Radiofrequency Radiation and Head and Neck Cancer and Gland Dysfunction: Cell Phone and Cordless Phone Use
- Parotid Gland
- Thyroid Gland
- Vestibular Neuroma (Acoustic Neuroma)
RFR and Cell Phone Radiation Exposures In The Head and Neck
The head and neck area is exposed to much higher levels of radiofrequency radiation (RFR) when a cell phone or cordless phone is placed in close proximity and usually right against the head, not as tested to comply with FCC standards which are millimeters to centimeters away, depending on the phone.
The thyroid gland, parotid gland and the vestibular nerve are more superficial and thus more vulnerable to the effects of electromagnetic fields. The thyroid gland is located in the midline of the mid neck and regulates many body functions by constantly releasing consistent amounts of thyroid hormones into the bloodstream, which regulate metabolism, growth and development. The parotid gland is located in front of and beneath the ear and functions to release salivary fluid which moistens the mouth, softens food during chewing, initiates digestion and protect the teeth from decay. The vestibular nerve is also called the vestibulocochlear nerve or auditory vestibular nerve and is located inside the ear and connects with nerves for hearing and balance. There are 12 cranial nerves that have a variety of functions in the head area including sensation and movement. The vestibular nerve is also called the eighth cranial nerve and it transmits sound and equilibrium (balance) information from the inner ear to the brain.
The older cell phones had antennas located higher and near the ear. The newer smartphones have many antennas (Cellular, Wi Fi, GPS, LTE and bluetooth) and the location of the primary cellular antenna is now typically located at the lower end of the device. It is no longer a non-retractable antenna but is hidden on a strip on the “smartphones” where the metal is interrupted to allow for transmisssion of the radiofrequency radiation. It is well known that there is a variable but long latency period between exposures to toxins and the development of cancer. Brain tumor studies have shown a significant increase in tumors on the same side of the head where cell phones were used by the subject (Hardell 2013) as well as an increase in brain tumors with long term use of a cell phone (Hardell 2013) and (Interphone Study 2011) .
Tumor Promotion was studied by Alahmad and colleagues (2018) who used chorioallantoic membrane (CAM) and human head and neck cancer cell lines. Their research revealed that cell phone radiofrequency could enhance head and neck cancer by stimulating angiogenesis, cell invasion and colony formation.
Thyroid cancer is now the 12th most common cancer in the United States and accounts for 3% of all new cancer cases. Thyroid cancer has been increasing at a rate of 3.1% per year for the last 10 years. It is estimated by the National Cancer Institute, Surveillance, Epidemiology, and End Results Program (SEER) that there will be 52,070 cases of thyroid cancer in 2019. There is debate about the increased incidence being a result of over diagnosis but research suggests there is a real increase incidence. Hilly et al (2013) demonstrated abnormalities in thyrocytes with just 3 hours of exposure to cell phone radiation frequencies. In addition, studies have show an association of altered thyroid function with increased cell phone use (Asl 2019) and (Baby 2017) and (Sinha 2008).
Thyroid cancer and genetic susceptibility is highlighted in a new study (Luo 2020), which showed a statistically significant increase in those with genetic variants and with longer use of the cell phone.
Parotid tumors are also rising according to SEER data (Del Signore 2017)In a review of the literature Misha (2017) revealed that non-ionizing radiation from cell phones also caused changes in mucous cells and salivary gland dysfunction.
Head and Neck Biological Effects of Cell Phones and Radiofrequency Radiation and Review Articles
- Exposure to non-ionizing electromagnetic fields emitted from mobile phones induced DNA damage in human ear canal hair follicle cells. (2018) Akdag M et al. Electromagn Biol Med. 2018;37:66–75. https://pubmed.ncbi.nlm.nih.gov/29667447/
- Effect of Cell Phone Radiations on Orofacial Structures: A Systematic Review. (2017) Mishra SK et al. J Clin Diagn Res. 2017 May;11(5):ZE01-ZE05. https://pubmed.ncbi.nlm.nih.gov/28658925/
Head and Neck Cancers- General Articles
- Effect of cell-phone radiofrequency on angiogenesis and cell invasion in human head and neck cancer cells. (2018) Alahmad YM. Head Neck. 2018 May 13. https://www.ncbi.nlm.nih.gov/pubmed/29756334
Parotid Gland Tumors
The parotid gland is the largest salivary gland and located in front of each ear. The salivary secretions consist of water, electrolytes, mucus and enzymes which help to pre-digest food (alpha amylase), provide moisture in the mouth for chewing and prevent tooth decay. Parotid tumors are rare and about 25% of parotid tumors are malignant. There is a noted increase in parotid tumors according to SEER data between 1973-2009.
Parotid Tumors and RFR Published Research
- The rising incidence of major salivary gland cancer in the United States. (2017) Del Signore AG et al. Ear Nose Throat J. 2017 Mar;96(3):E13-E16. https://www.ncbi.nlm.nih.gov/pubmed/28346649
- Does cell phone use increase the chances of parotid gland tumor development? A systematic review and meta-analysis. (2017) de Siqueira EC et al. J Oral Pathol Med. 2017 Aug;46(7):480-483. https://www.ncbi.nlm.nih.gov/pubmed/27935126
- Mobile Phone Use and the Risk of Parotid Gland Tumors: A Retrospective Case-Control Study. (2016) Al-Qahtani K. Gulf J Oncolog. 2016 Jan;1(20):71-8. https://www.ncbi.nlm.nih.gov/pubmed/27050182
- Histological and histochemical study of the protective role of rosemary extract against harmful effect of cell phone electromagnetic radiation on the parotid glands. (2016) Ghoneim FM. Acta Histochemica, 118(5):478-485. June 2016. https://www.ncbi.nlm.nih.gov/pubmed/27155802
- Mobile phone radiation and the risk of cancer; a review. (2008) Abdus-salam A et al. Afr J Med Med Sci. 2008 Jun;37(2):107-18. https://www.ncbi.nlm.nih.gov/pubmed/18939393
- Cellular phone use and risk of benign and malignant parotid gland tumors–a nationwide case-control study. (2008) Sadetzki S et al. Am J Epidemiol.2008 Feb 15;167(4):457-67. https://www.ncbi.nlm.nih.gov/pubmed/18063591
- Mobile phone use and risk of parotid gland tumor. (2006) Lonn S et al. Am J Epidemiol. 2006 Oct 1;164(7):637-43. https://www.ncbi.nlm.nih.gov/pubmed/16818464
- No association between the use of cellular or cordless telephones and salivary gland tumours. (2004) Hardell L et al. Occup Environ Med. 2004 Aug;61(8):675-9. https://www.ncbi.nlm.nih.gov/pubmed/15258273
Parotid Gland Dysfunction and Cell Phones- Published Research
- Effect of Cell Phone Radiations on Orofacial Structures: A Systematic Review. (2017) Mishra SK. J Clin Diagn Res. 2017 May;11(5):ZE01-ZE05. https://www.ncbi.nlm.nih.gov/pubmed/28658925
- Cell phone use is associated with an inflammatory cytokine profile of parotid gland saliva. (2016) Siqueira EC et al. J Oral Pathol Med. 2016 Oct;45(9):682-686. https://www.ncbi.nlm.nih.gov/pubmed/26876491
- Effect of electromagnetic radiations from mobile phone base stations on general health and salivary function. (2016) Singh K et al. J Int Soc Prev Community Dent. 2016 Jan-Feb;6(1):54-9. https://www.ncbi.nlm.nih.gov/pubmed/27011934
- Effect of cell phone use on salivary total protein, enzymes and oxidative stress markers in young adults: a pilot study. (2015) J Clin Diagn Res. 2015 Feb;9(2):BC19-22. https://www.ncbi.nlm.nih.gov/pubmed/25859446
- Evaluation of selected biochemical parameters in the saliva of young males using mobile phones. (2015) Abu Khadra KM. Electromagn Biol Med. 2015 Mar;34(1):72-6. https://www.ncbi.nlm.nih.gov/pubmed/24499288
- Effect of mobile phone radiations on oral health. (2015) Dagli R and Hans R. J Int Oral Health. 2015 Jan;7(1):i-ii. https://www.ncbi.nlm.nih.gov/pubmed/25709374
- Cell phone use and parotid salivary gland alterations: no molecular evidence. (2014) de Souza FT et al. Cancer Epidemiol Biomarkers Prev. 2014 Jul;23(7):1428-31. https://www.ncbi.nlm.nih.gov/pubmed/24753545
- Effect of mobile phone use on salivary concentrations of protein, amylase, lipase, immunoglobulin A, lysozyme, lactoferrin, peroxidase and C-reactive protein of the parotid gland. (2014) Hashemipour MS et al. J Laryngol Otol. 2014 May;128(5):454-62. https://www.ncbi.nlm.nih.gov/pubmed/24739140
- Is human saliva an indicator of the adverse health effects of using mobile phones? (2013). Hamzany Y et al. Antioxid Redox Signal. 2013 Feb 20;18(6):622-7. https://www.ncbi.nlm.nih.gov/pubmed/22894683
- Effect of handheld mobile phone use on parotid gland salivary flow rate and volume. (2012) Bhargava S et al. Oral Surgery Oral Med Oral Pathol Oral Radiol. 2012 Aug;114(2):200-6. https://www.ncbi.nlm.nih.gov/pubmed/22769405
Thyroid Gland Tumors
The thyroid gland is a paired endocrine organ located at the base of the neck below the Adam’s apple. The thyroid gland secretes thyroid hormones which affects functioning of all organs of the body. Normal metabolism as well as normal fetal development (especially the brain) is dependent on normal thyroid levels. Thyroid function is discussed here.
The American Thyroid Association in 2017 discussed the worldwide increase in thyroid cancer . They state, “The incidence of thyroid cancer has increased dramatically during the past three decades and it is now the fastest growing cancer in women. Almost all of this increase is in papillary thyroid cancer. The reason for this is unclear, although many point to the increase in imaging studies of the neck where small thyroid nodules are discovered before they become apparent on physical exam. This has led to some investigators stating that thyroid cancer is being over diagnosed, meaning that many of the small thyroid cancers being found would never progress to the stage where survival ort health would be affected. However, there are many factors in the environment that may also cause an increase in thyroid nodules and thyroid cancer, including the release of radiation from nuclear reactor accidents.”
Thyroid Tumors and RFR Published Research
- Is the Increasing Incidence of Thyroid Cancer in the Nordic Countries Caused by Use of Mobile Phones? (2020) Carlberg M et al. Int. J. Environ. Res. Public Health 2020, 17(23), 9129; https://www.mdpi.com/1660-4601/17/23/9129 https://doi.org/10.3390/ijerph17239129
- Genetic susceptibility may modify the association between cell phone use and thyroid cancer: A population-based case-control study in Connecticut. (2020) Luo J et al. Environmental Research, Volume 182. March 2020. https://www.sciencedirect.com/science/article/abs/pii/S0013935119308102?via%3Dihub
- The possible global hazard of cell phone radiation on thyroid cells and hormones: a systematic review of evidences. (2019) Asl JF et al. Environ Sci Pollut Res Int. 2019 Jun;26(18):18017-18031. https://www.ncbi.nlm.nih.gov/pubmed/31062236
- Cell phone use and risk of thyroid cancer: a population-based case-control study in Connecticut. (2019) Luo J et al. Ann Epidermiol. 2019 Jan;29:39-45. https://www.ncbi.nlm.nih.gov/pubmed/30446214
- Cancer Stat Facts: Thyroid Cancer. National Cancer Institute, Surveillance, Epidemiology, and End Results Program (SEER). (2019)
- The Effect of Electromagnetic Radiation due to Mobile Phone Use on Thyroid Function in Medical Students Studying in a Medical College in South India. (2017) Baby NM et al. Indian J Endocrinol Metab. 2017 Nov-Dec; 21(6): 797–802. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729662/
- The role of race in thyroid cancer: systematic review. (2017) Keane E et al. J Laryngol Otol. 2017 Jun;131(6):480-486. https://www.ncbi.nlm.nih.gov/pubmed/28367769
- Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013. (2017) Lim H et al.
- Increasing incidence of thyroid cancer in the Nordic countries with main focus on Swedish data. (2016) Carlberg M et al. BMC Cancer volume 16, Article number: 426 (2016). https://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2429-4
- Thyroid Cancer Screening in South Korea Increases Detection of Papillary Cancers with No Impact on Other Subtypes or Thyroid Cancer Mortality. (2016) Ann HS et al. Thyroid. 2016 Nov;26(11):1535-1540. https://www.ncbi.nlm.nih.gov/pubmed/27627550
- Association between screening and the thyroid cancer “epidemic” in South Korea: evidence from a nationwide study. (2016) Park S et al. BMJ. 2016 Nov 30;355:i5745. https://www.ncbi.nlm.nih.gov/pubmed/27903497
- Korea’s thyroid-cancer “epidemic”–screening and overdiagnosis. (2014) Ann HS et al. N Engl J Med. 2014 Nov 6;371(19):1765-7. https://www.ncbi.nlm.nih.gov/pubmed/25372084
- Trends in thyroid cancer incidence in Texas from 1995 to 2008 by socioeconomic status and race/ethnicity. (2014) Reitzel LR et al. Thyroid. 2014 Mar;24(3):556-67. https://www.ncbi.nlm.nih.gov/pubmed/24063701
- EFFECT OF NON-IONIZING ELECTROMAGNETIC RADIATION AT MOBILE PHONE FREQUENCY ON HUMAN THYROID CELLS. (2013) Hilly O et al.
- Impact of enhanced detection on the increase in thyroid cancer incidence in the United States: review of incidence trends by socioeconomic status within the surveillance, epidemiology, and end results registry, 1980-2008. (2013) Li N et al. Thyroid. 2013 Jan;23(1):103-10. https://www.ncbi.nlm.nih.gov/pubmed/23043274
- Thyroid cancer incidence patterns in the United States by histologic type, 1992-2006. (2011) Aschebrook-Kilfoy B et al. Thyroid. 2011 Feb;21(2):125-34. https://www.ncbi.nlm.nih.gov/pubmed/21186939
- Alterations in TSH and Thyroid Hormones following Mobile Phone Use. (2009) Mortavazi S. et al. Oman Med J. 2009 Oct;24(4):274-8. https://www.ncbi.nlm.nih.gov/pubmed/22216380
- Changing patterns in the incidence and survival of thyroid cancer with follicular phenotype–papillary, follicular, and anaplastic: a morphological and epidemiological study. (2007) Albores-Saavedra J et al. Endocrine Pathology. 2007 Spring;18(1):1-7. https://www.ncbi.nlm.nih.gov/pubmed/17652794
Thyroid Gland Dysfunction and Cell Phones
- The possible global hazard of cell phone radiation on thyroid cells and hormones: a systematic review of evidences. (2019) Asi JF et al. Environ Sci Pollut REs Int. 2019 Jun;26(18):18017-18031. https://www.ncbi.nlm.nih.gov/pubmed/31062236
- Exposure to non-ionizing radiation provokes changes in rat thyroid morphology and expression of HSP-90. (2015) Misa-Agustiño MJ et al. Exp Biol Med (Maywood). 2015 Feb 2. https://www.ncbi.nlm.nih.gov/pubmed/25649190
- Plasma thyroid hormones and corticosterone levels in blood of chicken embryos and post hatch chickens exposed during incubation to 1800 MHz electromagnetic field. (2014) Pawlak K, Sechman A, Nieckarz Z. Int J Occup Med Environ Health. 2014 Jan 31.https://www.ncbi.nlm.nih.gov/pubmed/24488772
- Modulation of wireless (2.45 GHz)-induced oxidative toxicity in laryngotracheal mucosa of rat by melatonin. ( 2013) Aynali G et al. Eur Arch Otorhinolaryngol. 2013;270(5):1695–700. https://www.ncbi.nlm.nih.gov/pubmed/23479077
- Pulse modulated 900 MHz radiation induces hypothyroidism and apoptosis in thyroid cells: a light, electron microscopy and immunohistochemical study. (2010) Esmekaya MA et al. Int J Radiat Biol. 2010 Dec;86(12):1106-16. https://www.ncbi.nlm.nih.gov/pubmed/20807179
- Alterations in TSH and thyroid hormones following mobile phone use. (2009) Mortavazi S et al. Oman Med J. 2009 Oct;24(4):274-8. https://www.ncbi.nlm.nih.gov/pubmed/22216380
- Chronic non-thermal exposure of modulated 2450 MHz microwave radiation alters thyroid hormones and behavior of male rats.(2008) Sinha RK. Int J Radiat Biol. 2008 Jun;84(6):505-13. https://www.ncbi.nlm.nih.gov/pubmed/18470749
- Effects of 900 MHz electromagnetic field on TSH and thyroid hormones in rats. (2005) Toxicol Lett. 2005 Jul 4;157(3):257-62. https://www.ncbi.nlm.nih.gov/pubmed/15917150
Other Relevant Articles on Thyroid Dysfunction
- Contaminant and Environmental Influences on Thyroid Hormone Action in Amphibian Metamorphosis. (2019) Thambirajah A et al. Frontiers in Endocrinology. Review May 14, 2019. https://pdfs.semanticscholar.org/6dda/b12f6bc70837d5c84991bddd82aa06937363.pdf
Vestibular Nerve Tumors (Acoustic Neuromas)
An acoustic neuroma (also known as vestibular Schwannoma) is a slow growing benign tumor of Schwann nerve cells located in the inner ear on the vestibular nerve (See #20 on the diagram). The Vestibular nerve transmits sensory information on hearing and balance to the brain. With slow tumor growth the nerve is gradually compressed and causes increased symptoms of hearing loss (usually just on the affected side), ringing in the ear, loss of balance and facial numbness.
As the facial nerve which controls facial motion is located nearby, facial weakness can occur as well, but it is very rare. About 1 in 100,000 people per year develop an acoustic neuroma.
Acoustic Neuroma (Vestibular Neuroma), Cell Phone and Cordless Phone Use and RFR Published Research
- Mobile phone use and risk of brain tumours: a systematic review of association between study quality, source of funding, and research outcomes. (2017) Neurol Sci. 2017 May;38(5):797-810. https://pubmed.ncbi.nlm.nih.gov/28213724/
- Association between vestibular schwannomas and mobile phone use. (2014) Moon S et al. Yumour Biology. 2014 Jan;35(1):581-7. https://pubmed.ncbi.nlm.nih.gov/23975478/
- Pooled analysis of case-control studies on acoustic neuroma diagnosed 1997-2003 and 2007-2009 and use of mobile and cordless phones. (2013) Hardell L et al. Int J Oncol. 2013 Oct; 43(4):1036-44. https://pubmed.ncbi.nlm.nih.gov/23877578/
- Use of mobile phones and cordless phones is associated with increased risk for glioma and acoustic neuroma. (2013) Hardell et al. Pathophysiology. 2013 Apr;20(2):85-110. https://www.ncbi.nlm.nih.gov/pubmed/23261330
- Mobile phones and head tumours. The discrepancies in cause-effect relationships in the epidemiological studies – how do they arise? Levis AG et al. Environ Health. 2011 Jun 17;10:59. https://pubmed.ncbi.nlm.nih.gov/21679472/
- Cell phone use and acoustic neuroma: the need for standardized questionnaires and access to industry data. (2009) Han YY et al. Surg Neurol. 2009 Sep;72(3):216-22. https://www.ncbi.nlm.nih.gov/pubmed/19328527
- Cell phones and brain tumors: a review including the long-term epidemiologic data. Khurana VG. Surg Neurol. 2009 Sep;72(3):205-14; https://pubmed.ncbi.nlm.nih.gov/19328536/
- Long-term use of cellular phones and brain tumours: increased risk associated with use for > or =10 years. (2007) Hardell L et al. Occup Environ Med. 2007 Sep;64(9):626-32. https://pubmed.ncbi.nlm.nih.gov/17409179/
- Pooled analysis of two Swedish case-control studies on the use of mobile and cordless telephones and the risk of brain tumours diagnosed during 1997-2003. (2007) Int J Occup Saf Ergon. 2007;13(1):63-71. https://pubmed.ncbi.nlm.nih.gov/17362659/
- Tumour risk associated with use of cellular telephones or cordless desktop telephones. (2006) Hardell L et al. World J Surg Oncol. 2006 Oct 11;4:74. https://pubmed.ncbi.nlm.nih.gov/17034627/
- Mobile telephones and cancer–a review of epidemiological evidence. (2004) Kundi et al . J Toxicol Environ Health B Crit Rev. 2004 Sep-Oct;7(5):351-84. https://www.ncbi.nlm.nih.gov/pubmed/15371240
- Further aspects on cellular and cordless telephones and brain tumours. (2003) Hardell L et al. Int J Oncol. 2003 Feb;22(2):399-407. https://pubmed.ncbi.nlm.nih.gov/12527940/
- Cellular and cordless telephones and the risk for brain tumours. (2002) Hardell L et al. Euro J Cancer Prev. 2002 Aug;11(4):377-86. https://pubmed.ncbi.nlm.nih.gov/12195165/
Incidence of Acoustic Neuroma
- Incidence of Vestibular Schwannoma in Taiwan from 2001 to 2012: A Population-Based National Health Insurance Study. ( 2018) Ann Otol Rhinol Laryngol. 2018 Oct;127(10):694-697. https://www.ncbi.nlm.nih.gov/pubmed/30032646
- Vestibular schwannoma appears to be very rare in a region of Sub-Saharan Africa. (2017) Surg Neurol Int. 2017; 8: 171. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551295/
- Real Incidence of Vestibular Schwannoma? Estimations From a National Registry. (2016) Kleijwegt M et al. Otol Neurotol.. 2016 Oct;37(9):1411-7. https://www.ncbi.nlm.nih.gov/pubmed/27525713
Hearing and Tinnitus Effects of Cell Phones and RFR
- Effects of exposure to 2100MHz GSM-like radiofrequency electromagnetic field on auditory system of rats. (2017) Çeliker M et al. Braz J Otorhinolaryngol. 2017 Nov – Dec;83(6):691-696. https://www.ncbi.nlm.nih.gov/pubmed/27865708
- A study on the effect of prolonged mobile phone use on pure tone audiometry thresholds of medical students of Sikkim. Das S et al. J Postgrad Med. Oct-Dec 2017;63(4):221-225. https://pubmed.ncbi.nlm.nih.gov/28272071/
- Tinnitus and cell phones: the role of electromagnetic radiofrequency radiation. Brazilian Journal of Otorhinolaryngology.Medeiros LN, Sanchez TG. 82(1):97-104.January–February 2016. Open Access: http://www.sciencedirect.com/science/article/pii/S1808869415001639
- Effects of chronic exposure to electromagnetic waves on the auditory system. (2015) Ozgur A et al. Acta Otolaryngol. 2015 Aug;135(8):765-70. https://www.ncbi.nlm.nih.gov/pubmed/25836770
- Audiologic disturbances in long-term mobile phone users. (2010) Panda NK et al. J Otolaryngol Head Neck Surg. 2010 Feb;39(1):5-11. https://www.ncbi.nlm.nih.gov/pubmed/20122338
- [Effects of electromagnetic fields emitted by cellular phone on auditory and vestibular labyrinth]. (2007) Sievert U. et al. Laryngorhinootologie. 2007 Apr;86(4):264-70. https://www.ncbi.nlm.nih.gov/pubmed/17163379
- Do mobile ‘phones have a detrimental impact on auditory function? (2006) Khalil Sand Nunez DA. J Laryngol Otol. 2006 Oct;120(10):822-6. https://www.ncbi.nlm.nih.gov/pubmed/16700958
- Effects of intensive and moderate cellular phone use on hearing function. (2006)Oktay MF and Dasdag S .Electromagn Biol Med. 2006;25(1):13-21. https://www.ncbi.nlm.nih.gov/pubmed/16595330
- The effect of mobile phone to audiologic system. (2005) J Med Assoc Thai. 2005 Sep;88 Suppl 4:S231-4. Kerekhanjanarong V et al. https://www.ncbi.nlm.nih.gov/pubmed/16623034
- Can mobile phone emissions affect auditory functions of cochlea or brain stem? (2005) Sievert U et al. Otolaryngol Head Neck Surg. 2005 Mar;132(3):451-5. https://www.ncbi.nlm.nih.gov/pubmed/15746860
- Thirty minutes mobile phone use has no short-term adverse effects on central auditory pathways. (2003) Arai N et al. Clin Neurophysiol. 2003 Aug;114(8):1390-4. https://www.ncbi.nlm.nih.gov/pubmed/12888020
Mucosal Tumors of the head and Neck
- Genotoxicity assessment data for exfoliated buccal cells exposed to mobile phone radiation. (2017) Oliveira F et al. https://www.ncbi.nlm.nih.gov/pubmed/29214197