TGIF and welcome back to Dr Euan's Friday Blog!
Many of us (MOH reports 6 /10 Singaporeans) have been infected by the SARS COVID 2 virus! Despite a high rate of vaccination and boosters, it seems that the new Variants eg BA 4 & BA 5 are managing to evade the current vaccines! Thankfully, most of us have only suffered mild symptoms eg. sore throat, cough, stuffy nose & fever.
However, a small percentage of us lose our Olfactory senses (smell) and / or taste due to the COVID infection. This loss in sense of smell can be temporary or permanent.
So what should you do?
Q: How does a covid infection affect my sense of smell/taste?
Temporary loss of Olfaction or smell, also known as anosmia, or a reduction in the sense of smell (hyposmia) is the main neurological symptom and one of the earliest and most commonly reported indicators of COVID-19. Studies suggest anosmia better predicts the disease than other well-known symptoms such as fever and cough, but the underlying mechanisms for the cause of loss of smell in patients with COVID-19 have been unclear.
Recently, an international team of researchers led by neuroscientists at Harvard Medical School has identified the olfactory cell types in the upper nasal cavity most vulnerable to infection by SARS-CoV-2, the virus that causes COVID-19.
Surprisingly, sensory neurones that detect and transmit the sense of smell to the brain are not among the vulnerable cell types.
Besides COVID infection, there are also many other possible causes of Anosmia and Hyposmia, including head trauma, contrecoup neck injuries, sino-nasal infections and tumours, to name a few.
Q: How common is anosmia?
A majority of COVID-19 patients experience some level of anosmia, most often temporary. Analyses of electronic health records indicate that COVID-19 patients are 27 times more likely to have smell loss but are only around 2.2 to 2.6 times more likely to have a fever, cough or respiratory difficulty, compared to patients without COVID-19.
Some studies have hinted that anosmia in COVID-19 differs from anosmia caused by other viral infections, including by other coronaviruses. For example, COVID-19 patients typically recover their sense of smell over the course of weeks—much faster than the months it can take to recover from anosmia caused by a subset of viral infections known to directly damage olfactory sensory neurons. In addition, many viruses cause temporary loss of smell by triggering upper respiratory issues such as a stuffy nose. Some COVID-19 patients, however, experience anosmia without any nasal obstruction.
Q: Will I be able to recover my sense of smell/taste?
Persistent COVID-19–related anosmia has an excellent prognosis with nearly complete recovery at 1 year.
As clinicians manage an increasing number of people with the post-COVID syndrome, data on long-term outcomes are needed for informed prognostication and counselling. In other words, time will tell!
Don't forget that almost any Acute Respiratory Virus Infection (ARI) virus can induce a loss of smell and/ or taste, and not just the COVID / SARS COV-2 virus 🦠
Q: When should I see a doctor about anosmia?
As there appears to be a relatively common sequela of the COVID / SARS COV -2 infection, most cases (90%) will spontaneously recover over time, usually within 4 to 6 weeks of onset.
If your anosmia / hyposmia persists for more than 1 month, then you can consult your GP / ENT Specialist for further investigations. Perhaps you can do a Naso-endoscopy to rule out any other causes of the hyposmia/ anosmia.
A doctor may perform a nasoendoscopy to observe the nose & airways for determining the cause of anosmia
Q: How can I tell if I have recovered my sense of smell?
There are also some SMELL KITs to test your sense of smell eg. including the U PENN smell test kit; The University of Pennsylvania Smell Identification Test (UPSIT) is a test that is commercially available for smell identification to test the function of an individual's olfactory system. Known for its accuracy among smell identification tests it is considered to be one of the most reliable (r=. 94) and trusted.
You can use a smell test kit with different essential oils to test your sense of smell
Q: How can I treat my anosmia?
Your sense of smell can be recovered through what's known as smell therapy.
The BBC has highlighted this issue in 2021, do have a read of the BBC article:
This is a process that involves sniffing different odours over a period of months to retrain the brain to recognise different scents.
A group of international experts say that smell training is cheap and simple. And unlike steroids, it is free from potential side effects.
A loss of smell is one of the main symptoms of coronavirus infection, along with a fever and a persistent cough. some common sentiments of patients who suffer from POST covid loss of smell and/ or taste are:
'The smells and tastes we still miss, long after Covid'
'Since I had Covid, food makes me want to vomit'
Covid-19 smell loss 'made meat taste like petrol'
In most cases, loss of smell will return relatively quickly after the illness has passed.
But around one in five people report they are still having problems eight weeks after falling ill.
One treatment that has been prescribed by doctors is a course of drugs known as corticosteroids, which lower inflammation in the body and are already used to treat conditions such as asthma.
Smell therapy provides a safe and simple way for our patients to "re-learn" how to smell.
Smell therapy can "retrain" the brain to remember certain scents over time
In a recent paper published in the journal International Forum of Allergy & Rhinology, the researchers suggest "smell training". This involves sniffing four things that have a distinctive, easily identifiable, and familiar smell - for example, oranges, mint, garlic, and coffee - twice a day for several months.
Prof Philpott said research shows that 90% of people fully recover their sense of smell after six months.
If it doesn't return, he says "smell training" helps to retrain the brain's smell pathways to recognise different odours. "It aims to help recovery based on neuroplasticity - the brain's ability to reorganise itself to compensate for a change or injury," he said.
Well, I hope this post has given you a little insight into the issue of COVID-related hyposmia & anosmia.
If you are interested, and would like to see Dr Euan about your Post-Covid loss in sense of smell, you can contact us at Euan's ENT Surgery & Clinic to make an appointment. We now also have smell test kits in clinic for you to try.
If you are keen to delve deeper into the topic, here are some useful references you can look up!
Meanwhile, here's wishing you a relaxing and peaceful weekend, to enjoy your favourite food and drink items!
1. Renaud M, Leon A, Trau G, et al. Acute smell and taste loss in outpatients: all infected with SARS-CoV-2? Rhinology. 2020;58(4):406-409. doi:10.4193/Rhin20.199PubMedGoogle Scholar
2.Struyf T, Deeks JJ, Dinnes J, et al; Cochrane COVID-19 Diagnostic Test Accuracy Group. Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19 disease. Cochrane Database Syst Rev. 2020;7(7):CD013665. doi:10.1002/14651858.CD013665PubMedGoogle Scholar
3.Rumeau C, Nguyen DT, Jankowski R. How to assess olfactory performance with the Sniffin’ Sticks test(®). Eur Ann Otorhinolaryngol Head Neck Dis. 2016;133(3):203-206. doi:10.1016/j.anorl.2015.08.004PubMedGoogle ScholarCrossref
4.Lechien JR, Chiesa-Estomba CM, Beckers E, et al. Prevalence and 6-month recovery of olfactory dysfunction: a multicentre study of 1363 COVID-19 patients. J Intern Med. Published online January 5, 2021. doi:10.1111/joim.13209PubMedGoogle Scholar
5.Lechien JR, Cabaraux P, Chiesa-Estomba CM, et al. Objective olfactory evaluation of self-reported loss of smell in a case series of 86 COVID-19 patients. Head Neck. 2020;42(7):1583-1590. doi:10.1002/hed.26279PubMedGoogle ScholarCrossref
6.Hummel T, Lötsch J. Prognostic factors of olfactory dysfunction. Arch Otolaryngol Head Neck Surg. 2010;136(4):347-351. doi:10.1001/archoto.2010.27PubMedGoogle ScholarCrossref
7. Li Q., Guan X., Wu P., Wang X., Zhou L., Tong Y. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020;382:1199–1207. doi: 10.1056/NEJMoa2001316. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
8. Guan W.J., Ni Z.Y., Hu Y., Liang W.H., Ou C.Q., He J.X. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708–1720. doi: 10.1056/NEJMoa2002032. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
9. World Health Organization Coronavirus disease 2019 (COVID-19) situation report-104. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200503-covid-19-sitrep-104.pdf?sfvrsn=53328f46_2
10. World Health Organization WHO Director-General's remarks at the media briefing on2019-nCoV on 11 February 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-februarv-2020
11. Mao L., Jin H., Wang M., Hu Y., Chen S., He Q. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020 doi: 10.1001/jamaneurol.2020.1127. [Apr 10. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
12. Lovato A., de Filippis C., Marioni G. Upper airway symptoms in coronavirus disease 2019 (COVID-19) Am J Otolaryngol. 2020:102474. doi: 10.1016/j.amjoto.2020.102474. [Apr 4. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
13. Lovato A., de Filippis C. Clinical presentation of COVID-19: a systematic review focusing on upper airway symptoms. Ear Nose Throat J. 2020 doi: 10.1177/0145561320920762. [145561320920762, Apr 13. [Epub ahead of print]] [PubMed] [CrossRef] [Google Scholar]
14. Marchese-Ragona R., Ottaviano G., Nicolai P., Vianello A., Carecchio M. Sudden hyposmia as a prevalent symptom of COVID-19 infection. medRxiv. 2020 doi: 10.1101/2020.04.06.20045393. [2004.2006.20045393, Apr 7. [Epub ahead of print]] [CrossRef] [Google Scholar]
15. Wu Y., Xu X., Chen Z., Duan J., Hashimoto K., Yang L. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun. Mar 30, 2020 doi:
17. Baig A.M., Khaleeq A., Ali U., Syeda H. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Nerosci. 2020;11:995–998. doi: 10.1021/acschemneuro.0c00122. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
18. Yeo C., Kaushal S., Yeo D. Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible? Lancet Gastroenterol Hepatol. 2020;5:335–337. doi: 10.1016/S2468-1253(20)30048-0. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
19. Koyuncu O.O., Hogue I.B., Enquist L.W. Virus infections in the nervous system. Cell Host Microbe. 2013;13:379–393. doi: 10.1016/j.chom.2013.03.010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
21. Rockx B., Kuiken T., Herfst S., Bestebroer T., Lamers M.M., Oude Munnink B.B. Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model. Science. 2020;368:1012–1015. doi: 10.1126/science.abb7314. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
22. Zou L., Ruan F., Huang M., Liang L., Huang H., Hong Z. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med. 2020;382:1177–1179. doi: 10.1056/NEJMc2001737. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
23. Sungnak W., Huang N., Bécavin C., Berg M., Queen R., Litvinukova M. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020;26:681–687. doi: 10.1038/s41591-020-0868-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
24. Gengler I., Wang J.C., Speth M.M., Sedaghat A.R. Laryngoscope investigative otolaryngology. April 10, 2020. Sinonasal pathophysiology of SARS-CoV-2 and COVID-19: a systematic review of the current evidence. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
25. Colavita F., Lapa D., Carletti F., Lalle E., Bordi L., Marsella P. SARS-CoV-2 isolation from ocular secretions of a patient with COVID-19 in Italy with prolonged viral RNA detection. Ann Intern Med. 2020 doi: 10.7326/M20-1176. [M20-1176, Apr 17. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
27. Soler Z.M., Patel Z.M., Turner J.H., Holbrook E.H. A primer on viral-associated olfactory loss in the era of COVID-19. Int Forum Allergy Rhinol. 2020 doi: 10.1002/alr.22578. [Apr 9. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
28. Akerlund A., Bende M., Murphy C. Olfactory threshold and nasal mucosal changes in experimentally induced common cold. Acta Otolaryngol. 1995;115:88–92. doi: 10.3109/00016489509133353. [PubMed] [CrossRef] [Google Scholar]
30. Lechien J.R., Chiesa-Estomba C.M., De Siati D.R., Horoi M., Le Bon S.D., Rodriguez A. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020 doi: 10.1007/s00405-020-05965-1. [Apr 6. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
31. Heidari F., Karimi E., Firouzifar M., Khamushian P., Ansari R., Mohammadi Ardehali M. Anosmia as a prominent symptom of COVID-19 infection. Rhinology. 2020;58:302–303. doi: 10.4193/Rhin20.140. [PubMed] [CrossRef] [Google Scholar]
33. Eliezer M., Hautefort C., Hamel A.L., Verillaud B., Herman P., Houdart E. Sudden and complete olfactory loss function as a possible symptom of COVID-19. JAMA Otolaryngol Head Neck Surg. 2020 doi: 10.1001/jamaoto.2020.0832. [Apr 8. [Epub ahead of print]] [PubMed] [CrossRef] [Google Scholar]
34. Klopfenstein T., Kadiane-Oussou N.J., Toko L., Royer P.Y., Lepiller Q., Gendrin V. Features of anosmia in COVID-19. Med Mal Infect. 2020 doi: 10.1016/j.medmal.2020.04.006. [pii: S0399-077X(20)30110-4, Apr 17. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
35. Luers J.C., Rokohl A.C., Loreck N., Wawer Matos P.A., Augustin M., Dewald F. Olfactory and gustatory dysfunction in coronavirus disease 19 (COVID-19) Clin Infect Dis. 2020 doi: 10.1093/cid/ciaa525. [ciaa525, May 1. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
36. Giacomelli A., Pezzati L., Conti F., Bernacchia D., Siano M., Oreni L. Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study. Clin Infect Dis. 2020 doi: 10.1093/cid/ciaa330. [ciaa330, Mar 26. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
37. Bagheri S.H.R., Asghari A.M., Farhadi M., Shamshiri A.R., Kabir A., Kamrava S.K. Coincidence of COVID-19 epidemic and olfactory dysfunction outbreak. medRxiv. 2020 doi: 10.1101/2020.03.23.20041889. [2020.2003.2023.20041889, March 27] [CrossRef] [Google Scholar]
38. Menni C., Valdes A., Freydin M.B., Ganesh S., El-Sayed Moustafa J., Visconti A. Loss of smell and taste in combination with other symptoms is a strong predictor of COVID-19 infection. medRxiv. 2020 doi: 10.1101/2020.04.05.20048421. [2020.2004.2005.20048421. April 07] [CrossRef] [Google Scholar]
39. Yan C.H., Faraji F., Prajapati D.P., Boone C.E., DeConde A.S. Association of chemosensory dysfunction and Covid-19 in patients presenting with influenza-like symptoms. Int Forum Allergy Rhinol. 2020 [Epub ahead of print] [PMC free article] [PubMed] [Google Scholar]
40. Spinato G., Fabbris C., Polesel J., Cazzador D., Borsetto D., Hopkins C. Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. Jama. 2020;323:2089–2090. doi: 10.1001/jama.2020.6771. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
41. Jafek B.W., Murrow B., Michaels R., Restrepo D., Linschoten M. Biopsies of human olfactory epithelium. Chem Senses. 2002;27:623–628. doi: 10.1093/chemse/27.7.623. [PubMed] [CrossRef] [Google Scholar]
42. Moein S.T., Hashemian S.M.R., Mansourafshar B., Khorram-Tousi A., Tabarsi P., Doty R.L. Smell dysfunction: a biomarker for COVID-19. Int Forum Allergy Rhinol. 2020 doi: 10.1002/alr.22587. [Apr 17. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
43. Beltrán-Corbellini Á., Chico-García J.L., Martínez-Poles J., Rodríguez-Jorge F., Natera-Villalba E., Gómez-Corral J. Acute-onset smell and taste disorders in the context of Covid-19: a pilot multicenter PCR-based case-control study. Eur J Neurol. 2020 doi: 10.1111/ene.14273. [Apr 22. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
44. Ottaviano G., Carecchio M., Scarpa B., Marchese-Ragona R. Olfactory and rhinological evaluations in SARS-CoV-2 patients complaining of olfactory loss. Rhinology. 2020 doi: 10.4193/Rhin20.136. [Apr 27. [Epub ahead of print]] [PubMed] [CrossRef] [Google Scholar]
45. Vaira L.A., Salzano G., Petrocelli M., Deiana G., Salzano F.A., De Riu G. Validation of a self-administered olfactory and gustatory test for the remotely evaluation of COVID-19 patients in home quarantine. Head Neck. 2020 doi: 10.1002/hed.26228. [May 1. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
46. Shweta F., Murugadoss K., Awasthi S., Venkatakrishnan A., Puranik A., Kang M. Augmented curation of unstructured clinical notes from a massive EHR system reveals specific phenotypic signature of impending COVID-19 diagnosis. arXiv preprint. 2020 [arXiv:200409338. Apr 17] [PMC free article] [PubMed] [Google Scholar]
47. Williams F.M., Freydin M., Mangino M., Couvreur S., Visconti A., Bowyer R.C. Self-reported symptoms of covid-19 including symptoms most predictive of SARS-CoV-2 infection, are heritable. medRxiv. 2020 doi: 10.1101/2020.04.22.20072124. [2020.2004.2022.20072124, April 27] [CrossRef] [Google Scholar]
48. Braun T., Harréus U. Medical nowcasting using Google trends: application in otolaryngology. Eur Arch Otorhinolaryngol. 2013;270:2157–2160. doi: 10.1007/s00405-013-2532-y. [PubMed] [CrossRef] [Google Scholar]
49. Walker A., Hopkins C., Surda P. The use of google trends to investigate the loss of smell related searches during COVID-19 outbreak. Int Forum Allergy Rhinol. 2020 [Epub ahead of print] [PMC free article] [PubMed] [Google Scholar]
50. Yao H., Lu X., Chen Q., Xu K., Chen Y., Cheng L. Patient-derived mutations impact pathogenicity of SARS-CoV-2. medRxiv. 2020 doi: 10.1101/2020.04.14.20060160. [2020.2004.2014.20060160, April 27] [CrossRef] [Google Scholar]
51. Forster P., Forster L., Renfrew C., Forster M. Phylogenetic network analysis of SARS-CoV-2 genomes. Proc Natl Acad Sci U S A. 2020;117:9241–9243. doi: 10.1073/pnas.2004999117. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
52. Hopkins C., Kumar N. Loss of sense of smell as marker of COVID-19 infection. https://www.entuk.org/sites/default/files/files/Loss%20of%20sense%20of%20smell%20as%20marker%20of%20COVID.pdf
53. American Academy of Otolaryngology- Head and Neck Surgery Anosmia: new! COVID-19 anosmia reporting tool open to all clinicians. https://www.entnet.org/content/coronavirus-disease-2019-resources
54. Centers for Disease Control and Prevention Symptoms of coronavirus. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html
55. Pleasure S.J., Green A.J., Josephson S.A. The Spectrum of neurologic disease in the severe acute respiratory syndrome coronavirus 2 pandemic infection: neurologists move to the frontlines. JAMA Neurol. 2020 doi: 10.1001/jamaneurol.2020.1065. [Apr 10. [Epub ahead of print]] [PubMed] [CrossRef] [Google Scholar]
56. Ruthberg J.S., Quereshy H.A., Jella T., Kocharyan A., D’Anza B., Maronian N. Geospatial analysis of COVID-19 and otolaryngologists above age 60. Am J Otolaryngol. 2020:102514. doi: 10.1016/j.amjoto.2020.102514. [Apr 30.[Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
57. Zhao C., Viana A., Jr., Wang Y., Wei H.Q., Yan A.H., Capasso R. Otolaryngology during COVID-19: preventive care and precautionary measures. Am J Otolaryngol. 2020:102508. [Epub ahead of print] [PMC free article] [PubMed] [Google Scholar]
58. Liu Y., Ning Z., Chen Y., Guo M., Liu Y., Gali N.K. Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals. Nature. 2020 doi: 10.1038/s41586-020-2271-3. [Apr 27. [Epub ahead of print]] [PubMed] [CrossRef] [Google Scholar]
59. Meng X., Dai Z., Hang C., Wang Y. Smartphone-enabled wireless otoscope-assisted online telemedicine during the COVID-19 outbreak. Am J Otolaryngol. 2020:102476. doi: 10.1016/j.amjoto.2020.102476. [Apr 4. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
60. Vaira L.A., Salzano G., Deiana G., De Riu G. Anosmia and ageusia: common findings in COVID-19 patients. Laryngoscope. 2020 doi: 10.1002/lary.28692. [Apr 1. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
61. Villalba N.L., Maouche Y., Ortiz M.B.A., Sosa Z.C., Chahbazian J.B., Syrovatkova A. Anosmia and dysgeusia in the absence of other respiratory diseases: should COVID-19 infection be considered? Eur J Case Rep Intern Med. 2020;7:1641. doi: 10.12890/2020_001641. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
62. Hjelmesæth J; Skaare D, Loss of smell or taste as the only symptom of COVID-19. Tidsskr Nor Laegeforen 2020;140:7.doi:10.4045/tidsskr.20.0287. [PubMed]
63. Yan C.H., Faraji F., Prajapati D.P., Ostrander B.T., DeConde A.S. Self-reported olfactory loss associates with outpatient clinical course in Covid-19. Int Forum Allergy Rhinol. 2020 doi: 10.1002/alr.22592. [Apr 24. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
64. Kaye R., Chang C.W.D., Kazahaya K., Brereton J., Denneny J.C., 3rd COVID-19 anosmia reporting tool: initial findings. Otolaryngol Head Neck Surg. 2020 [194599820922992, Epub ahead of print] [PubMed] [Google Scholar]
65. Gilani S., Roditi R., Naraghi M. COVID-19 and anosmia in Tehran, Iran. Med Hypotheses. 2020;141:109757. doi: 10.1016/j.mehy.2020.109757. [Apr 23. [Epub ahead of print]] [PMC free article] [PubMed] [CrossRef] [Google Scholar]