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  1. Article: The heart-placenta axis in the first month of pregnancy: induction and prevention of cardiovascular birth defects.

    Linask, Kersti K

    Journal of pregnancy

    2013  Volume 2013, Page(s) 320413

    Abstract: Extrapolating from animal studies to human pregnancy, our studies showed that folate (FA) deficiency as well as one-time exposure to environmental factors in the first two to three weeks of human gestation can result in severe congenital heart defects ( ... ...

    Abstract Extrapolating from animal studies to human pregnancy, our studies showed that folate (FA) deficiency as well as one-time exposure to environmental factors in the first two to three weeks of human gestation can result in severe congenital heart defects (CHDs). Considering that approximately 49% of pregnancies are unplanned, this period of pregnancy can be considered high-risk for cardiac, as well as for neural, birth defects, as the woman usually is not aware of her pregnancy and may not yet be taking precautionary actions to protect the developing embryo. Using avian and mouse vertebrate models, we demonstrated that FA supplementation prevents CHD induced by alcohol, lithium, or elevation of the metabolite homocysteine, a marker for FA deficiency. All three factors affected the important Wnt signaling pathway by suppressing Wnt-mediated gene expression in the heart fields, resulting in a delay of cardiomyocyte migration, cardiomyogenesis, and CHD. Optimal protection of cardiogenesis was observed to occur with FA supplementation provided upon morning after conception and at higher doses than the presently available in prenatal vitamin supplementation. Our studies demonstrate pathways and cell processes that are involved with protection of one-carbon metabolism during heart development.
    MeSH term(s) Animals ; Birds ; Cell Differentiation/physiology ; Dietary Supplements ; Disease Models, Animal ; Ethanol/toxicity ; Female ; Folic Acid/administration & dosage ; Folic Acid/pharmacology ; Folic Acid Deficiency/diet therapy ; Folic Acid Deficiency/embryology ; Folic Acid Deficiency/prevention & control ; Gestational Age ; Heart/embryology ; Heart Defects, Congenital/chemically induced ; Heart Defects, Congenital/embryology ; Heart Defects, Congenital/prevention & control ; Homocysteine/toxicity ; Humans ; Lithium Compounds/toxicity ; Maternal Exposure ; Mice ; Myocytes, Cardiac/cytology ; Placenta/embryology ; Pregnancy ; Prenatal Exposure Delayed Effects/prevention & control ; Signal Transduction ; Wnt Proteins/physiology
    Chemical Substances Lithium Compounds ; Wnt Proteins ; Homocysteine (0LVT1QZ0BA) ; Ethanol (3K9958V90M) ; Folic Acid (935E97BOY8)
    Language English
    Publishing date 2013-04-17
    Publishing country Egypt
    Document type Journal Article
    ZDB-ID 2595413-1
    ISSN 2090-2735 ; 2090-2727
    ISSN (online) 2090-2735
    ISSN 2090-2727
    DOI 10.1155/2013/320413
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Editorial: Mechanotransduction and development of cardiovascular form and function.

    Linask, Kersti K / Watanabe, Michiko

    Frontiers in physiology

    2015  Volume 6, Page(s) 131

    Language English
    Publishing date 2015-04-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2015.00131
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Acute alcohol exposure during mouse gastrulation alters lipid metabolism in placental and heart development: Folate prevention.

    Linask, Kersti K / Han, Mingda

    Birth defects research. Part A, Clinical and molecular teratology

    2016  Volume 106, Issue 9, Page(s) 749–760

    Abstract: Background: Embryonic acute exposure to ethanol (EtOH), lithium, and homocysteine (HCy) induces cardiac defects at the time of exposure; folic acid (FA) supplementation protects normal cardiogenesis (Han et al., , ... Serrano et al., ). Our hypothesis is ... ...

    Abstract Background: Embryonic acute exposure to ethanol (EtOH), lithium, and homocysteine (HCy) induces cardiac defects at the time of exposure; folic acid (FA) supplementation protects normal cardiogenesis (Han et al., ,

    Serrano et al., ). Our hypothesis is that EtOH exposure and FA protection relate to lipid and FA metabolism during mouse cardiogenesis and placentation.
    Methods: On the morning of conception, pregnant C57BL/6J mice were placed on either of two FA-containing diets: a 3.3 mg health maintenance diet or a high FA diet of 10.5 mg/kg. Mice were injected a binge level of EtOH, HCy, or saline on embryonic day (E) 6.75, targeting gastrulation. On E15.5, cardiac and umbilical blood flow were examined by ultrasound. Embryonic cardiac tissues were processed for gene expression of lipid and FA metabolism; the placenta and heart tissues for neutral lipid droplets, or for medium chain acyl-dehydrogenase (MCAD) protein.
    Results: EtOH exposure altered lipid-related gene expression on E7.5 in comparison to control or FA-supplemented groups and remained altered on E15.5 similarly to changes with HCy, signifying FA deficiency. In comparison to control tissues, the lipid-related acyl CoA dehydrogenase medium length chain gene and its protein MCAD were altered with EtOH exposure, as were neutral lipid droplet localization in the heart and placenta.
    Conclusion: EtOH altered gene expression associated with lipid and folate metabolism, as well as neutral lipids, in the E15.5 abnormally functioning heart and placenta. In comparison to controls, the high FA diet protected the embryo and placenta from these effects allowing normal development. Birth Defects Research (Part A) 106:749-760, 2016. © 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc.
    MeSH term(s) Animals ; Ethanol/toxicity ; Female ; Folic Acid/pharmacology ; Gastrulation/drug effects ; Gene Expression Regulation, Developmental/drug effects ; Heart/embryology ; Heart Defects, Congenital/chemically induced ; Heart Defects, Congenital/embryology ; Heart Defects, Congenital/prevention & control ; Lipid Metabolism/drug effects ; Mice ; Placenta/metabolism ; Pregnancy
    Chemical Substances Ethanol (3K9958V90M) ; Folic Acid (935E97BOY8)
    Language English
    Publishing date 2016-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2104792-3
    ISSN 1542-0760 ; 1542-0752 ; 1542-9733 ; 1542-975X
    ISSN (online) 1542-0760
    ISSN 1542-0752 ; 1542-9733 ; 1542-975X
    DOI 10.1002/bdra.23526
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Environmental origins of congenital heart disease: the heart-placenta connection.

    Huhta, James / Linask, Kersti K

    Seminars in fetal & neonatal medicine

    2013  Volume 18, Issue 5, Page(s) 245–250

    Abstract: Although the mammalian embryo is well protected in the uterus, environmental chemicals, drugs, and maternal nutritional imbalances can interfere with regulatory pathways directing placental and embryonic development early in gestation. Embryonic cells ... ...

    Abstract Although the mammalian embryo is well protected in the uterus, environmental chemicals, drugs, and maternal nutritional imbalances can interfere with regulatory pathways directing placental and embryonic development early in gestation. Embryonic cells are most susceptible to environmental influences during cellular specification and differentiation stages. Because biochemical differentiation precedes morphological outcome often by days, the period of susceptibility to environmental chemicals expectedly precedes visible morphogenic effects. The cellular mechanisms by which drugs and other environmental factors disrupt embryonic development and induce cardiac abnormalities have remained undefined.
    MeSH term(s) Animals ; Dietary Supplements ; Environmental Illness/congenital ; Environmental Illness/etiology ; Environmental Illness/physiopathology ; Environmental Illness/prevention & control ; Environmental Pollutants/toxicity ; Female ; Fetal Development/drug effects ; Fetal Heart/drug effects ; Fetal Heart/physiopathology ; Folic Acid/therapeutic use ; Heart Defects, Congenital/embryology ; Heart Defects, Congenital/etiology ; Heart Defects, Congenital/physiopathology ; Heart Defects, Congenital/prevention & control ; Heart Diseases/embryology ; Heart Diseases/etiology ; Heart Diseases/physiopathology ; Heart Diseases/prevention & control ; Humans ; Infant, Newborn ; Male ; Maternal Exposure/adverse effects ; Placenta/drug effects ; Placenta/physiopathology ; Pregnancy ; Prenatal Nutritional Physiological Phenomena
    Chemical Substances Environmental Pollutants ; Folic Acid (935E97BOY8)
    Language English
    Publishing date 2013-10
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2174416-6
    ISSN 1878-0946 ; 1744-165X
    ISSN (online) 1878-0946
    ISSN 1744-165X
    DOI 10.1016/j.siny.2013.05.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Calcium channel blockade in embryonic cardiac progenitor cells disrupts normal cardiac cell differentiation.

    Linask, Kaari L / Linask, Kersti K

    Stem cells and development

    2010  Volume 19, Issue 12, Page(s) 1959–1965

    Abstract: We suggest that characterization of processes involved in differentiation of the pluripotential cardiac precursor cells in their embryonic environment will permit identifying pathways important for induction of diverse stem cells toward the cardiac ... ...

    Abstract We suggest that characterization of processes involved in differentiation of the pluripotential cardiac precursor cells in their embryonic environment will permit identifying pathways important for induction of diverse stem cells toward the cardiac phenotype. Phenotypic characteristics of cardiac cells are their contractile and electrical properties. The objective of the present study was to define whether calcium (Ca(++)) has a regulatory role in the pluripotential precursor cell population during commitment into cardiomyocytes. We used the chick embryo model because of ease of staging the embryos and visibility of heart development. Using the Ca(++) indicator Fluo-3/acetoxymethyl and confocal microscopy, we demonstrated the existence of higher free Ca(++) levels in the cardiogenic precursor cells than in neighboring cell populations outside of the heart fields. Subsequently, gastrulation stage 4/5 chick embryos were set up in modified New cultures in the medium containing either the L-type Ca channel blocker, diltiazem, or the N-type Ca channel inhibitor, ω-conotoxin. The embryos were incubated for 22-24 h during which time the control embryos developed, beating looping hearts. At the end of incubation, exposure to the L-type channel blockade with diltiazem resulted in an inhibition of cardiomyogenesis in the most posterior, uncommitted, part of the heart fields. N-type channel blockade with ω-conotoxin was less intense. Cells in the most anterior cardiogenic regions that were already committed at time of exposure continued to differentiate. Thus, regulation and maintenance of normal cytosolic Ca levels are necessary for the early steps of cardiomyocyte specification and commitment leading to differentiation.
    MeSH term(s) Aniline Compounds ; Animals ; Calcium/metabolism ; Calcium Channel Blockers/pharmacology ; Calcium Channels, L-Type/metabolism ; Calcium Channels, N-Type/metabolism ; Cell Differentiation/drug effects ; Chick Embryo ; Diltiazem/pharmacology ; Heart/embryology ; Heart/growth & development ; Microscopy, Confocal ; Myocardial Contraction ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/physiology ; Stem Cells/cytology ; Stem Cells/metabolism ; Xanthenes ; omega-Conotoxins/pharmacology
    Chemical Substances Aniline Compounds ; Calcium Channel Blockers ; Calcium Channels, L-Type ; Calcium Channels, N-Type ; Xanthenes ; omega-Conotoxins ; Fluo-3 (23D4W0B50Y) ; Diltiazem (EE92BBP03H) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2010-09-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2142214-X
    ISSN 1557-8534 ; 1547-3287
    ISSN (online) 1557-8534
    ISSN 1547-3287
    DOI 10.1089/scd.2010.0192
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  6. Article ; Online: Folate protection from congenital heart defects linked with canonical Wnt signaling and epigenetics.

    Linask, Kersti K / Huhta, James

    Current opinion in pediatrics

    2010  Volume 22, Issue 5, Page(s) 561–566

    Abstract: Purpose of review: Environmental factors, such as drugs, chemicals, or abnormal concentrations of natural metabolites, induce birth defects. Environmental effects on cardiogenesis have been little studied in contrast to neurogenesis. This review ... ...

    Abstract Purpose of review: Environmental factors, such as drugs, chemicals, or abnormal concentrations of natural metabolites, induce birth defects. Environmental effects on cardiogenesis have been little studied in contrast to neurogenesis. This review presents evidence on three environmental factors: alcohol, the drug lithium, and the metabolite homocysteine, impacting the Wnt/β-catenin pathway during cardiac development and folate protection.
    Recent findings: Animal and epidemiological studies have shown that folate protects the embryo from birth defects. New animal studies demonstrate that folate prevents cardiovascular defects induced by the drug lithium, homocysteine, or alcohol, but protection occurs at a higher concentration than currently used in vitamin supplements. The data indicate that folate in combination with myo-inositol may further reduce the risk of birth defects. Discussion is presented of the cell specification stages that are impacted resulting in cardiac defects, how Wnt/β-catenin signaling is involved, and how folate and myo-inositol additively may protect embryonic pathways. The possible epigenetic role of folate in Wnt/β-catenin signaling is described.
    Summary: This review will enable better counseling of women by defining, during early pregnancy, a susceptible window of embryonic exposure leading to a high risk of cardiac defects, and provides a therapeutic means and the necessary timing for prevention of environmentally induced birth defects.
    MeSH term(s) Animals ; Epigenesis, Genetic/drug effects ; Female ; Folic Acid/pharmacology ; Gene Expression Regulation, Developmental/drug effects ; Heart/embryology ; Heart Defects, Congenital/embryology ; Heart Defects, Congenital/genetics ; Heart Defects, Congenital/prevention & control ; Humans ; Maternal Exposure/adverse effects ; Pregnancy ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Vitamin B Complex/pharmacology ; beta Catenin/genetics ; beta Catenin/metabolism
    Chemical Substances beta Catenin ; Vitamin B Complex (12001-76-2) ; Folic Acid (935E97BOY8)
    Language English
    Publishing date 2010-09-16
    Publishing country United States
    Document type Editorial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1049374-8
    ISSN 1531-698X ; 1040-8703
    ISSN (online) 1531-698X
    ISSN 1040-8703
    DOI 10.1097/MOP.0b013e32833e2723
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  7. Article: Regulation of heart morphology: current molecular and cellular perspectives on the coordinated emergence of cardiac form and function.

    Linask, Kersti K

    Birth defects research. Part C, Embryo today : reviews

    2003  Volume 69, Issue 1, Page(s) 14–24

    Abstract: Background: During early heart development, in addition to cells being induced to differentiate into cardiomyocytes, pathways are activated that lead to cardiac morphogenesis or the development of form.: Methods: Orchestration of organogenesis ... ...

    Abstract Background: During early heart development, in addition to cells being induced to differentiate into cardiomyocytes, pathways are activated that lead to cardiac morphogenesis or the development of form.
    Methods: Orchestration of organogenesis involves the incremental activation of regulatory pathways that lead to pivotal transition points, such as cardiac compartment delineation and looping. Each embryonic stage sets up the correct patterning of morphoregulatory molecules that will regulate the next process, until an organ is formed from the mesoderm layer after gastrulation. The current review provides an understanding of the morphoregulatory, cell adhesion and extracellular matrix-mediated, processes that coordinate development of heart form with that of function. The period reviewed encompasses the formation of a definitive cardiac compartment from the lateral plate mesoderm to the time-point in which the single, beating heart tube loops directionally to the right. Looping results in the correct spatial orientation for subsequent modeling of the four-chambered heart. Even subtle alterations in looping can form the basis upon which malformations of the inlet or the outlet regions of the heart, or both, are superimposed.
    Results: In the future, DNA microarray data sets may allow modeling the specific sequence of gene regulatory dynamics leading to these transition points to discover the regulatory "modes" that the cells adopt during heart organogenesis. The regulatory genes, however, can only specify the proteins that will be present.
    Conclusions: To fully understand the timing and mechanisms underlying heart development, it is necessary to define the sequential synthesis, patterning, and interaction of the proteins, and of still other receptors, which eventually drive cells to organize into functioning organs.
    MeSH term(s) Animals ; Cell Adhesion ; Cell Adhesion Molecules/physiology ; Cell Differentiation ; Cell Movement ; Chick Embryo ; Endocardium/cytology ; Endocardium/embryology ; Epithelial Cells/cytology ; Extracellular Matrix/physiology ; Fetal Heart/anatomy & histology ; Fetal Proteins/physiology ; Gestational Age ; Growth Substances/physiology ; Heart/anatomy & histology ; Heart/embryology ; Heart/growth & development ; Humans ; Mesoderm/physiology ; Mice ; Morphogenesis ; Muscle Proteins/physiology ; Myocardium/cytology
    Chemical Substances Cell Adhesion Molecules ; Fetal Proteins ; Growth Substances ; Muscle Proteins
    Language English
    Publishing date 2003-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Review
    ZDB-ID 2104792-3
    ISSN 1542-975X ; 1542-0752 ; 1542-9733
    ISSN 1542-975X ; 1542-0752 ; 1542-9733
    DOI 10.1002/bdrc.10004
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  8. Article ; Online: Embryonic exposures of lithium and homocysteine and folate protection affect lipid metabolism during mouse cardiogenesis and placentation.

    Han, Mingda / Evsikov, Alexei V / Zhang, Lifeng / Lastra-Vicente, Rosana / Linask, Kersti K

    Reproductive toxicology (Elmsford, N.Y.)

    2016  Volume 61, Page(s) 82–96

    Abstract: Embryonic exposures can increase the risk of congenital cardiac birth defects and adult disease. The present study identifies the predominant pathways modulated by an acute embryonic mouse exposure during gastrulation to lithium or homocysteine that ... ...

    Abstract Embryonic exposures can increase the risk of congenital cardiac birth defects and adult disease. The present study identifies the predominant pathways modulated by an acute embryonic mouse exposure during gastrulation to lithium or homocysteine that induces cardiac defects. High dose periconceptional folate supplementation normalized development. Microarray bioinformatic analysis of gene expression demonstrated that primarily lipid metabolism is altered after the acute exposures. The lipid-related modulation demonstrated a gender bias with male embryos showing greater number of lipid-related Gene Ontology biological processes altered than in female embryos. RT-PCR analysis demonstrated significant change of the fatty acid oxidation gene Acadm with homocysteine exposure primarily in male embryos than in female. The perturbations resulting from the exposures resulted in growth-restricted placentas with disorganized cellular lipid droplet distribution indicating lipids have a critical role in cardiac-placental abnormal development. High folate supplementation protected normal heart-placental function, gene expression and lipid localization.
    Language English
    Publishing date 2016-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 639342-1
    ISSN 1873-1708 ; 0890-6238
    ISSN (online) 1873-1708
    ISSN 0890-6238
    DOI 10.1016/j.reprotox.2016.03.039
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  9. Article: Changes in vitelline and utero-placental hemodynamics: implications for cardiovascular development.

    Linask, Kersti K / Han, Mingda / Bravo-Valenzuela, Nathalie J M

    Frontiers in physiology

    2014  Volume 5, Page(s) 390

    Abstract: Analyses of cardiovascular development have shown an important interplay between heart function, blood flow, and morphogenesis of heart structure during the formation of a four-chambered heart. It is known that changes in vitelline and placental blood ... ...

    Abstract Analyses of cardiovascular development have shown an important interplay between heart function, blood flow, and morphogenesis of heart structure during the formation of a four-chambered heart. It is known that changes in vitelline and placental blood flow seemingly contribute substantially to early cardiac hemodynamics. This suggests that in order to understand mammalian cardiac structure-hemodynamic functional relationships, blood flow from the extra-embryonic circulation needs to be taken into account and its possible impact on cardiogenesis defined. Previously published Doppler ultrasound analyses and data of utero-placental blood flow from human studies and those using the mouse model are compared to changes observed with environmental exposures that lead to cardiovascular anomalies. Use of current concepts and models related to mechanotransduction of blood flow and fluid forces may help in the future to better define the characteristics of normal and abnormal utero-placental blood flow and the changes in the biophysical parameters that may contribute to congenital heart defects. Evidence from multiple studies is discussed to provide a framework for future modeling of the impact of experimental changes in blood flow on the mouse heart during normal and abnormal cardiogenesis.
    Language English
    Publishing date 2014-11-11
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2014.00390
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: When should we prescribe high-dose folic acid to prevent congenital heart defects?

    Huhta, James C / Linask, Kersti

    Current opinion in cardiology

    2015  Volume 30, Issue 1, Page(s) 125–131

    Abstract: Purpose of review: Provide a rationale for attempting prevention of congenital heart defects (CHDs).: Recent findings: Prevention of neural-tube defects can be achieved with preconceptional use of folic acid. Extrapolating results from animal studies ...

    Abstract Purpose of review: Provide a rationale for attempting prevention of congenital heart defects (CHDs).
    Recent findings: Prevention of neural-tube defects can be achieved with preconceptional use of folic acid. Extrapolating results from animal studies to human pregnancy shows that folate deficiency as well as one-time exposure to environmental factors in the first 2 to 3 weeks of human gestation can result in severe CHD. Considering that approximately 50% of pregnancies are unplanned, this period of pregnancy can be considered high risk for cardiac, as well as neural, birth defects, as the woman usually is not aware of her pregnancy and may not yet be taking precautionary actions to protect the developing embryo. In mammals, folate supplementation prevents CHD induced by alcohol, by lithium, or by elevation of the metabolite homocysteine. Optimal protection of cardiogenesis was observed to occur with folate supplementation provided on the morning after conception and at higher doses than currently available in prenatal vitamin supplementation. Clinical studies show a similar pattern with high doses of folic acid required to prevent CHD.
    Summary: Today, all patients with a family history of CHD should discuss the prenatal use of folate supplementation with their obstetricians prior to becoming pregnant.
    MeSH term(s) Dietary Supplements ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Folic Acid/administration & dosage ; Gestational Age ; Heart Defects, Congenital/prevention & control ; Humans ; Infant, Newborn ; Male ; Neural Tube Defects/prevention & control ; Pregnancy ; Prenatal Care/methods ; Primary Prevention/methods ; Prognosis ; Randomized Controlled Trials as Topic ; Time Factors ; Treatment Outcome
    Chemical Substances Folic Acid (935E97BOY8)
    Language English
    Publishing date 2015-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 645186-x
    ISSN 1531-7080 ; 0268-4705
    ISSN (online) 1531-7080
    ISSN 0268-4705
    DOI 10.1097/HCO.0000000000000124
    Database MEDical Literature Analysis and Retrieval System OnLINE

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