 54 (3): 142–148. doi:10.3928/01913913-20170106-01. PMID   28092397.
  43. ↑ Walline, JJ (January 2016). "Myopia Control: A Review". Eye & Contact Lens. 42 (1): 3–8. doi:10.1097/ICL.0000000000000207. PMID   26513719. S2CID   24069302.
  44. ↑ Kandel H, Khadka J, Goggin M, Pesudovs K (2017). "Patient-reported outcomes for assessment of quality of life in refractive error: a systematic review". Optometry and Vision Science. 94 (12): 1102–1119. doi:10.1097/OPX.0000000000001143. PMID   29095758. S2CID   21512136.
  45. ↑ Kandel H, Khadka J, Lundström M, Goggin M, Pesudovs K (2017). "Questionnaires for measuring refractive surgery outcomes". Journal of Refractive Surgery. 33 (6): 416–424. doi:10.3928/1081597X-20170310-01. PMID   28586503.
  46. ↑ "WHO Disease and injury country estimates". World Health Organization. 2009. Archived from the original on 11 November 2009. Retrieved 11 November 2009.
  47. ↑ Hashemi, Hassan; Fotouhi, Akbar; Yekta, Abbasali; Pakzad, Reza; Ostadimoghaddam, Hadi; Khabazkhoob, Mehdi (27 September 2017). "Global and regional estimates of prevalence of refractive errors: Systematic review and meta-analysis". Journal of Current Ophthalmology. 30 (1): 3–22. doi:10.1016/j.joco.2017.08.009. ISSN   2452-2325. PMC   5859285 . PMID   29564404.
  48. ↑ "Global Disease Burden of Uncorrected Refractive Error Among Adolescents From 1990 to 2019" (PDF). Archived from the original (PDF) on 24 June 2021. Retrieved 21 March 2023.
  49. ↑ Kuryan J, Cheema A, Chuck RS (2017). "Laser-assisted subepithelial keratectomy (LASEK) versus laser-assisted in-situ keratomileusis (LASIK) for correcting myopia". Cochrane Database Syst Rev. 2017 (2): CD011080. doi:10.1002/14651858.CD011080.pub2. PMC   5408355 . PMID   28197998.
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