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{{Gangrene}}
{{Gangrene}}
{{CMG}}{{AE}} [[User:Edzelco|Edzel Lorraine Co, D.M.D., M.D.]]
{{CMG}}; {{AE}} [[User:Edzelco|Edzel Lorraine Co, D.M.D., M.D.]]


==Overview==
==Overview==


There are three main types of [[gangrene]] which include wet, dry, and [[gas gangrene]]. Sometimes it can be classified according to its site.
There are three main types of [[gangrene]] which include wet, dry, and [[gas gangrene]]. Sometimes, [[gangrene]] is also classified according to its site.
<ref name="pmid19540438">{{cite journal| author=Christopoulou-Aletra H, Papavramidou N| title=The manifestation of "gangrene" in the Hippocratic corpus. | journal=Ann Vasc Surg | year= 2009 | volume= 23 | issue= 4 | pages= 548-51 | pmid=19540438 | doi=10.1016/j.avsg.2009.02.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19540438  }} </ref>
<ref name="pmid19540438">{{cite journal| author=Christopoulou-Aletra H, Papavramidou N| title=The manifestation of "gangrene" in the Hippocratic corpus. | journal=Ann Vasc Surg | year= 2009 | volume= 23 | issue= 4 | pages= 548-51 | pmid=19540438 | doi=10.1016/j.avsg.2009.02.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19540438  }} </ref>


==Classification==
==Classification==
There are three main types of [[gangrene]] which include wet, dry, and [[gas gangrene]]. Sometimes it can be classified according to its site. <ref name="pmid19540438">{{cite journal| author=Christopoulou-Aletra H, Papavramidou N| title=The manifestation of "gangrene" in the Hippocratic corpus. | journal=Ann Vasc Surg | year= 2009 | volume= 23 | issue= 4 | pages= 548-51 | pmid=19540438 | doi=10.1016/j.avsg.2009.02.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19540438  }} </ref>
There are three main types of [[gangrene]] which include wet, dry, and [[gas gangrene]]. Sometimes, [[gangrene]] is also classified according to its site. Table 1 summarizes the classification of [[gangrene]].<ref name="pmid19540438">{{cite journal| author=Christopoulou-Aletra H, Papavramidou N| title=The manifestation of "gangrene" in the Hippocratic corpus. | journal=Ann Vasc Surg | year= 2009 | volume= 23 | issue= 4 | pages= 548-51 | pmid=19540438 | doi=10.1016/j.avsg.2009.02.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19540438  }} </ref>




{| style="border: 0px; font-size: 90%; margin: 2px; width: "950px;" align="center"
{| style="border: 0px; font-size: 90%; margin: 1px; width: " align="center" 400px;"
| valign="top" |
| valign="top" |
|+<big>'''Classification of [[Gangrene]]'''</big>
|+<big>''' Table 1. Classification of [[Gangrene]].'''</big>
! style="background: #00CED1; width: 200px;" |{{fontcolor|#FFF|Classification}}
! align="center" style="background: #00CED1; width: 200px;" |{{fontcolor|#FFF|Classification}}
! style="background: #00CED1; width: 200px;" |{{fontcolor|#FFF|Example}}
! align="center" style="background: #00CED1; width: 200px;" |{{fontcolor|#FFF|Example}}
! style="background: #00CED1; width: 500px;" |{{fontcolor|#FFF|Description}}
! align="center" style="background: #00CED1; width: 500px;" |{{fontcolor|#FFF|Description}}
! style="background: #00CED1; width: 500px;" |{{fontcolor|#FFF|Images}}
! align="center" style="background: #00CED1; width: 500px;" |{{fontcolor|#FFF|Images}}
|-
|-
| style="padding: 5px 5px; background: #E6E6FA; font-weight: bold" |Based on Type
| rowspan="3" align="center" style="padding: 5px 5px; background: #E6E6FA; font-weight: bold" |Based on Type
| style="padding: 5px 5px; background: #F5F5F5;" |[[Dry Gangrene]]
| align="center" style="padding: 5px 5px; background: #F5F5F5;" |[[Dry Gangrene]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Dry gangrene]] refers to a [[dehydrated]] [[necrotic tissue]] brought about by worsening [[ischemia]] [[distal]] to the [[occlusion]] of [[arteries]]. </br></br></br> This is usually a worsening condition of [[peripheral artery disease]].<ref name="pmid32809387">{{cite journal| author=| title=StatPearls | journal= | year= 2022 | volume=  | issue=  | pages=  | pmid=32809387 | doi= | pmc= | url= }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |[[Dry gangrene]] refers to a [[dehydrated]] [[necrotic tissue]] brought about by worsening [[ischemia]] [[distal]] to the [[occlusion]] of [[arteries]]. <br><br> This is usually a worsening condition of [[peripheral artery disease]].<ref name="pmid32809387">{{cite journal| author=| title=StatPearls | journal= | year= 2022 | volume=  | issue=  | pages=  | pmid=32809387 | doi= | pmc= | url= }} </ref>
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
| style="padding: 5px 5px; background: #F5F5F5; font-weight: bold" |[[Image:Dry_gangrene.jpeg|thumb|280px|center|[[Dry gangrene]] on the right [[foot]] of a [[patient]] with [[peripheral artery disease]]. ('''Image courtesy of Wikipedia''')]]
|-
|-
| style="padding: 5px 5px; background: #E6E6FA; font-weight: bold" |
| align="center" style="padding: 5px 5px; background: #F5F5F5;" |[[Wet Gangrene]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Wet Gangrene]]
| style="padding: 5px 5px; background: #F5F5F5;" |This is an [[infection]] of a compromised [[tissue]] due to poor [[venous]] or [[arterial]] [[flow]]. <br><br> Most cases of [[wet gangrene]] are seen in [[lower extremities]], where pool of gravity leading to [[edema]] is most likely to happen. <br><br> However, there are some instances that [[wet gangrene]] is seen in [[oral]] and [[genitourinary]] areas. <br><br> People with [[diabetes]] are at [[high-risk]] to have this [[infection]], which is attributed to [[hyperglycemia]] and poor [[wound healing]].<ref name="pmid29910628">{{cite journal| author=Al Wahbi A| title=Autoamputation of diabetic toe with dry gangrene: a myth or a fact? | journal=Diabetes Metab Syndr Obes | year= 2018 | volume= 11 | issue=  | pages= 255-264 | pmid=29910628 | doi=10.2147/DMSO.S164199 | pmc=5987754 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29910628  }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |[[Image:AUTOAMPUTATE1.JPG|thumb|280px|center|[[Wet gangrene]] seen on a [[patient]] with [[diabetes]] and is suffering with [[severe infection]] and loss of [[toes]] ('''Image courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, CA'''.)]]
| style="padding: 5px 5px; background: #F5F5F5;" |<div align="center">
<gallery heights="175" widths="175">
Image:AUTOAMPUTATE1.JPG|Diabetic with severe infection and loss of toes - wet gangrene in center. <br> (Image courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, CA)
</gallery>
</div>
|-
|-
| style="padding: 5px 5px; background: #E6E6FA; font-weight: bold" |
| align="center" style="padding: 5px 5px; background: #F5F5F5;" |[[Gas Gangrene]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Gas Gangrene]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Gas gangrene]] involves the production of [[gas]] by some [[bacteria]] within the [[body]] [[tissues]] causing [[infections]]. <br><br> It is a deadly form of [[gangrene]] usually caused by ''[[Clostridium perfringens]]'' [[bacteria]]. <br><br> [[Infection]] spreads very fast brought about by rapid expansion of [[gases]] produced by ''[[Clostridium perfringens]], thereby infiltrating the surrounding [[healthy tissues]].<br><br> Because of its ability to quickly spread to surrounding [[tissues]], [[gas gangrene]] should be treated as a [[medical emergency]]. <br><br>[[Gas gangrene]] often causes [[gas production]], [[necrosis]]and [[sepsis]].<br><br> Rapid progression to [[bacteremia]] and [[septic shock]] is often noted.''
| style="padding: 5px 5px; background: #F5F5F5;" |Gas gangrene is a bacterial infection that produces gas within tissues. </br> It is a deadly form of gangrene usually caused by ''[[Clostridium perfringens]]'' bacteria. </br></br></br> Infection spreads rapidly as the gases produced by bacteria expand and infiltrate healthy tissue in the vicinity.</br></br></br> Because of its ability to quickly spread to surrounding tissues, gas gangrene should be treated as a medical emergency. Gas gangrene can cause [[necrosis]], gas production, and [[sepsis]].</br></br></br> Progression to [[bacteremia|toxemia]] and [[septic shock|shock]] is often very rapid.
| style="padding: 5px 5px; background: #F5F5F5;" |[[Image:Gas_gangrene.jpg|thumb|280px|center|[[Gas gangrene]] on the right [[leg]] and [[pelvis]] of a [[patient]] with palpable [[crepitus]], [[swelling]], [[bullae]], and [[discoloration]]. ('''Image courtesy of Wikipedia'''.)]]
| style="padding: 5px 5px; background: #F5F5F5;" |
|-
|-
| style="padding: 5px 5px; background: #E6E6FA; font-weight: bold" |Based on Site
| rowspan="7" align="center" style="padding: 5px 5px; background: #E6E6FA; font-weight: bold" |Based on Site
| style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[skull]]
| align="center" style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[skull]]
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[skull]] is a dark-colored area transitioning to a yellowish-off white color. <br><br> This happens after a [[fracture]], and it is considered a [[deadly]] condition once it becomes [[purulent]], with [[bleb]]-formation on the [[tongue]]. <br><br> [[Swelling]], [[spasm]] on one side of the [[body]], and [[exfoliation]] are the usual [[clinical manifestations]] of this condition. <ref name="pmid19540438">{{cite journal| author=Christopoulou-Aletra H, Papavramidou N| title=The manifestation of "gangrene" in the Hippocratic corpus. | journal=Ann Vasc Surg | year= 2009 | volume= 23 | issue= 4 | pages= 548-51 | pmid=19540438 | doi=10.1016/j.avsg.2009.02.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi? dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19540438  }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
| align="center" style="padding: 5px 5px; background: #F5F5F5;" |[[Image:Gangrenous_skull.png|thumb|300px|center|[[Gangrenous abscess]] extending into the [[skull]]. <br> ('''Image courtesy of National Library of Medicine'''.)]]
|-
|-
| style="padding: 5px 5px; background: #E6E6FA; font-weight: bold" |
| align="center" style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[face]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[face]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Noma]] is the term used to refer to the [[gangrene]] of the [[face]].
| style="padding: 5px 5px; background: #F5F5F5;" |[[Noma]] is the term used to refer to the [[gangrene]] of the [[face]].
 
| style="padding: 5px 5px; background: #F5F5F5;" |[[Image:Noma.jpg|thumb|250px|center|[[Mucous membranes]] of the [[mouth]] are destroyed. <br>('''Image courtesy of A.D.A.M., Inc. thru National Library of Medicine'''.)]][[Image:Gangrene_of_face.png|thumb|300px|center|[[Periorbital]] [[gangrene]] on the [[face]].<br> ('''Image courtesy of National Library of Medicine'''.)]]
| style="padding: 5px 5px; background: #F5F5F5;" |
|-
|-
| style="padding: 5px 5px; background: #E6E6FA; font-weight: bold" |
| align="center" style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[jaw]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[jaw]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Tooth]] [[fracture]] and [[inflammation]] cause [[gangrene]] of the [[jaw]].  <ref name="pmid19540438">{{cite journal| author=Christopoulou-Aletra H, Papavramidou N| title=The manifestation of "gangrene" in the Hippocratic corpus. | journal=Ann Vasc Surg | year= 2009 | volume= 23 | issue= 4 | pages= 548-51 | pmid=19540438 | doi=10.1016/j.avsg.2009.02.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi? dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19540438  }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
| align="center" style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
|-
|-
| style="padding: 5px 5px; background: #E6E6FA; font-weight: bold" |
| align="center" style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[extremities]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[extremities]]
| style="padding: 5px 5px; background: #F5F5F5;" |There are several possible causes of [[gangrene]] of the [[extremities]]. These include:
| style="padding: 5px 5px; background: #F5F5F5;" |
 
| style="padding: 5px 5px; background: #F5F5F5;" |
*Old [[ulcer]] or [[lesion]] in the affected part
*Careless [[positioning]] after [[prolonged bed rest]]
*Improper [[bandage application]] on the [[extremity]]
 
[[Clinical manifestations]] include:
 
*"Sticky serum" appearance
*[[Chills]]
*[[Fever]]
*Difficulties in speech
*[[Convulsions]]
*[[Trembling]]
*[[Sweating]]
*[[Pain]]
*[[Hiccoughs]]
*[[Ecchymoses]]
 
[[Signs]] that a [[gangrene]] is about to develop:
 
*[[Hardness]] and [[paleness]]. <br>
 
[[Signs]] that a [[gangrene]] will not develop:
 
*Livid after the [[ecchymosis]], greenish or yellowish, and soft. <ref name="pmid19540438">{{cite journal| author=Christopoulou-Aletra H, Papavramidou N| title=The manifestation of "gangrene" in the Hippocratic corpus. | journal=Ann Vasc Surg | year= 2009 | volume= 23 | issue= 4 | pages= 548-51 | pmid=19540438 | doi=10.1016/j.avsg.2009.02.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19540438  }} </ref>
 
| style="padding: 5px 5px; background: #F5F5F5;" |[[Image:Gangrene_of_digits.png|thumb|300px|center|[[Digital]] [[gangrene]] of the [[upper extremities]].<br> ('''Image courtesy of National Library of Medicine'''.)]][[Image:Gangrene_of_extremities.png|thumb|300px|center|[[Digital]] [[gangrene]] of the [[lower extremities]] due to ''[[Streptococcus pyogenes]]''.<br> ('''Image courtesy of National Library of Medicine'''.)]]
|-
|-
| style="padding: 5px 5px; background: #E6E6FA; font-weight: bold" |
| align="center" style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[ribs]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[ribs]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[ribs]] can bring about [[hemoptysis]], [[coughs]], and [[abscesses]].<ref name="pmid19540438">{{cite journal| author=Christopoulou-Aletra H, Papavramidou N| title=The manifestation of "gangrene" in the Hippocratic corpus. | journal=Ann Vasc Surg | year= 2009 | volume= 23 | issue= 4 | pages= 548-51 | pmid=19540438 | doi=10.1016/j.avsg.2009.02.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19540438  }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
| align="center" style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
|-
|-
| style="padding: 5px 5px; background: #E6E6FA; font-weight: bold" |
| align="center" style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[skin]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[skin]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Necrotizing fasciitis]] affects the deeper layers of the [[skin]].
| style="padding: 5px 5px; background: #F5F5F5;" |[[Necrotizing fasciitis]] affects the deeper layers of the skin.
| style="padding: 5px 5px; background: #F5F5F5;" |[[Image:Necrotizing_fasciitis.png|thumb|300px|center|[[Necrotizing fasciitis]] in an [[immunocompromised]] [[patient]].<br> ('''Image courtesy of National Library of Medicine'''.)]]
| style="padding: 5px 5px; background: #F5F5F5;" |
|-
|-
| style="padding: 5px 5px; background: #E6E6FA; font-weight: bold" |
| align="center" style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[genitals]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Gangrene]] of the [[genitals]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Fournier's gangrene]] usually affects the [[male genitals]].
| style="padding: 5px 5px; background: #F5F5F5;" |[[Fournier gangrene]] usually affects the male genitals.
| style="padding: 5px 5px; background: #F5F5F5;" |[[Image:Gangrenous_hemiscrotum.png|thumb|300px|center|[[Patient]] with a [[Fournier's gangrene]] and [[Type 2 Diabetes Mellitus]]. <br> ('''Image courtesy of National Library of Medicine'''.)]]
| style="padding: 5px 5px; background: #F5F5F5;" |
|}
|}


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Latest revision as of 17:49, 14 July 2022

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, D.M.D., M.D.

Overview

There are three main types of gangrene which include wet, dry, and gas gangrene. Sometimes, gangrene is also classified according to its site. [1]

Classification

There are three main types of gangrene which include wet, dry, and gas gangrene. Sometimes, gangrene is also classified according to its site. Table 1 summarizes the classification of gangrene.[1]


Table 1. Classification of Gangrene.
Classification Example Description Images
Based on Type Dry Gangrene Dry gangrene refers to a dehydrated necrotic tissue brought about by worsening ischemia distal to the occlusion of arteries.

This is usually a worsening condition of peripheral artery disease.[2]
Dry gangrene on the right foot of a patient with peripheral artery disease. (Image courtesy of Wikipedia)
Wet Gangrene This is an infection of a compromised tissue due to poor venous or arterial flow.

Most cases of wet gangrene are seen in lower extremities, where pool of gravity leading to edema is most likely to happen.

However, there are some instances that wet gangrene is seen in oral and genitourinary areas.

People with diabetes are at high-risk to have this infection, which is attributed to hyperglycemia and poor wound healing.[3]
Wet gangrene seen on a patient with diabetes and is suffering with severe infection and loss of toes (Image courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, CA.)
Gas Gangrene Gas gangrene involves the production of gas by some bacteria within the body tissues causing infections.

It is a deadly form of gangrene usually caused by Clostridium perfringens bacteria.

Infection spreads very fast brought about by rapid expansion of gases produced by Clostridium perfringens, thereby infiltrating the surrounding healthy tissues.

Because of its ability to quickly spread to surrounding tissues, gas gangrene should be treated as a medical emergency.

Gas gangrene often causes gas production, necrosisand sepsis.

Rapid progression to bacteremia and septic shock is often noted.
Gas gangrene on the right leg and pelvis of a patient with palpable crepitus, swelling, bullae, and discoloration. (Image courtesy of Wikipedia.)
Based on Site Gangrene of the skull Gangrene of the skull is a dark-colored area transitioning to a yellowish-off white color.

This happens after a fracture, and it is considered a deadly condition once it becomes purulent, with bleb-formation on the tongue.

Swelling, spasm on one side of the body, and exfoliation are the usual clinical manifestations of this condition. [1]
Gangrenous abscess extending into the skull.
(Image courtesy of National Library of Medicine.)
Gangrene of the face Noma is the term used to refer to the gangrene of the face.
Mucous membranes of the mouth are destroyed.
(Image courtesy of A.D.A.M., Inc. thru National Library of Medicine.)
Periorbital gangrene on the face.
(Image courtesy of National Library of Medicine.)
Gangrene of the jaw Tooth fracture and inflammation cause gangrene of the jaw. [1]
Gangrene of the extremities There are several possible causes of gangrene of the extremities. These include:

Clinical manifestations include:

Signs that a gangrene is about to develop:

Signs that a gangrene will not develop:

Digital gangrene of the upper extremities.
(Image courtesy of National Library of Medicine.)
Digital gangrene of the lower extremities due to Streptococcus pyogenes.
(Image courtesy of National Library of Medicine.)
Gangrene of the ribs Gangrene of the ribs can bring about hemoptysis, coughs, and abscesses.[1]
Gangrene of the skin Necrotizing fasciitis affects the deeper layers of the skin.
Necrotizing fasciitis in an immunocompromised patient.
(Image courtesy of National Library of Medicine.)
Gangrene of the genitals Fournier's gangrene usually affects the male genitals.
Patient with a Fournier's gangrene and Type 2 Diabetes Mellitus.
(Image courtesy of National Library of Medicine.)

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 Christopoulou-Aletra H, Papavramidou N (2009). "The manifestation of "gangrene" in the Hippocratic corpus". Ann Vasc Surg. 23 (4): 548–51. doi:10.1016/j.avsg.2009.02.002. PMID 19540438.
  2. "StatPearls". 2022. PMID 32809387 Check |pmid= value (help).
  3. Al Wahbi A (2018). "Autoamputation of diabetic toe with dry gangrene: a myth or a fact?". Diabetes Metab Syndr Obes. 11: 255–264. doi:10.2147/DMSO.S164199. PMC 5987754. PMID 29910628.