Edward Jenner

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Edward Jenner
Edward Jenner by James Northcote.jpg
Edward Jenner by James Northcote
Born 17 May 1749
Berkeley, Gloucestershire
Died 26 January 1823(1823-01-26) (aged 73)
Berkeley, Gloucestershire
Residence Berkeley, Gloucestershire
Nationality English
Fields Medicine/surgery, natural history
Alma mater St George's, University of London University of St. Andrews
Academic advisors John Hunter
Known for Smallpox vaccine; Vaccination

Edward Jenner, FRS (/ˈɛnər/; 17 May 1749 – 26 January 1823) was an English physician and scientist who was the pioneer of smallpox vaccine, the world's first vaccine.[1][2] He is often called "the father of immunology", and his work is said to have "saved more lives than the work of any other human".[3][4][5]

Early life[edit]

Memorial to Edward Jenner in Gloucester Cathedral

Edward Jenner was born on 17 May 1749[6] (6 May Old Style) in Berkeley, as the eighth of nine children. His father, the Reverend Stephen Jenner, was the vicar of Berkeley, so Jenner received a strong basic education.[7]

Edward Jenner went to school in Wotton-under-Edge and Cirencester.[8] During this time he was inoculated for smallpox, which had a lifelong effect upon his general health.[8] At the age of 14 he was apprenticed for seven years to Mr Daniel Ludlow, a surgeon of Chipping Sodbury, South Gloucestershire, where he gained most of the experience needed to become a surgeon himself.[8]

In 1770, Edward Jenner became apprenticed in surgery and anatomy under surgeon John Hunter and others at St George's Hospital.[9] William Osler records that Hunter gave Jenner William Harvey's advice, very famous in medical circles (and characteristic of the Age of Enlightenment), "Don't think; try."[10] Hunter remained in correspondence with Jenner over natural history and proposed him for the Royal Society. Returning to his native countryside by 1773, Jenner became a successful family doctor and surgeon, practicing on dedicated premises at Berkeley.

Jenner and others formed the Fleece Medical Society or Gloucestershire Medical Society, so called because it met in the parlor of the Fleece Inn, Rodborough, in Rodborough, Gloucestershire, meeting to dine together and read papers on medical subjects. Jenner contributed papers on angina pectoris, ophthalmia, and cardiac valvular disease and commented on cowpox. He also belonged to a similar society that met in Alveston, near Bristol.[11]

He became a Master Mason December 30, 1802 in Lodge of Faith and Friendship #449. From 1812-1813, he served as Worshipful Master of Royal Berkeley Lodge of Faith and Friendship.[12]

Zoology[edit]

Jenner was elected Fellow of the Royal Society in 1788, following his publication of a careful study of the previously misunderstood life of the nested cuckoo that combined observation, experiment, and dissection.

Common cuckoo

His description of the newly hatched cuckoo, pushing its host's eggs and fledgling chicks out of the nest (contrary to existing belief that the adult cuckoo did it) was only confirmed in the 20th century,[13] when photography became available. Having observed this behaviour, Jenner demonstrated an anatomical adaptation for it—the baby cuckoo has a depression in its back, not present after 12 days of life, that enables it to cup eggs and other chicks. The adult does not remain long enough in the area to perform this task. Jenner's findings were published in Philosophical Transactions of the Royal Society in 1788.[14][15]

"The singularity of its shape is well adapted to these purposes; for, different from other newly hatched birds, its back from the scapula downwards is very broad, with a considerable depression in the middle. This depression seems formed by nature for the design of giving a more secure lodgement to the egg of the Hedge-sparrow, or its young one, when the young Cuckoo is employed in removing either of them from the nest. When it is about twelve days old, this cavity is quite filled up, and then the back assumes the shape of nestling birds in general." (Letter to Hunter at the Royal Society, as above)

Jenner's nephew assisted in the study.

Marriage and human medicine[edit]

Jenner married Catherine Kingscote (died 1815 from tuberculosis) in March 1788 after meeting her while he and other Fellows were experimenting with balloons. Jenner's trial balloon descended into Kingscote Park, Gloucestershire, owned by Anthony Kingscote, one of whose daughters was Catherine.

Jenner earned his MD from the University of St Andrews in 1792.

Jenner is also credited with advancing understanding of angina pectoris.[16] In his correspondence with Heberden, he wrote, "How much the heart must suffer from the coronary arteries not being able to perform their functions."

Invention of the vaccine[edit]

Inoculation was already a standard practice, but involved serious risks. In 1721, Lady Mary Wortley Montagu had imported variolation to Britain after having observed it in Istanbul, where her husband was the British ambassador. Voltaire, writing of this, estimates that at this time 60% of the population caught smallpox and 20% of the population died of it.[17] Voltaire also states that the Circassians used the inoculation from times immemorial, and the custom may have been borrowed by the Turks from the Circassians.[18]

In 1765, Dr John Fewster published a paper in the London Medical Society entitled "Cow pox and its ability to prevent smallpox", but he did not pursue the subject further.[19]

In the years following 1770, at least five investigators in England and Germany (Sevel, Jensen, Jesty 1774, Rendell, Plett 1791) successfully tested a cowpox vaccine in humans against smallpox.[20] For example, Dorset farmer Benjamin Jesty[21] successfully vaccinated and presumably induced immunity with cowpox in his wife and two children during a smallpox epidemic in 1774, but it was not until Jenner's work some 20 years later that the procedure became widely understood. Indeed, Jenner may have been aware of Jesty's procedures and success.[22]

Noting the common observation that milkmaids were generally immune to smallpox, Jenner postulated that the pus in the blisters that milkmaids received from cowpox (a disease similar to smallpox, but much less virulent) protected them from smallpox.

On 14 May 1796, Jenner tested his hypothesis by inoculating James Phipps, an eight-year-old boy who was the son of Jenner's gardener. He scraped pus from cowpox blisters on the hands of Sarah Nelmes, a milkmaid who had caught cowpox from a cow called Blossom,[23] whose hide now hangs on the wall of the St George's medical school library (now in Tooting). Phipps was the 17th case described in Jenner's first paper[24] on vaccination.

Jenner inoculated Phipps in both arms that day, subsequently producing in Phipps a fever and some uneasiness, but no full-blown infection. Later, he injected Phipps with variolous material, the routine method of immunization at that time. No disease followed. The boy was later challenged with variolous material and again showed no sign of infection.

Donald Hopkins has written, "Jenner's unique contribution was not that he inoculated a few persons with cowpox, but that he then proved [by subsequent challenges] that they were immune to smallpox. Moreover, he demonstrated that the protective cowpox pus could be effectively inoculated from person to person, not just directly from cattle.[25] Jenner successfully tested his hypothesis on 23 additional subjects.

Jenner continued his research and reported it to the Royal Society, which did not publish the initial paper. After revisions and further investigations, he published his findings on the 23 cases. Some of his conclusions were correct, some erroneous; modern microbiological and microscopic methods would make his studies easier to reproduce. The medical establishment, cautious then as now, deliberated at length over his findings before accepting them. Eventually, vaccination was accepted, and in 1840, the British government banned variolation – the use of smallpox to induce immunity – and provided vaccination using cowpox free of charge. (See Vaccination acts). The success of his discovery soon spread around Europe and, for example, was used en masse in the Spanish Balmis Expedition,[26] a three-year-long mission to the Americas, the Philippines, Macao, China, and Saint Helena Island led by Dr. Francisco Javier de Balmis with the aim of giving thousands the smallpox vaccine. The expedition was successful, and Jenner wrote, "I don’t imagine the annals of history furnish an example of philanthropy so noble, so extensive as this."

1802 caricature of Jenner vaccinating patients who feared it would make them sprout cowlike appendages.

Jenner's continuing work on vaccination prevented him continuing his ordinary medical practice. He was supported by his colleagues and the King in petitioning Parliament, and was granted £10,000 for his work on vaccination. In 1806, he was granted another £20,000 for his continuing work in microbiology.

In 1803 in London, he became involved with the Jennerian Institution, a society concerned with promoting vaccination to eradicate smallpox. In 1808, with government aid, this society became the National Vaccine Establishment. Jenner became a member of the Medical and Chirurgical Society on its founding in 1805 and presented a number of papers there. The society is now the Royal Society of Medicine. In 1806, Jenner was elected a foreign member of the Royal Swedish Academy of Sciences.

Returning to London in 1811, Jenner observed a significant number of cases of smallpox after vaccination. He found that in these cases the severity of the illness was notably diminished by previous vaccination. In 1821, he was appointed Physician Extraordinary to King George IV, a great national honour, and was also made Mayor of Berkeley and Justice of the Peace. He continued to investigate natural history, and in 1823, the last year of his life, he presented his "Observations on the Migration of Birds" to the Royal Society.

hair cut from Jenner's body after his death

Jenner was found in a state of apoplexy on 25 January 1823, with his right side paralysed. He never fully recovered and eventually died of an apparent stroke, his second, on 26 January 1823, aged 73. He was survived by one son and one daughter, his elder son having died of tuberculosis at the age of 21.

His original report is in the Royal College of Surgeons (London)

Legacy[edit]

In 1979, the World Health Organization declared smallpox an eradicated disease.[27] This was the result of coordinated public health efforts by many people, but vaccination was an essential component. And although the disease was declared eradicated, some pus samples still remain in laboratories in Centers for Disease Control and Prevention in Atlanta, Georgia, in the United States and State Research Center of Virology and Biotechnology VECTOR in Koltsovo, Novosibirsk Oblast, Russia.

Jenner's vaccine also laid the foundation for contemporary discoveries in immunology.[28]

An illustrated history of smallpox eradication, Smallpox Zero,[29] was published with the support of Sanofi Pasteur and distributed on 17 May 2010, in Geneva during an event sponsored by the World Health Organization.[30][31] Smallpox Zero includes President Thomas Jefferson's letter of congratulations to Edward Jenner.

In 2002, Jenner was named in the BBC's list of the 100 Greatest Britons following a UK-wide vote.[32]

The lunar crater Jenner is named in his honor.

Monuments and buildings[edit]

Dr Jenner's House, The Chantry, Church Lane, Berkeley, Gloucestershire, England
Bronze in Kensington Gardens, London

Publications[edit]

  • 1798 An Inquiry into the Causes and Effects of the Variolæ Vaccinæ[36]
  • 1799 Further Observations on the Variolæ Vaccinæ, or Cow-Pox.[37]
  • 1800 A Continuation of Facts and Observations relative to the Variolæ Vaccinæ 40pgs[38]
  • 1801 The Origin of the Vaccine Inoculation 12pgs

In popular culture[edit]

See also[edit]

References[edit]

  1. ^ Stefan Riedel, MD, PhD (January 2005). Edward Jenner and the history of smallpox and vaccination 18 (1). Baylor University Medical Center. pp. 21–25. PMC 1200696. PMID 16200144. 
  2. ^ Baxby, Derrick. "Jenner, Edward (1749–1823)". Oxford Dictionary of National Biography. Oxford University Press. Retrieved 14 February 2014. 
  3. ^ "Edward Jenner - (1749–1823)". Sundaytimes.lk. 1 June 2008. Retrieved 28 July 2009. 
  4. ^ "History - Edward Jenner (1749 - 1823)". BBC. 1 November 2006. Retrieved 28 July 2009. 
  5. ^ "Edward Jenner - Smallpox and the Discovery of Vaccination". Retrieved 28 July 2009. 
  6. ^ The Jenner Institute
  7. ^ "About Edward Jenner". The Jenner Institute. Retrieved 25 February 2012. 
  8. ^ a b c "About Edward Jenner". The Jenner Institute. Retrieved 12 January 2013. 
  9. ^ "Young Edward Jenner, Born in Berkeley". Edward Jenner Museum. Retrieved 4 September 2012. 
  10. ^ Loncarek K (April 2009). "Revolution or reformation". Croatian Medical Journal 50 (2): 195–7. doi:10.3325/cmj.2009.50.195. PMC 2681061. PMID 19399955. 
  11. ^ Papers at the Royal College of Physicians summarised at http://www.aim25.ac.uk/cgi-bin/search2?coll_id=7135&inst_id=8
  12. ^ http://freemasonry.bcy.ca/biography/jenner_e/jenner_e.html
  13. ^ http://www.jennermuseum.com/ej/cuckoo.shtml[dead link]
  14. ^ Observations on the Natural History of the Cuckoo. By Mr. Edward Jenner. In a Letter to John Hunter, Esq. F. R. S Jenner, E Philosophical Transactions of the Royal Society of London (1776-1886). 1788-01-01. 78:219–237 (Text at http://www.archive.org/details/philtrans06624558 )
  15. ^ Cuckoo chicks evicting their nest mates: coincidental observations by Edward Jenner in England and Antoine Joseph Lottinger in France Spencer G. Sealy and Mélanie F. Guigueno Department of Biological Sciences, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada (e-mail: sgsealy@cc.umanitoba.ca). Citation Information. Archives of natural history. Volume 38, Page 220-228 DOI 10.3366/anh.2011.0030, ISSN 0260-9541, Available Online October 2011
  16. ^ J R Coll Physicians Edinb 2011; 41:361–5doi:10.4997/JRCPE.2011.416
  17. ^ François Marie Arouet de Voltaire (1778). "Letters on the English or Lettres Philosophiques". 
  18. ^ "Voltaire on Circassian Medicine: Inoculation". Circassian World.  from Voltaire (1733). The Works of Voltaire. Vol. XIX (Philosophical Letters). 
  19. ^ Hopkins, Donald R. (2002). The greatest killer: smallpox in history, with a new introduction. University Of Chicago Press. ISBN 978-0-226-35168-1. 
  20. ^ Plett PC (2006). "Peter Plett and other discoverers of cowpox vaccination before Edward Jenner" [Peter Plett and other discoverers of cowpox vaccination before Edward Jenner]. Sudhoffs Archiv (in German) 90 (2): 219–32. PMID 17338405. 
  21. ^ Hammarsten J. F. et al. (1979). "Who discovered smallpox vaccination? Edward Jenner or Benjamin Jesty?". Transactions of the American Clinical and Climatological Association 90: 44–55. PMC 2279376. PMID 390826. 
  22. ^ Grant, John (2007). Corrupted Science: Fraud, Ideology and Politics in Science. London: Facts, Figures & Fun. p. 24. ISBN 978-1-904332-73-2. 
  23. ^ "Edward Jenner & Smallpox". The Edward Jenner Museum. Retrieved 13 July 2009. [dead link]
  24. ^ An Inquiry into the Causes and Effects of the Variolae Vaccinae, Edward Jenner. Retrieved 17 November 2012
  25. ^ Hopkins, Donald R. (2002). The greatest killer: smallpox in history, with a new introduction. Chicago: University of Chicago Press. p. 80. ISBN 978-0-226-35168-1. OCLC 49305765. 
  26. ^ Carlos Franco-Paredes, Lorena Lammoglia, and José Ignacio Santos-Preciado (2005). The Spanish Royal Philanthropic Expedition to Bring Smallpox Vaccination to the New World and Asia in the 19th Century 41 (9). Clinical Infectious Diseases. pp. 1285–1289. doi:10.1086/496930. 
  27. ^ World Health Organization (2001). "Smallpox". 
  28. ^ "Dr. Edward Jenner and the small pox vaccination". Essortment.com. Retrieved 28 July 2009. 
  29. ^ "Smallpox Zero". African Comic Production House, Johannesburg, South Africa. ISBN 978-0-620-43765-3. 
  30. ^ "Smallpox". 
  31. ^ Jonathan Roy (November 2010). Smallpox Zero: An Illustrated History of Smallpox and Its Eradication 16 (11). Centers for Disease Control and Prevention. doi:10.3201/eid1611.101145. 
  32. ^ "100 great Britons - A complete list". Daily Mail. 21 August 2002. Retrieved 2 August 2012. 
  33. ^ "Edward Jenner - St Mary's Church, Berkeley, Gloucestershire". Retrieved 2010-12-15. 
  34. ^ Royal College of Physicians. "JENNER, Edward (1749-1750)". AIM25 Archives. 
  35. ^ St George's, University of London. "Our History". 
  36. ^ Edward Jenner. (1909–14.). "An Inquiry Into the Causes and Effects of the Variolæ Vaccinæ, Or Cow-Pox. 1798". The Harvard Classics. 
  37. ^ Edward Jenner. (1909–14.). "Further Observations on the Variolæ Vaccinæ, or Cow-Pox. 1799". The Harvard Classics. 
  38. ^ Edward Jenner. (1909–14.). "A Continuation of Facts and Observations Relative to the Variolæ Vaccinæ, or Cow-Pox. 1800". The Harvard Classics. 

Further reading[edit]

  • Papers at the Royal College of Physicians
  • Baron, John M.D. F.R.S., "The Life of Edward Jenner MD LLD FRS", Henry Colburn, London, 1827.
  • Baron, John, "The Life of Edward Jenner with illustrations of his doctrines and selections from his correspondence". Two volumes. London 1838.
  • Edward Jenner, the man and his work. BMJ 1949 E Ashworth Underwood
  • Fisher, Richard B., "Edward Jenner 1749-1823," Andre Deutsch, London, 1991.
  • Cartwright K (October 2005). "From Jenner to modern smallpox vaccines". Occupational Medicine 55 (7): 563–563. doi:10.1093/occmed/kqi163. PMID 16251374. 
  • Riedel S (January 2005). "Edward Jenner and the history of smallpox and vaccination". Proceedings 18 (1): 21–5. PMC 1200696. PMID 16200144. 
  • Tan SY (November 2004). "Edward Jenner (1749-1823): conqueror of smallpox". Singapore Medical Journal 45 (11): 507–8. PMID 15510320. 
  • van Oss CJ (November 2000). "Inoculation against smallpox as the precursor to vaccination". Immunological Investigations 29 (4): 443–6. PMID 11130785. 
  • Gross CP, Sepkowitz KA (1998). "The myth of the medical breakthrough: smallpox, vaccination, and Jenner reconsidered". International Journal of Infectious Diseases 3 (1): 54–60. doi:10.1016/S1201-9712(98)90096-0. PMID 9831677. 
  • Willis NJ (August 1997). "Edward Jenner and the eradication of smallpox". Scottish Medical Journal 42 (4): 118–21. PMID 9507590. 
  • Theves G (1997). "Smallpox: an historical review" [Smallpox: an historical review]. Bulletin De La Société Des Sciences Médicales Du Grand-Duché De Luxembourg (in German) 134 (1): 31–51. PMID 9303824. 
  • Kempa ME (December 1996). "Edward Jenner (1749-1823)--benefactor to mankind (100th anniversary of the first vaccination against smallpox)" [Edward Jenner (1749-1823)--benefactor to mankind (100th anniversary of the first vaccination against smallpox)]. Polski Merkuriusz Lekarski (in Polish) 1 (6): 433–4. PMID 9273243. 
  • Baxby D (November 1996). "The Jenner bicentenary: the introduction and early distribution of smallpox vaccine". FEMS Immunology and Medical Microbiology 16 (1): 1–10. doi:10.1111/j.1574-695X.1996.tb00105.x. PMID 8954347. 
  • Larner AJ (September 1996). "Smallpox". The New England Journal of Medicine 335 (12): 901; author reply 902. PMID 8778627. 
  • Aly A, Aly S (September 1996). "Smallpox". The New England Journal of Medicine 335 (12): 900–1; author reply 902. doi:10.1056/NEJM199609193351217. PMID 8778626. 
  • Magner J (September 1996). "Smallpox". The New England Journal of Medicine 335 (12): 900–902. doi:10.1056/NEJM199609193351217. PMID 8778624. 
  • Kumate-Rodríguez J (1996). "Bicentennial of smallpox vaccine: experiences and lessons" [Bicentennial of smallpox vaccine: experiences and lessons]. Salud Pública De México (in Spanish) 38 (5): 379–85. PMID 9092091. 
  • Budai J (August 1996). "200th anniversary of the Jenner smallpox vaccine" [200th anniversary of the Jenner smallpox vaccine]. Orvosi Hetilap (in Hungarian) 137 (34): 1875–7. PMID 8927342. 
  • Rathbone J (June 1996). "Lady Mary Wortley Montague's contribution to the eradication of smallpox". Lancet 347 (9014): 1566. doi:10.1016/S0140-6736(96)90724-2. PMID 8684145. 
  • Baxby D (June 1996). "The Jenner bicentenary; still uses for smallpox vaccine". Epidemiology and Infection 116 (3): 231–4. doi:10.1017/S0950268800052523. PMC 2271423. PMID 8666065. 
  • Cook GC (May 1996). "Dr William Woodville (1752-1805) and the St Pancras Smallpox Hospital". Journal of Medical Biography 4 (2): 71–8. PMID 11616267. 
  • Baxby D (1996). "Jenner and the control of smallpox". Transactions of the Medical Society of London 113: 18–22. PMID 10326082. 
  • Dunn PM (January 1996). "Dr Edward Jenner (1749-1823) of Berkeley, and vaccination against smallpox". Archives of Disease in Childhood 74 (1): F77–8. doi:10.1136/fn.74.1.F77. PMC 2528332. PMID 8653442. 
  • Meynell E (August 1995). "French reactions to Jenner's discovery of smallpox vaccination: the primary sources". Social History of Medicine 8 (2): 285–303. doi:10.1093/shm/8.2.285. PMID 11639810. 
  • Bloch H (July 1993). "Edward Jenner (1749-1823). The history and effects of smallpox, inoculation, and vaccination". American Journal of Diseases of Children 147 (7): 772–4. doi:10.1001/archpedi.1993.02160310074022. PMID 8322750. 
  • Roses DF (October 1992). "From Hunter and the Great Pox to Jenner and smallpox". Surgery, Gynecology & Obstetrics 175 (4): 365–72. PMID 1411896. 
  • Turk JL, Allen E (April 1990). "The influence of John Hunter's inoculation practice on Edward Jenner's discovery of vaccination against smallpox". Journal of the Royal Society of Medicine 83 (4): 266–7. PMC 1292617. PMID 2187990. 
  • Poliakov VE (December 1985). "Edward Jenner and vaccination against smallpox" [Edward Jenner and vaccination against smallpox]. Meditsinskaia Sestra (in Russian) 44 (12): 49–51. PMID 3912642. 
  • Hammarsten JF, Tattersall W, Hammarsten JE (1979). "Who discovered smallpox vaccination? Edward Jenner or Benjamin Jesty?". Transactions of the American Clinical and Climatological Association 90: 44–55. PMC 2279376. PMID 390826. 
  • Rodrigues BA (1975). "Smallpox eradication in the Americas". Bulletin of the Pan American Health Organization 9 (1): 53–68. PMID 167890. 
  • Wynder EL (March 1974). "A corner of history: Jenner and his smallpox vaccine". Preventive Medicine 3 (1): 173–5. doi:10.1016/0091-7435(74)90074-7. PMID 4592685. 
  • Andreae H (June 1973). "Edward Jenner, initiator of cowpox vaccination against human smallpox, died 150 years ago" [Edward Jenner, initiator of cowpox vaccination against human smallpox, died 150 years ago]. Das Offentliche Gesundheitswesen (in German) 35 (6): 366–7. PMID 4269783. 
  • Friedrich I (February 1973). "A cure for smallpox. On the 150th anniversary of Edward Jenner's death" [A cure for smallpox. On the 150th anniversary of Edward Jenner's death]. Orvosi Hetilap (in Hungarian) 114 (6): 336–8. PMID 4567814. 
  • MacNalty AS (January 1968). "The prevention of smallpox: from Edward Jenner to Monckton Copeman". Medical History 12 (1): 1–18. doi:10.1017/s0025727300012722. PMC 1033768. PMID 4867646. 
  • Udovitskaia EF (November 1966). "Edward Jenner and the history of his scientific achievement. (On the 170th anniversary of the discovery of smallpox vaccination)" [Edward Jenner and the history of his scientific achievement. (On the 170th anniversary of the discovery of smallpox vaccination)]. Vrachebnoe Delo (in Russian) 11: 111–5. PMID 4885910. 
  • Voigt K (1964). "THE PHARMACY DISPLAY WINDOW. EDWARD JENNER DISCOVERED SMALLPOX VACCINATION" [The Pharmacy Display Window. Edward Jenner Discovered Smallpox Vaccination]. Pharmazeutische Praxis (in German) 106: 88–9. PMID 14237138. 
  • Ordnance Survey showing reference to Smallpox Hil: http://explore.ordnancesurvey.co.uk/os_routes/show/1539
  • 1970 Davies JW. A historical note on the Reverend John Clinch, first Canadian vaccinator. CMAJ 1970;102:957–61.
  • 1970 Roberts KB. Smallpox: an historic disease. Memorial University of Newfoundland Occas Papers Med Hist 1978;1:31–9.
  • 1951 LeFanu WR. A bio-bibliography of Edward Jenner, 1749–1823. London (UK): Harvey and Blythe; 1951. p. 103–8.

External links[edit]