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==Overview==
==Overview==
[[Primary prevention]] of [[smallpox]] consists in the administration of the ''vaccinia [[vaccine]]'', which attenuates or suppresses the manifestations of the disease, if administrated soon after [[infection]] has occurred. In the absence of an [[outbreak]], the [[vaccine]] is only administered to clinical and/or laboratory workers dealing with the [[smallpox virus|virus]] in specialized laboratories. It has several adverse effects, particularly in [[immunosuppressed]] individuals, those with [[heart]] conditions or [[allergies]], for whom its administration must be guided by specific rules.


==Vaccination==
==Primary Prevention==
At the age of thirteen, Jenner was apprenticed to Dr. Ludlow in Sodbury. He observed that people who caught cowpox while working with cows were known not to catch smallpox. He assumed a causal connection. The idea was not taken up by Dr. Ludlow at that time. After Jenner returned from medical school in London, a smallpox epidemic struck his home town of Berkeley, England. He advised the local cow workers to be inoculated. The farmers told him that cowpox prevented smallpox. This confirmed his childhood suspicion, and he studied cowpox further, presenting a paper on it to his local medical society.
The administration of the [[vaccine]] can attenuate, sometimes prevent, the manifestations of [[smallpox]]. The [[vaccine]] is made from a [[virus]] called vaccinia which is a “pox”-type [[virus]] related to [[smallpox]]. The [[vaccine]] does not contain the [[smallpox virus]] and therefore cannot transmit [[smallpox]]. However, it contains the “live” vaccinia [[virus]], not a dead [[virus]] like many others, for which the [[vaccination]] site must be cared for carefully, in order to prevent the [[virus]] from spreading.<ref name="BremanHenderson2002">{{cite journal|last1=Breman|first1=Joel G.|last2=Henderson|first2=D.A.|title=Diagnosis and Management of Smallpox|journal=New England Journal of Medicine|volume=346|issue=17|year=2002|pages=1300–1308|issn=0028-4793|doi=10.1056/NEJMra020025}}</ref> The [[vaccine]] is given in the upper arm, using a bifurcated needle, that is dipped into the [[vaccine]] solution. When removed, the needle retains a droplet of the [[vaccine]]. It is used to prick the [[skin]] a number of times in a few seconds. The pricking is not deep, reaching basilar [[epithelium]], but it will cause a sore spot and one or two droplets of [[blood]] will be formed.<ref name=CDC3>{{cite web | title = Emergence preparedness and response | url = http://www.bt.cdc.gov/agent/smallpox/vaccination/facts.asp }}</ref>


Perhaps there was already an informal public understanding of some connection between disease resistance and working with cows.  The “beautiful milkmaid” seems to have been a frequent image in the art and literature of this period. But we know for a fact: In the years following 1770 there were at least six people in England and Germany (Sevel, Jensen, Jesty 1774, Rendall, Plett 1791), who tested successfully the possibility of using the cowpox vaccine as an immunisation for smallpox in humans. In 1796 Sarah Nelmes, a local milkmaid, contracted cowpox and went to Jenner for treatment. Jenner took the opportunity to test his theory.  He inoculated James Phipps, the eight-year-old son of his gardener, not with smallpox but with cowpox. After an extremely weak bout of cowpox, James recovered. Jenner then tried to infect James with smallpox but nothing happened—the boy was immune to smallpox.
If the [[vaccination]] is successful, 1 or 2 droplets of [[blood]] will be formed within the site of the [[vaccine]], a few seconds after administration, and a [[cellular]] reaction will then occur. This will lead to the formation of the ''Jennerian pustule'' (1-2 cm), considered to be the ''major reaction''. The ''Jennerian pustule'' is a sign of successful [[vaccination]], which leads to full [[immunity]] in more than 95% of cases, possibly for 5 to 10 years.
Thanks to the development of the smallpox [[vaccine]], the disease was officially eradicated in 1979.


Jenner reported his observations to the Royal Society.  Further work was suggested, and Jenner published a series of 23 cases, including his son Edward, none suffered severely from smallpox<!-- did any contract it at all? -->. Two years later a society to oppose vaccination had been established in Boston, Massachusetts — an indication of rapid spread and deep interest. By 1800 Jenner’s work had been published in all of the major European languages. The process was performed all over Europe and the United States. The death rate was close to zero with the process, which became known as [[vaccination]] and was continued to around 1974 in the UK. A typical death rate at that time was roughly one per million, making vaccination against smallpox with [[vaccinia]] the most dangerous immunisation widely provided in modern times.  
Below is the progression of the appearance of the local of administrations of the [[vaccine]]: a red and [[itchy]] bump develops at the [[vaccine]] site within 3 to 4 days. During the first week, the bump becomes a large [[blister]], fills with [[pus]], and begins to drain. During the second week, the blister begins to dry up and a [[scab]] is formed. The scab then falls off during the third week, leaving a small [[scar]].<ref name=CDC3>{{cite web | title = Emergence preparedness and response | url = http://www.bt.cdc.gov/agent/smallpox/vaccination/facts.asp }}</ref>


The [[Balmis Expedition]] (1803) carried the vaccine to Spanish America, the Philippines and China under commission of the Spanish Crown.
[[Image:Smallpox vaccine.jpg|thumb|center|500px|<SMALL><SMALL>''[http://www.bt.cdc.gov/agent/smallpox/smallpox-images/vaxsit5a.htm  Adapted from Centers for Disease Control and Prevention (CDC), Centers for Disease Control and Prevention.]''<ref name="CDC">{{Cite web | title = Centers for Disease Control and Prevention (CDC) | url = http://www.bt.cdc.gov/agent/smallpox/smallpox-images/vaxsit5a.htm}}</ref></SMALL></SMALL>]]


Some years before Dr. Jenner, [[Benjamin Jesty]], a farmer at Yetminster in Dorset (he later moved to and is buried at Worth Matravers) is recorded as observing the two milkmaids living with his family to have been immune to smallpox and then inoculating his family with cowpox to protect them from smallpox. This was done in 1774 and can be found with Crookshank's History and Pathology of Vaccination, London 1889, vol. 1, p.110ff. But the question of who first initiated smallpox inoculation/vaccination can not be answered properly, as there is in the sources the exact date and time only for the predecessor Plett (1791), but not for Sevel, Jensen and Rendall.
People who were [[vaccinated]] prior to 1972, if revaccinated, may experience accelerated [[immune response]].
Louis T. Wright,<ref name=North_by_South>{{cite web | title=A Brief Biography of Dr. Louis T. Wright | work=North by South: from Charleston to Harlem, the great migration | url=http://northbysouth.kenyon.edu/1998/health/wright.htm | accessdate=2006-09-23}}</ref> an African-American and Harvard medical school graduate (1915), introduced intradermal vaccination for smallpox for the soldiers while serving in the Army during World War I.<ref name=MITRE_CDAC>{{cite web | title=Spotlight on Black Inventors, Scientists, and Engineers | work=Department of Computer Science of Georgetown University | url=http://www.cs.georgetown.edu/~blakeb/mm/BHM/Spotlight%20on%20Black%20Inventors,%20Scientists,%20and%20Engineers.htm | accessdate=2006-09-23}}</ref>
 
===Vaccine Generation===
Three generations of [[vaccines]] have been developed so far:
* ''1st generation'' - a mixture of related [[virus]]es, which differ from the remaining [[orthopoxvirus]]es. Reactions to these generation include:<ref name="BremanHenderson2002">{{cite journal|last1=Breman|first1=Joel G.|last2=Henderson|first2=D.A.|title=Diagnosis and Management of Smallpox|journal=New England Journal of Medicine|volume=346|issue=17|year=2002|pages=1300–1308|issn=0028-4793|doi=10.1056/NEJMra020025}}</ref><ref name="pmid13974310">{{cite journal| author=ROBERTS JA| title=Histopathogenesis of mousepox. I. Respiratory infection. | journal=Br J Exp Pathol | year= 1962 | volume= 43 | issue=  | pages= 451-61 | pmid=13974310 | doi= | pmc=PMC2095140 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13974310  }} </ref><ref name="MooreSeward2006">{{cite journal|last1=Moore|first1=Zack S|last2=Seward|first2=Jane F|last3=Lane|first3=J Michael|title=Smallpox|journal=The Lancet|volume=367|issue=9508|year=2006|pages=425–435|issn=01406736|doi=10.1016/S0140-6736(06)68143-9}}</ref>
:* [[Fever]]
:* Regional [[swelling]]
:* [[Edema]]
:* [[Headache]]
:* Painful [[lymphadenitis]]
 
* ''2nd generation'' - individual vaccinia clones, derived from [[virus]]es which are genetically similar, to the ones that made the 1st generation vaccine. This generation had a more efficient production of the [[vaccine]].<ref name="MooreSeward2006">{{cite journal|last1=Moore|first1=Zack S|last2=Seward|first2=Jane F|last3=Lane|first3=J Michael|title=Smallpox|journal=The Lancet|volume=367|issue=9508|year=2006|pages=425–435|issn=01406736|doi=10.1016/S0140-6736(06)68143-9}}</ref><ref name="pmid15014500">{{cite journal| author=Earl PL, Americo JL, Wyatt LS, Eller LA, Whitbeck JC, Cohen GH et al.| title=Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox. | journal=Nature | year= 2004 | volume= 428 | issue= 6979 | pages= 182-5 | pmid=15014500 | doi=10.1038/nature02331 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15014500  }} </ref>
 
* ''3rd generation'' - developed from the attenuated vaccinia strains, after [[genetic]] manipulation or multiple passage through non-human tissue. Contains [[strains]] not as virulent as previous generations, and therefore safer, mainly because of a delay in replication of the [[virus]].<ref name="MooreSeward2006">{{cite journal|last1=Moore|first1=Zack S|last2=Seward|first2=Jane F|last3=Lane|first3=J Michael|title=Smallpox|journal=The Lancet|volume=367|issue=9508|year=2006|pages=425–435|issn=01406736|doi=10.1016/S0140-6736(06)68143-9}}</ref><ref name="pmid15014500">{{cite journal| author=Earl PL, Americo JL, Wyatt LS, Eller LA, Whitbeck JC, Cohen GH et al.| title=Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox. | journal=Nature | year= 2004 | volume= 428 | issue= 6979 | pages= 182-5 | pmid=15014500 | doi=10.1038/nature02331 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15014500  }} </ref><ref name="pmid11395204">{{cite journal| author=Stittelaar KJ, Kuiken T, de Swart RL, van Amerongen G, Vos HW, Niesters HG et al.| title=Safety of modified vaccinia virus Ankara (MVA) in immune-suppressed macaques. | journal=Vaccine | year= 2001 | volume= 19 | issue= 27 | pages= 3700-9 | pmid=11395204 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11395204  }} </ref><ref name="pmid1566575">{{cite journal| author=Tartaglia J, Perkus ME, Taylor J, Norton EK, Audonnet JC, Cox WI et al.| title=NYVAC: a highly attenuated strain of vaccinia virus. | journal=Virology | year= 1992 | volume= 188 | issue= 1 | pages= 217-32 | pmid=1566575 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1566575  }} </ref>
 
===Vaccine Recommendations===
Since [[smallpox]] was declared eradicated, [[vaccination]] is not advised for common citizens. The only people with formal indication for ''vaccinia vaccine'' are the laboratory or clinical individuals who work with the [[smallpox virus|virus]] at specialized laboratories.<ref name="BremanHenderson2002">{{cite journal|last1=Breman|first1=Joel G.|last2=Henderson|first2=D.A.|title=Diagnosis and Management of Smallpox|journal=New England Journal of Medicine|volume=346|issue=17|year=2002|pages=1300–1308|issn=0028-4793|doi=10.1056/NEJMra020025}}</ref>
 
===Vaccine Adverse Events===
The following adverse events to the [[vaccine]] have been reported:<ref name="MooreSeward2006">{{cite journal|last1=Moore|first1=Zack S|last2=Seward|first2=Jane F|last3=Lane|first3=J Michael|title=Smallpox|journal=The Lancet|volume=367|issue=9508|year=2006|pages=425–435|issn=01406736|doi=10.1016/S0140-6736(06)68143-9}}</ref><ref name="pmid12824210">{{cite journal| author=Halsell JS, Riddle JR, Atwood JE, Gardner P, Shope R, Poland GA et al.| title=Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel. | journal=JAMA | year= 2003 | volume= 289 | issue= 24 | pages= 3283-9 | pmid=12824210 | doi=10.1001/jama.289.24.3283 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12824210  }} </ref><ref name="Arness2004">{{cite journal|last1=Arness|first1=M. K.|title=Myopericarditis following Smallpox Vaccination|journal=American Journal of Epidemiology|volume=160|issue=7|year=2004|pages=642–651|issn=0002-9262|doi=10.1093/aje/kwh269}}</ref><ref name="pmid14585633">{{cite journal| author=Chen RT, Lane JM| title=Myocarditis: the unexpected return of smallpox vaccine adverse events. | journal=Lancet | year= 2003 | volume= 362 | issue= 9393 | pages= 1345-6 | pmid=14585633 | doi=10.1016/S0140-6736(03)14674-0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14585633  }} </ref>
* Fetal vaccinia
* Progressive vaccinia
* Generalized vaccinia
* Non-specific [[rashes]]
* [[Eczema vaccinatum]]
* [[Encephalitis]]
* [[Myopericarditis]]
 
===Vaccine Contraindications===
In the absence of reintroduction of [[smallpox]], [[vaccination]] is contraindicated in the following:<ref name="MooreSeward2006">{{cite journal|last1=Moore|first1=Zack S|last2=Seward|first2=Jane F|last3=Lane|first3=J Michael|title=Smallpox|journal=The Lancet|volume=367|issue=9508|year=2006|pages=425–435|issn=01406736|doi=10.1016/S0140-6736(06)68143-9}}</ref><ref name=CDC2>{{cite web | title = Recommendations for Using Smallpox Vaccine in a Pre-Event Vaccination Program
| url = http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5207a1.htm }}</ref>
* Patients with [[allergy]] to [[vaccine]] components
* History of [[atopic dermatitis]]
* History of exfoliative [[skin]] disorders
* [[Inflammatory]] eye disorders
* [[Immunosuppressed]] patients
* [[Heart disease]]
* [[Pregnancy]]
* Disease cases in the family
* Children <1 year
* [[Breastfeeding]]
 
====Post-Vaccination====
After [[vaccination]] it is important to follow instructions for the care of the [[vaccine]] site. Because the [[virus]] is alive, it can spread to other parts of the body, or to other people. The [[vaccinia virus]] may cause:<ref name=CDC3>{{cite web | title = Emergence preparedness and response | url = http://www.bt.cdc.gov/agent/smallpox/vaccination/facts.asp }}</ref>
* [[Rash]]
* [[Fever]]
* [[Headache]]
* [[Body]] pain
Elderly and pregnant women are prone to severe [[complications]] following the [[vaccinia virus]] vaccine.
 
====Vaccine Benefit====
[[Vaccination]] within 3 days of exposure will prevent or significantly lessen the severity of [[smallpox]] [[symptoms]] in the vast majority of people. [[Vaccination]] 4 to 7 days after exposure likely offers some protection from the disease or may modify its severity.<ref name=CDC3>{{cite web | title = Emergence preparedness and response | url = http://www.bt.cdc.gov/agent/smallpox/vaccination/facts.asp }}</ref>
 
===Vaccine===
The algorithm below demonstrates the action protocol in the presence of a patient who appears to show an adverse reaction to the [[smallpox]] vaccine.<ref name=CDC3>{{cite web | title = Emergence preparedness and response | url = http://www.bt.cdc.gov/agent/smallpox/vaccination/facts.asp }}</ref>
 
[[Image:Smallpox lab vaccine.jpg|thumb|center|800px|<SMALL><SMALL>''[http://emergency.cdc.gov/agent/smallpox/diagnosis/pdf/poxalgorithm5-2-14.pdf  Adapted from Laboratory Response Network (LRN [CDC]), Laboratory Response Network.]''<ref name="LRN(CDC)">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://emergency.cdc.gov/agent/smallpox/diagnosis/pdf/poxalgorithm5-2-14.pdf}}</ref></SMALL></SMALL>]]


==References==
==References==
{{reflist|2}}
{{Reflist|2}}
 
[[Category:Disease]]
 
[[Category:Pediatrics]]
[[Category:Smallpox]]
[[Category:Viral diseases]]
[[Category:Poxviruses]]


{{WH}}
{{WH}}
{{WS}}
{{WS}}
[[Category:Disease]]
[[Category:Infectious disease]]
[[Category:Pediatrics]]

Latest revision as of 19:05, 18 September 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Primary prevention of smallpox consists in the administration of the vaccinia vaccine, which attenuates or suppresses the manifestations of the disease, if administrated soon after infection has occurred. In the absence of an outbreak, the vaccine is only administered to clinical and/or laboratory workers dealing with the virus in specialized laboratories. It has several adverse effects, particularly in immunosuppressed individuals, those with heart conditions or allergies, for whom its administration must be guided by specific rules.

Primary Prevention

The administration of the vaccine can attenuate, sometimes prevent, the manifestations of smallpox. The vaccine is made from a virus called vaccinia which is a “pox”-type virus related to smallpox. The vaccine does not contain the smallpox virus and therefore cannot transmit smallpox. However, it contains the “live” vaccinia virus, not a dead virus like many others, for which the vaccination site must be cared for carefully, in order to prevent the virus from spreading.[1] The vaccine is given in the upper arm, using a bifurcated needle, that is dipped into the vaccine solution. When removed, the needle retains a droplet of the vaccine. It is used to prick the skin a number of times in a few seconds. The pricking is not deep, reaching basilar epithelium, but it will cause a sore spot and one or two droplets of blood will be formed.[2]

If the vaccination is successful, 1 or 2 droplets of blood will be formed within the site of the vaccine, a few seconds after administration, and a cellular reaction will then occur. This will lead to the formation of the Jennerian pustule (1-2 cm), considered to be the major reaction. The Jennerian pustule is a sign of successful vaccination, which leads to full immunity in more than 95% of cases, possibly for 5 to 10 years.

Below is the progression of the appearance of the local of administrations of the vaccine: a red and itchy bump develops at the vaccine site within 3 to 4 days. During the first week, the bump becomes a large blister, fills with pus, and begins to drain. During the second week, the blister begins to dry up and a scab is formed. The scab then falls off during the third week, leaving a small scar.[2]

Adapted from Centers for Disease Control and Prevention (CDC), Centers for Disease Control and Prevention.[3]

People who were vaccinated prior to 1972, if revaccinated, may experience accelerated immune response.

Vaccine Generation

Three generations of vaccines have been developed so far:

  • 2nd generation - individual vaccinia clones, derived from viruses which are genetically similar, to the ones that made the 1st generation vaccine. This generation had a more efficient production of the vaccine.[5][6]
  • 3rd generation - developed from the attenuated vaccinia strains, after genetic manipulation or multiple passage through non-human tissue. Contains strains not as virulent as previous generations, and therefore safer, mainly because of a delay in replication of the virus.[5][6][7][8]

Vaccine Recommendations

Since smallpox was declared eradicated, vaccination is not advised for common citizens. The only people with formal indication for vaccinia vaccine are the laboratory or clinical individuals who work with the virus at specialized laboratories.[1]

Vaccine Adverse Events

The following adverse events to the vaccine have been reported:[5][9][10][11]

Vaccine Contraindications

In the absence of reintroduction of smallpox, vaccination is contraindicated in the following:[5][12]

Post-Vaccination

After vaccination it is important to follow instructions for the care of the vaccine site. Because the virus is alive, it can spread to other parts of the body, or to other people. The vaccinia virus may cause:[2]

Elderly and pregnant women are prone to severe complications following the vaccinia virus vaccine.

Vaccine Benefit

Vaccination within 3 days of exposure will prevent or significantly lessen the severity of smallpox symptoms in the vast majority of people. Vaccination 4 to 7 days after exposure likely offers some protection from the disease or may modify its severity.[2]

Vaccine

The algorithm below demonstrates the action protocol in the presence of a patient who appears to show an adverse reaction to the smallpox vaccine.[2]

Adapted from Laboratory Response Network (LRN [CDC), Laboratory Response Network.][13]

References

  1. ↑ 1.0 1.1 1.2 Breman, Joel G.; Henderson, D.A. (2002). "Diagnosis and Management of Smallpox". New England Journal of Medicine. 346 (17): 1300–1308. doi:10.1056/NEJMra020025. ISSN 0028-4793.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Emergence preparedness and response".
  3. ↑ "Centers for Disease Control and Prevention (CDC)".
  4. ↑ ROBERTS JA (1962). "Histopathogenesis of mousepox. I. Respiratory infection". Br J Exp Pathol. 43: 451–61. PMC 2095140. PMID 13974310.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Moore, Zack S; Seward, Jane F; Lane, J Michael (2006). "Smallpox". The Lancet. 367 (9508): 425–435. doi:10.1016/S0140-6736(06)68143-9. ISSN 0140-6736.
  6. ↑ 6.0 6.1 Earl PL, Americo JL, Wyatt LS, Eller LA, Whitbeck JC, Cohen GH; et al. (2004). "Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox". Nature. 428 (6979): 182–5. doi:10.1038/nature02331. PMID 15014500.
  7. ↑ Stittelaar KJ, Kuiken T, de Swart RL, van Amerongen G, Vos HW, Niesters HG; et al. (2001). "Safety of modified vaccinia virus Ankara (MVA) in immune-suppressed macaques". Vaccine. 19 (27): 3700–9. PMID 11395204.
  8. ↑ Tartaglia J, Perkus ME, Taylor J, Norton EK, Audonnet JC, Cox WI; et al. (1992). "NYVAC: a highly attenuated strain of vaccinia virus". Virology. 188 (1): 217–32. PMID 1566575.
  9. ↑ Halsell JS, Riddle JR, Atwood JE, Gardner P, Shope R, Poland GA; et al. (2003). "Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel". JAMA. 289 (24): 3283–9. doi:10.1001/jama.289.24.3283. PMID 12824210.
  10. ↑ Arness, M. K. (2004). "Myopericarditis following Smallpox Vaccination". American Journal of Epidemiology. 160 (7): 642–651. doi:10.1093/aje/kwh269. ISSN 0002-9262.
  11. ↑ Chen RT, Lane JM (2003). "Myocarditis: the unexpected return of smallpox vaccine adverse events". Lancet. 362 (9393): 1345–6. doi:10.1016/S0140-6736(03)14674-0. PMID 14585633.
  12. ↑ "Recommendations for Using Smallpox Vaccine in a Pre-Event Vaccination Program".
  13. ↑ "Public Health Image Library (PHIL), Centers for Disease Control and Prevention" (PDF).

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