Selection of high potential embryos using time-lapse imaging: the era of morphokinetics
2013; Elsevier BV; Volume: 99; Issue: 4 Linguagem: Inglês
10.1016/j.fertnstert.2013.01.089
ISSN1556-5653
AutoresJavier Herrero, Marcos Meseguer,
Tópico(s)Prenatal Screening and Diagnostics
ResumoIncorporation of time-lapse imaging in the field of IVF has provided much information about embryo development. The combination of the embryo appearance (morphology) and the importance of when and how the cellular processes that lead to this appearance occur (kinetics) are now integrated into the unique concept of morphokinetics. At present, efforts are focused on using this information to improve embryo selection and existing success rates without losing sight of the ever-present objective of implementing a single ET strategy to avoid multiple gestations. Several investigative groups have identified predictive morphokinetic variables for embryo viability and implantation potential. Promising supplementary models of embryo selection based on time-dependent markers have been proposed and are currently being verified in prospective trials. Pending further results of these studies that confirm the clinical validity of time-lapse imaging, the present article tries to summarize the studies conducted to date to take stock of what has been done and the prospects that are emerging from this technology. Incorporation of time-lapse imaging in the field of IVF has provided much information about embryo development. The combination of the embryo appearance (morphology) and the importance of when and how the cellular processes that lead to this appearance occur (kinetics) are now integrated into the unique concept of morphokinetics. At present, efforts are focused on using this information to improve embryo selection and existing success rates without losing sight of the ever-present objective of implementing a single ET strategy to avoid multiple gestations. Several investigative groups have identified predictive morphokinetic variables for embryo viability and implantation potential. Promising supplementary models of embryo selection based on time-dependent markers have been proposed and are currently being verified in prospective trials. Pending further results of these studies that confirm the clinical validity of time-lapse imaging, the present article tries to summarize the studies conducted to date to take stock of what has been done and the prospects that are emerging from this technology. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/herreroj-time-lapse-morphokinetics-cleavage/ Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/herreroj-time-lapse-morphokinetics-cleavage/ Conventional embryo selection methods are still associated with a relatively low IVF success rate with a clinical pregnancy rate (PR) of ∼30% per transfer (1Andersen A.N. Goossens V. Ferraretti A.P. Bhattacharya S. Felberbaum R. de Mouzon J. et al.Assisted reproductive technology in Europe, 2004: results generated from European registers by ESHRE.Hum Reprod. 2008; 23: 756-771Crossref PubMed Scopus (301) Google Scholar). This often leads to the transfer of more than one embryo at a time, which increases the risk of multiple pregnancies and the associated neonatal complications and maternal pregnancy-related health problems (2Stromberg B. Dahlquist G. Ericson A. Finnstrom O. Koster M. Stjernqvist K. Neurological sequelae in children born after in-vitro fertilisation: a population-based study.Lancet. 2002; 359: 461-465Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar, 3Pinborg A. IVF/ICSI twin pregnancies: risks and prevention.Hum Reprod Update. 2005; 11: 575-593Crossref PubMed Scopus (212) Google Scholar, 4Walker M.C. Murphy K.E. Pan S. Yang Q. Wen S.W. Adverse maternal outcomes in multifetal pregnancies.BJOG. 2004; 111: 1294-1296Crossref PubMed Scopus (106) Google Scholar). Clinical researchers have focused on the search for noninvasive embryonic markers that improve embryo selection and make it possible to offer a single embryo protocol without penalizing the overall IVF success. Serial observation remains the most commonly used technique of embryo evaluation because it is specific, sensitive, and safe (5Cummins J.M. Breen T.M. Harrison K.L. Shaw J.M. Wilson L.M. Hennessey J.F. A formula for scoring human embryo growth rates in in vitro fertilization: its value in predicting pregnancy and in comparison with visual estimates of embryo quality.J In Vitro Fert Embryo Transf. 1986; 3: 284-295Crossref PubMed Scopus (414) Google Scholar, 6Scott L. The biological basis of non-invasive strategies for selection of human oocytes and embryos.Hum Reprod Update. 2003; 9: 237-249Crossref PubMed Scopus (91) Google Scholar), but from a concern for the safety and stability of culture conditions, the frequency of observation and thus the amount of information available is limited (7Payne D. Flaherty S.P. Barry M.F. Matthews C.D. Preliminary observations on polar body extrusion and pronuclear formation in human oocytes using time-lapse video cinematography.Hum Reprod. 1997; 12: 532-541Crossref PubMed Scopus (315) Google Scholar). Establishment of the viability and implantation potential of embryos through discontinuous frames may result in a high degree of subjectivity associated with the observer (6Scott L. The biological basis of non-invasive strategies for selection of human oocytes and embryos.Hum Reprod Update. 2003; 9: 237-249Crossref PubMed Scopus (91) Google Scholar). Image capturing with time-lapse devices is a noninvasive method that offers the possibility for 24-hour monitoring of embryo development, increasing the quantity and quality of information without disturbing the culture conditions (7Payne D. Flaherty S.P. Barry M.F. Matthews C.D. Preliminary observations on polar body extrusion and pronuclear formation in human oocytes using time-lapse video cinematography.Hum Reprod. 1997; 12: 532-541Crossref PubMed Scopus (315) Google Scholar, 8Scott L. Pronuclear scoring as a predictor of embryo development.Reprod Biomed Online. 2003; 6: 201-214Abstract Full Text PDF PubMed Scopus (129) Google Scholar, 9Kirkegaard K. Agerholm I.E. Ingerslev H.J. Time-lapse monitoring as a tool for clinical embryo assessment.Hum Reprod. 2012; 27: 1277-1285Crossref PubMed Scopus (148) Google Scholar). Serial imaging is not a new technology, but the commercial availability of devices designed to work with embryos has led to a resurgence of this technique in recent years. Timing of embryo development is another piece of knowledge in the puzzle of human embryology and may help to select the single embryo with highest developmental competence in a cohort (9Kirkegaard K. Agerholm I.E. Ingerslev H.J. Time-lapse monitoring as a tool for clinical embryo assessment.Hum Reprod. 2012; 27: 1277-1285Crossref PubMed Scopus (148) Google Scholar). The safety of the technique was analyzed in a study that compared embryo development in a time-lapse imaging system with the development in a normal reference incubator (10Cruz M. Gadea B. Garrido N. Pedersen K.S. Martinez M. Perez-Cano I. et al.Embryo quality, blastocyst and ongoing pregnancy rates in oocyte donation patients whose embryos were monitored by time-lapse imaging.J Assist Reprod Genet. 2011; 28: 569-573Crossref PubMed Scopus (158) Google Scholar). It concluded that time-lapse image acquisition did not impair embryo quality and implantation potential. In the search for markers of embryo viability it should be noted that the choice of end point can influence the clinical validity of the marker. Studies using blastocyst formation as end point may not identify criteria for the prediction of implantation potential and vice versa (9Kirkegaard K. Agerholm I.E. Ingerslev H.J. Time-lapse monitoring as a tool for clinical embryo assessment.Hum Reprod. 2012; 27: 1277-1285Crossref PubMed Scopus (148) Google Scholar). However, studies that do look for these criteria need to consider other parameters that are not directly related to embryo viability (e.g., endometrial receptivity). The isolated investigation of the ability of an embryo to reach the blastocyst stage without demonstrating its subsequent implantation potential presents a challenge that needs to be addressed. In addition, we should consider that the live birth rate is the final clinical goal that any study of embryo quality markers should try to validate. Before the era of time-lapse, kinetics of embryo cleavage had already been widely analyzed with special attention to the phenomenon of early cleavage (11Edwards R.G. Fishel S.B. Cohen J. Fehilly C.B. Purdy J.M. Slater J.M. et al.Factors influencing the success of in vitro fertilization for alleviating human infertility.J In Vitro Fert Embryo Transf. 1984; 1: 3-23Crossref PubMed Scopus (422) Google Scholar, 12Hesters L. Prisant N. Fanchin R. Mendez Lozano D.H. Feyereisen E. 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The limitation of those studies was the reduced number of observations as a result of changes in culture conditions. Their evaluation involves working with qualitative variables, presence or absence, that do not allow establishing at what moment morphological changes occur. In the past 25 years, cell biology has benefited from major achievements within image technology. During the 1980s, the use of analogue videos greatly expanded the use of the microscope as an analytical tool (20Inoué S. Video microscopy. Plenum Press, New York1986Crossref Google Scholar) and most recently, analogue systems have been replaced by digital systems (21Inoué S. Spring K. Video microscopy.2nd ed. Plenum Press, New York1997Crossref Google Scholar). At present there are several commercially available time-lapse devices that differ in the design strategy, either building an incubator around a conventional microscope (7Payne D. Flaherty S.P. Barry M.F. Matthews C.D. Preliminary observations on polar body extrusion and pronuclear formation in human oocytes using time-lapse video cinematography.Hum Reprod. 1997; 12: 532-541Crossref PubMed Scopus (315) Google Scholar, 22Mio Y. Maeda K. Time-lapse cinematography of dynamic changes occurring during in vitro development of human embryos.Am J Obstet Gynecol. 2008; 199: 660.e1-660.e5Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar), inserting a microscope inside a conventional incubator (23Pribenszky C. Losonczi E. Molnar M. Lang Z. Matyas S. Rajczy K. et al.Prediction of in-vitro developmental competence of early cleavage-stage mouse embryos with compact time-lapse equipment.Reprod Biomed Online. 2010; 20: 371-379Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 24Wong C.C. Loewke K.E. Bossert N.L. Behr B. De Jonge C.J. Baer T.M. et al.Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage.Nat Biotechnol. 2010; 28: 1115-1121Crossref PubMed Scopus (563) Google Scholar), or having all the items integrated into a single piece of equipment (10Cruz M. Gadea B. Garrido N. Pedersen K.S. Martinez M. Perez-Cano I. et al.Embryo quality, blastocyst and ongoing pregnancy rates in oocyte donation patients whose embryos were monitored by time-lapse imaging.J Assist Reprod Genet. 2011; 28: 569-573Crossref PubMed Scopus (158) Google Scholar, 25Cruz M. Garrido N. Herrero J. Perez-Cano I. Munoz M. Meseguer M. Timing of cell division in human cleavage-stage embryos is linked with blastocyst formation and quality.Reprod Biomed Online. 2012; 25: 371-381Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 26Meseguer M. Rubio I. Cruz M. Basile N. Marcos J. Requena A. Embryo incubation and selection in a time-lapse monitoring system improves pregnancy outcome compared with a standard incubator: a retrospective cohort study.Fertil Steril. 2012; 98: 1481-1489Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). These noninvasive techniques offer the possibility to monitor embryos safely without removing them from the stable gas and temperature conditions (10Cruz M. Gadea B. Garrido N. Pedersen K.S. Martinez M. Perez-Cano I. et al.Embryo quality, blastocyst and ongoing pregnancy rates in oocyte donation patients whose embryos were monitored by time-lapse imaging.J Assist Reprod Genet. 2011; 28: 569-573Crossref PubMed Scopus (158) Google Scholar). Within the world of assisted reproduction, time-lapse has been in use for more than 40 years in either animals (27Cole R.J. Cinemicrographic observations on the trophoblast and zona pellucida of the mouse blastocyst.J Embryol Exp Morphol. 1967; 17: 481-490PubMed Google Scholar, 28Massip A. 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Behr B. De Jonge C.J. Baer T.M. et al.Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage.Nat Biotechnol. 2010; 28: 1115-1121Crossref PubMed Scopus (563) Google Scholar, 25Cruz M. Garrido N. Herrero J. Perez-Cano I. Munoz M. Meseguer M. Timing of cell division in human cleavage-stage embryos is linked with blastocyst formation and quality.Reprod Biomed Online. 2012; 25: 371-381Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 34Nagy Z.P. Liu J. Joris H. Devroey P. van Steirteghem A. Time-course of oocyte activation, pronucleus formation and cleavage in human oocytes fertilized by intracytoplasmic sperm injection.Hum Reprod. 1994; 9: 1743-1748PubMed Google Scholar, 35Van Blerkom J. Davis P. Alexander S. A microscopic and biochemical study of fragmentation phenotypes in stage-appropriate human embryos.Hum Reprod. 2001; 16: 719-729Crossref PubMed Scopus (126) Google Scholar, 36Hardarson T. Lofman C. Coull G. Sjogren A. Hamberger L. Edwards R.G. Internalization of cellular fragments in a human embryo: time-lapse recordings.Reprod Biomed Online. 2002; 5: 36-38Abstract Full Text PDF PubMed Scopus (71) Google Scholar, 37Lemmen J.G. Agerholm I. Ziebe S. Kinetic markers of human embryo quality using time-lapse recordings of IVF/ICSI-fertilized oocytes.Reprod Biomed Online. 2008; 17: 385-391Abstract Full Text PDF PubMed Scopus (218) Google Scholar, 38Montag M. Liebenthron J. Koster M. Which morphological scoring system is relevant in human embryo development?.Placenta. 2011; 32: S252-S256Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Limiting ourselves to the work in humans, Payne and colleagues (7Payne D. Flaherty S.P. Barry M.F. Matthews C.D. Preliminary observations on polar body extrusion and pronuclear formation in human oocytes using time-lapse video cinematography.Hum Reprod. 1997; 12: 532-541Crossref PubMed Scopus (315) Google Scholar) pioneered the use of time-lapse observations in 1997 when they documented the processes during fertilization and the first steps of development of 38 oocytes. The acquisition of one image per minute allowed cellular events, such as timing of extrusion of the second polar body, synchrony in appearance of pronuclei (PN), and abuttal of PN to be described and correlated with subsequent embryo quality on day 3. Ten years later, Mio and Maeda (22Mio Y. Maeda K. Time-lapse cinematography of dynamic changes occurring during in vitro development of human embryos.Am J Obstet Gynecol. 2008; 199: 660.e1-660.e5Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar) extended the analysis period until the blastocyst stage and characterized the dynamic and morphokinetic events from fertilization to the hatching of the blastocyst in 286 embryos. In a publication also published that year, Lemmen et al. (37Lemmen J.G. Agerholm I. Ziebe S. Kinetic markers of human embryo quality using time-lapse recordings of IVF/ICSI-fertilized oocytes.Reprod Biomed Online. 2008; 17: 385-391Abstract Full Text PDF PubMed Scopus (218) Google Scholar) analyzed events occurring during the first day of development after fertilization by means of a microscope with a camera in a closed system using a small data set of 102 zygotes. They found a correlation between early disappearance of PN after fertilization, early onset of first cleavage, and many blastomeres on day 2 of development. They were also the first to extend the analysis of correlations to include PR, identifying synchrony in appearance of nuclei after the first cleavage as a marker, but time ranges of reference for the proposed variables were not provided. More recently, two reports (24Wong C.C. Loewke K.E. Bossert N.L. Behr B. De Jonge C.J. Baer T.M. et al.Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage.Nat Biotechnol. 2010; 28: 1115-1121Crossref PubMed Scopus (563) Google Scholar, 39Meseguer M. Herrero J. Tejera A. Hilligsoe K.M. Ramsing N.B. Remohi J. The use of morphokinetics as a predictor of embryo implantation.Hum Reprod. 2011; 26: 2658-2671Crossref PubMed Scopus (586) Google Scholar) have proposed algorithms to predict embryo viability based on early morphokinetic variables measured with different time-lapse systems. Wong and colleagues (24Wong C.C. Loewke K.E. Bossert N.L. Behr B. De Jonge C.J. Baer T.M. et al.Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage.Nat Biotechnol. 2010; 28: 1115-1121Crossref PubMed Scopus (563) Google Scholar) conducted a study on 242 frozen 2PN embryos that included time-lapse image analysis and gene expression profiling to identify predictive parameters for the successful development to the blastocyst stage and differential molecular programs between normal and abnormal embryos in relation to the cleavage rate. Images were captured every 5 minutes using time-lapse microscopes equipped with low-power, dark-field illumination. They proposed a combination of three parameters to predict blastocyst formation: duration of the first cleavage (14.3 ± 6.0 minutes), time interval between the first and second mitotic division (i.e., duration of the two-cell stage) (11.1 ± 2.2 hours), and the time interval between the second and third mitosis (i.e., duration of the three-cell stage) (1.0 ± 1.6 hours). In addition, embryos catalogued as "abnormal" (those that did not reach the blastocyst stage) also showed abnormal molecular programs. In the other report, Meseguer and colleagues (39Meseguer M. Herrero J. Tejera A. Hilligsoe K.M. Ramsing N.B. Remohi J. The use of morphokinetics as a predictor of embryo implantation.Hum Reprod. 2011; 26: 2658-2671Crossref PubMed Scopus (586) Google Scholar) used a time-lapse system equipped with a modified Hoffmann contrast objective designed for low-intensity red illumination (635 nm) that acquired images at 15-minute intervals. The study included a total of 2,903 oocytes, which resulted in 2,120 embryos, of which 522 were transferred on day 3. More specifically, the results presented in the report refer to 247 known implantation embryos—those cases where the number of gestational sacs matched the number of transferred embryos (full implantation) and embryos from treatments where no biochemical pregnancy was achieved (no implantation) were included in the analysis. Using implantation success as an end point and applying a logistic regression model to sort the best predictor variables, the time interval between the first and second mitotic division, called cc2 (≤11.9 hours), and the time interval between the second and third mitosis, defined as the synchrony during the second set of cleavage divisions or s2 (≤0.76 hours), were also identified as predictive markers, consistent with the findings of the Wong et al. study. Furthermore, a third and different parameter was also identified, namely the time span between intracytoplasmic sperm injection (ICSI) and the five-cell embryo formation or t5 (48.8–56.6 hours). A hierarchical relationship between the variables was established with t5 being the strongest predictor, cc2 the second-strongest, and s2 as the third step in the model. The investigators also identified a set of three negative predictive factors associated with a very limited implantation rate: direct cleavage from the one- to three-blastomere embryo, uneven blastomere size at the two-cell stage, and multinucleation at the four-cell stage. By using negative and positive predictive variables, an algorithm for embryo selection based on morphokinetics was defined, categorizing embryos into 10 categories. Using the same time-lapse system and similar procedures to those described in the study by Meseguer et al. (39Meseguer M. Herrero J. Tejera A. Hilligsoe K.M. Ramsing N.B. Remohi J. The use of morphokinetics as a predictor of embryo implantation.Hum Reprod. 2011; 26: 2658-2671Crossref PubMed Scopus (586) Google Scholar), several studies have been published subsequently. A clinical multicenter retrospective study (40Rubio I. Kuhlmann R. Agerholm I. Kirk J. Herrero J. Escribá M.J. et al.Limited implantation success of direct-cleaved human zygotes: a time-lapse study.Fertil Steril. 2012; 98: 1458-1463Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar) provided results that confirm direct cleavage as a negative marker of implantation. Time-lapse observations were extended to the blastocyst stage in another study analyzing 834 embryos (25Cruz M. Garrido N. Herrero J. Perez-Cano I. Munoz M. Meseguer M. Timing of cell division in human cleavage-stage embryos is linked with blastocyst formation and quality.Reprod Biomed Online. 2012; 25: 371-381Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar). Hierarchical selection criteria proposed by Meseguer et al. (39Meseguer M. Herrero J. Tejera A. Hilligsoe K.M. Ramsing N.B. Remohi J. The use of morphokinetics as a predictor of embryo implantation.Hum Reprod. 2011; 26: 2658-2671Crossref PubMed Scopus (586) Google Scholar) showed predictive ability using as end point blastocyst rate and blastocyst morphology. Hashimoto et al. (41Hashimoto S. Kato N. Saeki K. Morimoto Y. Selection of high-potential embryos by culture in poly(dimethylsiloxane) microwells and time-lapse imaging.Fertil Steril. 2012; 97: 332-337Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar) also found a link between the timing of early embryo cell divisions and the probability of subsequent development of embryos into blastocysts using a different time-lapse device. They identified the synchronization and timing of the second and third cell divisions as critical parameters. The influence on development kinetics of the type and total dose of gonadotropins and of steroid concentration during ovarian stimulation has also been evaluated (42Munoz M. Cruz M. Humaidan P. Garrido N. Perez-Cano I. Meseguer M. Dose of recombinant FSH and oestradiol concentration on day of HCG affect embryo development kinetics.Reprod Biomed Online. 2012; 25: 382-389Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). Part results from this study showed that the type of gonadotropin used seemed not to affect embryo kinetics, but gonadotropin dosage and E2 concentration influenced the timing of analyzed variables. In a recent article (26Meseguer M. Rubio I. Cruz M. Basile N. Marcos J. Requena A. Embryo incubation and selection in a time-lapse monitoring system improves pregnancy outcome compared with a standard incubator: a retrospective cohort study.Fertil Steril. 2012; 98: 1481-1489Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar) worth mentioning, the effect on reproductive outcome of the use of similar procedures for culturing and selecting embryos with a time-lapse monitoring system in 10 IVF clinics has been retrospectively contrasted. The relative probability of achieving clinical pregnancy was +20.1% per oocyte retrieval and +15.7% per ET compared with a conventional incubator. The most recent articles in this area have focused on the analysis of the PN (43Azzarello A. Hoest T. Mikkelsen A.L. The impact of pronuclei morphology and dynamicity on live birth outcome after time-lapse culture.Hum Reprod. 2012; 27: 2649-2657Crossref PubMed Scopus (104) Google Scholar), cleavage times until the eight-cell stage (44Dal Canto M. Coticchio G. Mignini Renzini M. De Ponti E. Novara P.V. Brambillasca F. et al.Cleavage kinetics analysis of human embryos predicts development to blastocyst and implantation.Reprod Biomed Online. 2012; 25: 474-480Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar), and different types of culture media (45Ciray H.N. Aksoy T. Goktas C. Ozturk B. Bahceci M. Time-lapse evaluation of human embryo development in single versus sequential culture media-a sibling oocyte study.J Assist Reprod Genet. 2012; 29: 891-900Crossref PubMed Scopus (112) Google Scholar). Azzarello et al. (43Azzarello A. Hoest T. Mikkelsen A.L. The impact of pronuclei morphology and dynamicity on live birth outcome after time-lapse culture.Hum Reprod. 2012; 27: 2649-2657Crossref PubMed Scopus (104) Google Scholar) found that pronuclear breakdown occurred later in embryos resulting in live birth compared with those that resulted in no live birth, which contrasts the study by Lemmen et al. (37Lemmen J.G. Agerholm I. Ziebe S. Kinetic markers of human embryo quality using time-lapse recordings of IVF/ICSI-fertilized oocytes.Reprod Biomed Online. 2008; 17: 385-391Abstract Full Text PDF PubMed Scopus (218) Google Scholar), observing that early pronuclear breakdown was a good marker of embryo potential but agrees with Meseguer et al. (39Meseguer M. Herrero J. Tejera A. Hilligsoe K.M. Ramsing N.B. Remohi J. The use of morphokinetics as a predictor of embryo implantation.Hum Reprod. 2011; 26: 2658-2671Crossref PubMed Scopus (586) Google Scholar) who saw that too early cleavage may be detrimental to the subsequent implantation. The investigators found no correlation with the distribution of pronuclear scores, which is consistent with observations of Montag et al. (38Montag M. Liebenthron J. Koster M. Which morphological scoring system is relevant in human embryo development?.Placenta. 2011; 32: S252-S256Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar), indicating that this score can vary markedly in a short time. Dal Canto et al. (44Dal Canto M. Coticchio G. Mignini Renzini M. De Ponti E. Novara P.V. Brambillasca F.
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