Diamond-Blackfan anemia pathophysiology: Difference between revisions

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{{Diamond-Blackfan anemia}}
{{Diamond-Blackfan anemia}}
{{CMG}}[[Roghayeh Marandi]]<br>
Keywords:RP: Ribosomal proteins, RPS: small ribosomal subunit, RPL: large ribosomal subunit, DBA: Diamond-Blackfan anemia


{{CMG}}


==Overview==
==Overview==
The exact pathogenesis of [[Diamond-Blackfan anemia|DBA]] is "Ribosomapathy". [[Mutations]] in [[ribosomal protein]] [[genes]] have been confirmed to be the direct cause of faulty [[erythropoiesis]] and [[anemia]]. [[Mutations]] reduce the actual numbers of [[ribosomes]] in [[Progenitor cells|blood precursor cells]]. Without enough [[ribosomes]], the [[precursors]] can’t produce enough [[GATA1]], so mature [[red cells]] never form. Other [[blood cells]] — like [[platelets]], [[T cells]], and [[B cells]] — are not affected since they’re not dependent on [[GATA1]]. Based on a documented pathogenetic hypothesis that has been named "ribosomal stress", ultimately a defective [[ribosome]] biosynthesis leads to [[apoptosis]] in those defective [[erythroid progenitors]] which in turn is leading to [[erythroid]] failure. In "ribosomal stress", reduced [[Ribosomal protein|RP]] synthesis activates [[p53]] that induces the downstream events and leads to [[cell cycle]] termination or [[apoptosis]], leading to [[erythroid]] failure.


==Pathophysiology==
==[[Diamond-Blackfan anemia pathophysiology| Pathophysiology]]==
*The exact pathogenesis of [[Diamond-Blackfan anemia|DBA]] is "Ribosomapathy."
*Mutations in [[ribosomal protein]] [[genes]] is the  cause of faulty [[erythropoiesis]] and [[anemia]].<ref name="pmid23463023">{{cite journal |vauthors=Vlachos A, Dahl N, Dianzani I, Lipton JM |title=Clinical utility gene card for Diamond-Blackfan anemia--update 2013 |journal=Eur. J. Hum. Genet. |volume=21 |issue=10 |pages= |date=October 2013 |pmid=23463023 |pmc=3778360 |doi=10.1038/ejhg.2013.34 |url=}}</ref>.


*[[Diamond-Blackfan anemia]] is characterized by a block in erythropoiesis which is due to the ribosomal protein gene mutation in about 80-85% of those affected. <ref name="pmid30503522">{{cite journal |vauthors=Ulirsch JC, Verboon JM, Kazerounian S, Guo MH, Yuan D, Ludwig LS, Handsaker RE, Abdulhay NJ, Fiorini C, Genovese G, Lim ET, Cheng A, Cummings BB, Chao KR, Beggs AH, Genetti CA, Sieff CA, Newburger PE, Niewiadomska E, Matysiak M, Vlachos A, Lipton JM, Atsidaftos E, Glader B, Narla A, Gleizes PE, O'Donohue MF, Montel-Lehry N, Amor DJ, McCarroll SA, O'Donnell-Luria AH, Gupta N, Gabriel SB, MacArthur DG, Lander ES, Lek M, Da Costa L, Nathan DG, Korostelev AA, Do R, Sankaran VG, Gazda HT |title=The Genetic Landscape of Diamond-Blackfan Anemia |journal=Am. J. Hum. Genet. |volume=103 |issue=6 |pages=930–947 |date=December 2018 |pmid=30503522 |pmc=6288280 |doi=10.1016/j.ajhg.2018.10.027 |url=}}</ref>
{|class="wikitable"
*Sporadic mutation(55%) occurs in genes encoding several different ribosomal proteins, although based on the latest studies, approximately 40 – 45% of DBA cases are hereditary which are inherited with an autosomal dominant inheritance, means that a single copy of an altered gene in each cell is adequate to cause the disorder and is inherited from one affected parent.<ref name="pmid22160079">{{cite journal |vauthors=Ball S |title=Diamond Blackfan anemia |journal=Hematology Am Soc Hematol Educ Program |volume=2011 |issue= |pages=487–91 |date=2011 |pmid=22160079 |doi=10.1182/asheducation-2011.1.487 |url=}}</ref><ref name="pmid23744582">{{cite journal |vauthors=Garçon L, Ge J, Manjunath SH, Mills JA, Apicella M, Parikh S, Sullivan LM, Podsakoff GM, Gadue P, French DL, Mason PJ, Bessler M, Weiss MJ |title=Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients |journal=Blood |volume=122 |issue=6 |pages=912–21 |date=August 2013 |pmid=23744582 |pmc=3739037 |doi=10.1182/blood-2013-01-478321 |url=}}</ref> and they have a family history of the disease with varying phenotypes.<ref name="pmid30228860">{{cite journal |vauthors=Da Costa L, Narla A, Mohandas N |title=An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia |journal=F1000Res |volume=7 |issue= |pages= |date=2018 |pmid=30228860 |pmc=6117846 |doi=10.12688/f1000research.15542.1 |url=}}</ref> about 25% of patients have mutations in the [[ribosomal|ribosome]] protein S19 (RPS19) gene on chromosome 19 at [[cytogenetic]] position 19q13.2. RPS19 protein has been demonstrated to play an important role in 18S rRNA maturation in yeast and in human cells. However, the disease characterized by genetic [[heterogeneity]] and other mutated genes also been found in RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS24, and RPS26, and rarely in RPL15, RPL17, RPL19, RPL26, RPL27, RPL31, RPS15A, RPS20, RPS27, RPS28, RPS29, that result in alterations of pre-RNA processing and small or large ribosomal subunit synthesis which were demonstrated in human cells with RPL11, RPL35A, RPS24, and RPL26, RPS7 deficiency<ref name="pmid18230666">{{cite journal |vauthors=Choesmel V, Fribourg S, Aguissa-Touré AH, Pinaud N, Legrand P, Gazda HT, Gleizes PE |title=Mutation of ribosomal protein RPS24 in Diamond-Blackfan anemia results in a ribosome biogenesis disorder |journal=Hum. Mol. Genet. |volume=17 |issue=9 |pages=1253–63 |date=May 2008 |pmid=18230666 |doi=10.1093/hmg/ddn015 |url=}}</ref> , also "non-RP" genes such as TSR2 and GATA1. TSR2 plays a role in ribosome biogenesis since it is involved in the pre-rRNA processing and binds to RPS26.GATA1 which is the major erythroid transcription factor as being essential for precursor cells to differentiate into red blood cells and plays a critical role in regulating normal erythroid differentiation by activating an array of erythroid genes. Researchers found DBA mutations reduce the actual numbers of ribosomes in blood precursor cells. Without enough ribosomes, the precursors can’t produce enough GATA1, so mature red cells never form. Other blood cells — like platelets, T cells, and B cells — can still develop since they’re not dependent on GATA1.<ref name="pmid28377399">{{cite journal |vauthors=O'Brien KA, Farrar JE, Vlachos A, Anderson SM, Tsujiura CA, Lichtenberg J, Blanc L, Atsidaftos E, Elkahloun A, An X, Ellis SR, Lipton JM, Bodine DM |title=Molecular convergence in ex vivo models of Diamond-Blackfan anemia |journal=Blood |volume=129 |issue=23 |pages=3111–3120 |date=June 2017 |pmid=28377399 |pmc=5465839 |doi=10.1182/blood-2017-01-760462 |url=}}</ref><ref name="pmid28615220">{{cite journal |vauthors=Ulirsch JC, Lareau C, Ludwig LS, Mohandas N, Nathan DG, Sankaran VG |title=Confounding in ex vivo models of Diamond-Blackfan anemia |journal=Blood |volume=130 |issue=9 |pages=1165–1168 |date=August 2017 |pmid=28615220 |pmc=5580274 |doi=10.1182/blood-2017-05-783191 |url=}}</ref><ref name="pmid24999938">{{cite journal |vauthors=Boultwood J, Pellagatti A |title=Reduced translation of GATA1 in Diamond-Blackfan anemia |journal=Nat. Med. |volume=20 |issue=7 |pages=703–4 |date=July 2014 |pmid=24999938 |doi=10.1038/nm.3630 |url=}}</ref><ref name="pmid24952648">{{cite journal |vauthors=Ludwig LS, Gazda HT, Eng JC, Eichhorn SW, Thiru P, Ghazvinian R, George TI, Gotlib JR, Beggs AH, Sieff CA, Lodish HF, Lander ES, Sankaran VG |title=Altered translation of GATA1 in Diamond-Blackfan anemia |journal=Nat. Med. |volume=20 |issue=7 |pages=748–53 |date=July 2014 |pmid=24952648 |pmc=4087046 |doi=10.1038/nm.3557 |url=}}</ref><ref name="pmid29551269">{{cite journal |vauthors=Khajuria RK, Munschauer M, Ulirsch JC, Fiorini C, Ludwig LS, McFarland SK, Abdulhay NJ, Specht H, Keshishian H, Mani DR, Jovanovic M, Ellis SR, Fulco CP, Engreitz JM, Schütz S, Lian J, Gripp KW, Weinberg OK, Pinkus GS, Gehrke L, Regev A, Lander ES, Gazda HT, Lee WY, Panse VG, Carr SA, Sankaran VG |title=Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis |journal=Cell |volume=173 |issue=1 |pages=90–103.e19 |date=March 2018 |pmid=29551269 |pmc=5866246 |doi=10.1016/j.cell.2018.02.036 |url=}}</ref> In the remaining 10-15% of DBA cases, no abnormal genes have yet been identified. It is likely that mutations are in a regulatory region including intronic regions and promoters in one of the known RP genes may account for the DBA phenotype. <ref name="pmid30228860">{{cite journal |vauthors=Da Costa L, Narla A, Mohandas N |title=An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia |journal=F1000Res |volume=7 |issue= |pages= |date=2018 |pmid=30228860 |pmc=6117846 |doi=10.12688/f1000research.15542.1 |url=}}</ref>
|+
![[Ribosomal]] protein gene mutations---> [[Ribosomal]] protein Insufficiency ---> Imbalance of [[Ribosomal]] Assembly Intermediates ---> Free [[Ribosomal]] proteins bind to inhibitors of [[P53]] and Stabilize [[P53]] expression ---> [[P53]] Activation ---> [[Cell Cycle]] Arrest
|}


*Mutations in RP genes have been confirmed to be the direct cause of faulty erythropoiesis and anemia.<ref name="pmid23463023">{{cite journal |vauthors=Vlachos A, Dahl N, Dianzani I, Lipton JM |title=Clinical utility gene card for: Diamond-Blackfan anemia--update 2013 |journal=Eur. J. Hum. Genet. |volume=21 |issue=10 |pages= |date=October 2013 |pmid=23463023 |pmc=3778360 |doi=10.1038/ejhg.2013.34 |url=}}</ref>.A generally documented pathogenetic hypothesis implies that a defective ribosome biosynthesis leads to apoptosis in erythroid progenitors which in turn is leading to erythroid failure. This mechanism has been named ‘‘ribosomal stress . in ‘‘ribosomal stress,  reduced RP synthesis activates p53 that induces the downstream events and leads to cell cycle termination or apoptosis. Finally, this phenomenon results in the DBA phenotype of anemia, deprived growth, and results in congenital abnormalities. Mutated RP genes in DBA encode ribosomal proteins which are involved in either the small (RPS) or large (RPL) subunits of these proteins and the scarcity of these proteins can cause the development of the disease.<ref name="pmid19327583">{{cite journal |vauthors=Lipton JM, Ellis SR |title=Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis |journal=Hematol. Oncol. Clin. North Am. |volume=23 |issue=2 |pages=261–82 |date=April 2009 |pmid=19327583 |pmc=2886591 |doi=10.1016/j.hoc.2009.01.004 |url=}}</ref>
*Researchers found [[Ribosomal protein]] [[gene mutation|gene mutations]] reduce the actual numbers of [[ribosomes]] in [[Progenitor cells|blood precursor cells]]. Without enough [[ribosomes]], the [[Progenitor cells|precursors]] can’t produce enough [[GATA1]], which is essential for [[Progenitor cells|precursor cells]] to differentiate into [[red blood cells]], so mature [[red cells]] never form.
 
*Based on a documented pathogenetic hypothesis which has been named "''' ribosomal stress '''", ultimately a defective [[ribosome]] [[biosynthesis]] leads to [[apoptosis]] in those defective [[erythroid progenitors]] which in turn is leading to [[erythroid]] failure. In ‘‘ribosomal stress,  reduced [[Ribosomal protein|RP]] [[synthesis]] activates [[p53]] that induces the downstream events and leads to [[cell cycle]] termination or [[apoptosis]].<ref name="pmid18641651">{{cite journal |vauthors=McGowan KA, Li JZ, Park CY, Beaudry V, Tabor HK, Sabnis AJ, Zhang W, Fuchs H, de Angelis MH, Myers RM, Attardi LD, Barsh GS |title=Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects |journal=Nat. Genet. |volume=40 |issue=8 |pages=963–70 |date=August 2008 |pmid=18641651 |pmc=3979291 |doi=10.1038/ng.188 |url=}}</ref> Finally, this phenomenon results in the DBA phenotype of [[anemia]], deprived [[growth]], and results in [[congenital]] abnormalities.  
 
*Mutated [[Ribosomal protein|RP]] [[genes]] in [[Diamond-Blackfan anemia|DBA]] encode [[Ribosomal protein|ribosomal proteins]] which are involved in either the small (RPS) or large (RPL) subunits of these [[proteins]] and the scarcity of these [[proteins]] can result in the development of the disease.
*Non-Rp genes such as TSR2 and [[GATA1]]  also have an important role in the [[pathogenesis]] of [[DBA]]. [[TSR2]] plays a role in [[ribosome]] [[biogenesis]] since it is involved in the [[pre-rRNA]] processing and binds to RPS26
*[[GATA1]] which is the major [[erythroid]] [[transcription factor]] as being essential for precursor cells to differentiate into [[red blood cells]] and plays a critical role in regulating normal [[erythroid]] differentiation by activating of other [[erythroid]] [[genes]].<ref name="pmid19327583">{{cite journal |vauthors=Lipton JM, Ellis SR |title=Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis |journal=Hematol. Oncol. Clin. North Am. |volume=23 |issue=2 |pages=261–82 |date=April 2009 |pmid=19327583 |pmc=2886591 |doi=10.1016/j.hoc.2009.01.004 |url=}}</ref>
 
*Other [[blood cells]] — like [[platelets]], [[T cells]], and [[B cells]] —  are not affected and can still develop since they’re not dependent on [[GATA1]].<ref name="pmid28377399">{{cite journal |vauthors=O'Brien KA, Farrar JE, Vlachos A, Anderson SM, Tsujiura CA, Lichtenberg J, Blanc L, Atsidaftos E, Elkahloun A, An X, Ellis SR, Lipton JM, Bodine DM |title=Molecular convergence in ex vivo models of Diamond-Blackfan anemia |journal=Blood |volume=129 |issue=23 |pages=3111–3120 |date=June 2017 |pmid=28377399 |pmc=5465839 |doi=10.1182/blood-2017-01-760462 |url=}}</ref><ref name="pmid28615220">{{cite journal |vauthors=Ulirsch JC, Lareau C, Ludwig LS, Mohandas N, Nathan DG, Sankaran VG |title=Confounding in ex vivo models of Diamond-Blackfan anemia |journal=Blood |volume=130 |issue=9 |pages=1165–1168 |date=August 2017 |pmid=28615220 |pmc=5580274 |doi=10.1182/blood-2017-05-783191 |url=}}</ref><ref name="pmid24999938">{{cite journal |vauthors=Boultwood J, Pellagatti A |title=Reduced translation of GATA1 in Diamond-Blackfan anemia |journal=Nat. Med. |volume=20 |issue=7 |pages=703–4 |date=July 2014 |pmid=24999938 |doi=10.1038/nm.3630 |url=}}</ref><ref name="pmid24952648">{{cite journal |vauthors=Ludwig LS, Gazda HT, Eng JC, Eichhorn SW, Thiru P, Ghazvinian R, George TI, Gotlib JR, Beggs AH, Sieff CA, Lodish HF, Lander ES, Sankaran VG |title=Altered translation of GATA1 in Diamond-Blackfan anemia |journal=Nat. Med. |volume=20 |issue=7 |pages=748–53 |date=July 2014 |pmid=24952648 |pmc=4087046 |doi=10.1038/nm.3557 |url=}}</ref><ref name="pmid29551269">{{cite journal |vauthors=Khajuria RK, Munschauer M, Ulirsch JC, Fiorini C, Ludwig LS, McFarland SK, Abdulhay NJ, Specht H, Keshishian H, Mani DR, Jovanovic M, Ellis SR, Fulco CP, Engreitz JM, Schütz S, Lian J, Gripp KW, Weinberg OK, Pinkus GS, Gehrke L, Regev A, Lander ES, Gazda HT, Lee WY, Panse VG, Carr SA, Sankaran VG |title=Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis |journal=Cell |volume=173 |issue=1 |pages=90–103.e19 |date=March 2018 |pmid=29551269 |pmc=5866246 |doi=10.1016/j.cell.2018.02.036 |url=}}</ref>
 
*In the remaining 10-15% of [[Diamond-Blackfan anemia|DBA]] cases, no abnormal [[genes]] have yet been identified. It is likely that [[mutations]] are in a regulatory region including [[Intron|intronic]] regions and [[promoters]] in one of the known [[Ribosomal protein|RP]] genes may account for the [[Diamond-Blackfan anemia|DBA]] [[phenotype]]. <ref name="pmid30228860">{{cite journal |vauthors=Da Costa L, Narla A, Mohandas N |title=An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia |journal=F1000Res |volume=7 |issue= |pages= |date=2018 |pmid=30228860 |pmc=6117846 |doi=10.12688/f1000research.15542.1 |url=}}</ref>


==References==
==References==

Latest revision as of 19:34, 28 September 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Roghayeh Marandi
Keywords:RP: Ribosomal proteins, RPS: small ribosomal subunit, RPL: large ribosomal subunit, DBA: Diamond-Blackfan anemia


Overview

The exact pathogenesis of DBA is "Ribosomapathy". Mutations in ribosomal protein genes have been confirmed to be the direct cause of faulty erythropoiesis and anemia. Mutations reduce the actual numbers of ribosomes in blood precursor cells. Without enough ribosomes, the precursors can’t produce enough GATA1, so mature red cells never form. Other blood cells — like platelets, T cells, and B cells — are not affected since they’re not dependent on GATA1. Based on a documented pathogenetic hypothesis that has been named "ribosomal stress", ultimately a defective ribosome biosynthesis leads to apoptosis in those defective erythroid progenitors which in turn is leading to erythroid failure. In "ribosomal stress", reduced RP synthesis activates p53 that induces the downstream events and leads to cell cycle termination or apoptosis, leading to erythroid failure.

Pathophysiology

Ribosomal protein gene mutations---> Ribosomal protein Insufficiency ---> Imbalance of Ribosomal Assembly Intermediates ---> Free Ribosomal proteins bind to inhibitors of P53 and Stabilize P53 expression ---> P53 Activation ---> Cell Cycle Arrest

References

  1. Vlachos A, Dahl N, Dianzani I, Lipton JM (October 2013). "Clinical utility gene card for Diamond-Blackfan anemia--update 2013". Eur. J. Hum. Genet. 21 (10). doi:10.1038/ejhg.2013.34. PMC 3778360. PMID 23463023.
  2. McGowan KA, Li JZ, Park CY, Beaudry V, Tabor HK, Sabnis AJ, Zhang W, Fuchs H, de Angelis MH, Myers RM, Attardi LD, Barsh GS (August 2008). "Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects". Nat. Genet. 40 (8): 963–70. doi:10.1038/ng.188. PMC 3979291. PMID 18641651.
  3. Lipton JM, Ellis SR (April 2009). "Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis". Hematol. Oncol. Clin. North Am. 23 (2): 261–82. doi:10.1016/j.hoc.2009.01.004. PMC 2886591. PMID 19327583.
  4. O'Brien KA, Farrar JE, Vlachos A, Anderson SM, Tsujiura CA, Lichtenberg J, Blanc L, Atsidaftos E, Elkahloun A, An X, Ellis SR, Lipton JM, Bodine DM (June 2017). "Molecular convergence in ex vivo models of Diamond-Blackfan anemia". Blood. 129 (23): 3111–3120. doi:10.1182/blood-2017-01-760462. PMC 5465839. PMID 28377399.
  5. Ulirsch JC, Lareau C, Ludwig LS, Mohandas N, Nathan DG, Sankaran VG (August 2017). "Confounding in ex vivo models of Diamond-Blackfan anemia". Blood. 130 (9): 1165–1168. doi:10.1182/blood-2017-05-783191. PMC 5580274. PMID 28615220.
  6. Boultwood J, Pellagatti A (July 2014). "Reduced translation of GATA1 in Diamond-Blackfan anemia". Nat. Med. 20 (7): 703–4. doi:10.1038/nm.3630. PMID 24999938.
  7. Ludwig LS, Gazda HT, Eng JC, Eichhorn SW, Thiru P, Ghazvinian R, George TI, Gotlib JR, Beggs AH, Sieff CA, Lodish HF, Lander ES, Sankaran VG (July 2014). "Altered translation of GATA1 in Diamond-Blackfan anemia". Nat. Med. 20 (7): 748–53. doi:10.1038/nm.3557. PMC 4087046. PMID 24952648.
  8. Khajuria RK, Munschauer M, Ulirsch JC, Fiorini C, Ludwig LS, McFarland SK, Abdulhay NJ, Specht H, Keshishian H, Mani DR, Jovanovic M, Ellis SR, Fulco CP, Engreitz JM, Schütz S, Lian J, Gripp KW, Weinberg OK, Pinkus GS, Gehrke L, Regev A, Lander ES, Gazda HT, Lee WY, Panse VG, Carr SA, Sankaran VG (March 2018). "Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis". Cell. 173 (1): 90–103.e19. doi:10.1016/j.cell.2018.02.036. PMC 5866246. PMID 29551269.
  9. Da Costa L, Narla A, Mohandas N (2018). "An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia". F1000Res. 7. doi:10.12688/f1000research.15542.1. PMC 6117846. PMID 30228860.