Publications by authors named "Navid Esfandiari"

61 Publications

Catastrophic Human Error in Assisted Reproductive Technologies: A Systematic Review.

J Patient Saf 2020 Nov 16. Epub 2020 Nov 16.

From the Department of Obstetrics and Gynecology, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire.

Objective: Assisted reproductive technologies (ARTs) are complex processes with multiple and diverse opportunities for human error. Errors in ART are thought to be rare, but can have devastating consequences for patients and their offspring. The objectives of this article are to review known cases of human error in the ART laboratory and suggest preventative strategies.

Methods: We performed a systematic review of the literature in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines using PubMed and Google Scholar databases. Studies were eligible for inclusion if they involved known cases of unintentional human error in the ART laboratory. Only full-text articles in English were included. References of the resulted studies were considered for inclusion.

Results: A total of 420 articles were screened and 37 articles were selected for inclusion. These largely included case reports and reviews in the medical and legal literature. Twenty-two adverse events due to human error in the ART laboratory were identified. Eight of these adverse events were the result of the insemination with the wrong sperm, 6 errors lead to the transfer of the wrong embryo, 3 lead to an error in preimplantation genetic testing, and 5 adverse events lead to the failure of gamete and embryo cryostorage.

Conclusions: Since the advent of ART, there have been reports of catastrophic events occurring secondary to human error in the laboratory to include incidents of unintended parentage, and have resulted in the loss of embryos and gametes through cryostorage failure. Proposed solutions include the stringent implementation and adherence to safety protocols, adequate laboratory staffing and training, and novel methods for specimen labeling and tracking. Of utmost importance is having knowledge of these errors and the ability to determine cause so that future events can be prevented.
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http://dx.doi.org/10.1097/PTS.0000000000000763DOI Listing
November 2020

Advanced paternal age: effects on sperm parameters, assisted reproduction outcomes and offspring health.

Reprod Biol Endocrinol 2020 Nov 13;18(1):110. Epub 2020 Nov 13.

Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont Medical Center, Larner College of Medicine, 111 Colchester Ave, Burlington, VT, 05401, USA.

Many factors, including postponement of marriage, increased life expectancy, and improved success with assisted reproductive technologies have been contributing to increased paternal age in developed nations. This increased average paternal age has led to concerns about adverse effects of advanced paternal age on sperm quality, assisted reproductive outcomes, and the health of the offspring conceived by older fathers. This review discusses the association between advanced paternal age and sperm parameters, assisted reproduction success rates, and offspring health.
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http://dx.doi.org/10.1186/s12958-020-00668-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664076PMC
November 2020

Early Serum hCG in IVF: Are We Trending in the Right Direction?

Reprod Sci 2020 Oct 9. Epub 2020 Oct 9.

Department of Obstetrics and Gynecology and Reproductive Sciences, University of Vermont Medical Center, Larner College of Medicine, 111 Colchester Ave, Burlington, VT, 05401, USA.

Human chorionic gonadotropin (hCG) measurements may be the earliest indicator of fertility cycle success, available several weeks before an ultrasound would be diagnostic for pregnancy. Outcomes of these cycles are high stakes for a couple, and the earliest reassurance of a normal pregnancy would be beneficial for their well-being. Additionally, earlier diagnosis can allow for more rapid management by providers in the case of abnormal pregnancies. Therefore, establishing normal values for initial hCG level and early hCG kinetics is of great interest. There are many factors involved in assisted reproductive techniques that may lead to alterations in hCG kinetics when compared with spontaneous pregnancies. We aim to characterize normal hCG values for in vitro fertilization (IVF) pregnancies and review how different aspects of the IVF process may alter these trends in order to establish how best to counsel patients during the waiting period.
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http://dx.doi.org/10.1007/s43032-020-00347-8DOI Listing
October 2020

Does sperm DNA fragmentation have negative impact on embryo morphology and morphokinetics in IVF programme?

Andrologia 2020 Dec 5;52(11):e13798. Epub 2020 Oct 5.

Department of Obstetrics and Gynecology, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.

Evaluation of sperm integrity may predict the in vitro fertilisation (IVF) outcomes. The aim was to evaluate the relationship between the sperm DNA fragmentation (sDNAf) with embryo morphology and morphokinetic using time-laps monitoring (TLM) and to select the best time points for normalisation in IVF setting. After evaluating the fertilisation and pronuclei (Z) scoring, 328 normally fertilised oocytes were assessed to time of pronuclei fading, time of 2 to 8 discrete cells (t2-t8) and abnormal cleavage patterns, such as multinucleation, direct cleavage, reverse cleavage and fragmentation. Sperm chromatin dispersion (SCD) assay was used for assessment of prepared sperm chromatin status. SCD was categorised into 4 groups of <6.5, 6.5-10.7, 10.7-20.1 and >20.1. The finding showed significant differences in t6 (p = .012), t7 (p = .045), t8 (p = .013) and s1 (p = .001) between 4 SCD groups. When morphokinetic variables were normalised to tPNf, this difference was observed in t2 (p = .003) and t6 (p = .017). Subsequently, the percentage of top quality embryos and Z scoring were dependent to the sDNAf rate. In conclusion, tPNf was the best reference time point in IVF cycles. Also, we found high sDNAf rate had no negative impact on embryo morphology and morphokinetics in conventional IVF.
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http://dx.doi.org/10.1111/and.13798DOI Listing
December 2020

Preimplantation genetic testing as a component of root cause analysis of errors and reassignment of embryos in IVF.

Reprod Biomed Online 2020 Dec 27;41(6):975-977. Epub 2020 Aug 27.

Department of Obstetrics and Gynecology and Reproductive Sciences, University of Vermont Medical Center, Larner College of Medicine, Burlington, VT, USA. Electronic address:

The risks of embryo/gamete mix-up are a threat to the integrity of the IVF process, with significant implications for affected families. The use of preimplantation genetic testing through single-nucleotide polymorphism array or next-generation sequencing technology can help to identify, characterize and ultimately help, in some cases, to find the root cause, and to mitigate the extent of these errors for a given patient or laboratory.
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http://dx.doi.org/10.1016/j.rbmo.2020.08.031DOI Listing
December 2020

Mouse embryo assay for human in vitro fertilization quality control: a fresh look.

J Assist Reprod Genet 2020 May 12;37(5):1123-1127. Epub 2020 Apr 12.

IVF and Andrology Laboratories, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont Medical Center, Burlington, VT, 05401, USA.

The mouse embryo assay (MEA) has been used in the field of human in vitro fertilization (IVF) for multiple purposes such as developing embryo culture media, quality control within the laboratory, and procedural training and proficiency testing for embryology staff. In addition, manufacturing companies use the MEA as a means of quality control for the development of embryo culture media and medical devices and to meet the standards of testing for FDA approval of new products. It has long been considered by embryologists and laboratory scientists whether the MEA is an accurate or sensitive test in the quality assessment of culture media and medical devices or if use of this testing is more an obligation. There is no uniformly accepted gold standard method for IVF lab quality control or FDA approval. This review aims to revisit the role of the use of mouse embryos in the formulation of IVF media for clinical use and the different methods of employing the mouse embryo assay for quality control. In addition, we will review the use of the MEA as an important adjunct in the training for embryology staff and fellows in training in reproductive endocrinology and infertility (REI), as well as alternatives to the use of the MEA for these purposes.
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http://dx.doi.org/10.1007/s10815-020-01768-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244663PMC
May 2020

High prevalence of allergy in patients undergoing in vitro fertilization and embryo transfer.

J Assist Reprod Genet 2020 Feb 21;37(2):311-320. Epub 2020 Jan 21.

Department of Obstetrics and Gynecology, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.

Purpose: To determine the prevalence of allergy in couples undergoing in vitro fertilization (IVF) and the relationship between having allergy and IVF treatment outcomes.

Design: A retrospective cohort study of female infertility patients aged 20-49 years and their male partners undergoing IVF cycles from August 2010 to December 2016 in an academic fertility program.

Results: Prevalence data was collected for 493 couples (935 cycles). Over half of the female patients (54%) had at least one reported allergy versus the cited US prevalence of 10-30%. Antibiotic (54.7%) and non-antibiotic medication (39.2%) were the most common female allergy subtypes. Fewer male patients reported allergy (21.7%). Data on β-hCG outcomes were calculated for 841 cycles from 458 couples with no significant relationship found except for number of cycles including ICSI and number of embryos transferred per cycle (1.81 for those without allergy vs 2.07 for those with allergy, p = 0.07). Female patients with allergy were marginally statistically more likely to have a negative β-hCG (p = 0.07) and less likely to have a successful cycle (p = 0.06). When allergy subgroups were evaluated, there were no significant differences between groups except for a higher number of embryos transferred in women with environmental/other allergies (p = 0.02).

Conclusion: The prevalence of allergy among patients seeking infertility treatment is high compared with the general population. However, allergy was not found to be associated with IVF cycle outcomes. These findings are likely primarily limited by difficulty in defining specific allergy types within a retrospective study.
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http://dx.doi.org/10.1007/s10815-020-01691-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056777PMC
February 2020

Co-Enzyme Q10 Supplementation Rescues Cumulus Cells Dysfunction in a Maternal Aging Model.

Antioxidants (Basel) 2019 Mar 8;8(3). Epub 2019 Mar 8.

Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, 25 Orde Street, Toronto, ON M5T 3H7, Canada.

Over the past four decades, due to cultural and social changes, women in the developed world have significantly delayed childbirth. This trend is even worse for patients who attend infertility clinics. It is well-known that live birth rates in women older than 35 are significantly lower than in those younger, both naturally and with assisted reproduction. Fertility decline is, in part, due to an increase in oocyte aneuploidy that leads to a reduced embryo quality, as well as an increased incidence of miscarriages and birth defects. Here we show that aging-associated malfunction is not restricted to the oocyte, as cumulus granulosa cells also display a series of defects linked to mitochondrial activity. In, both, human and mouse model, a decline in cumulus cell function due to increased maternal age is accompanied by a decreased expression of enzymes responsible for Coenzyme Q (CoQ) production, particularly Pdss2 and CoQ6. In an aged mouse model supplementation with Coenzyme Q10-a potent stimulator of mitochondrial function-restored cumulus cell number, stimulated glucose uptake, and increased progesterone production. CoQ10 supplementation might, thus, improve oocyte and cumulus cells quantity and quality, by improving the mitochondrial metabolism in females of advanced maternal age.
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http://dx.doi.org/10.3390/antiox8030058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466589PMC
March 2019

Egg freezing for fertility preservation and family planning: a nationwide survey of US Obstetrics and Gynecology residents.

Reprod Biol Endocrinol 2019 Jan 29;17(1):16. Epub 2019 Jan 29.

Department of Obstetrics and Gynecology, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03765, USA.

Background: Little is known about resident attitudes toward elective egg freezing (EF) or how educational exposure to EF affects residents' views and ability to counsel patients. This study aimed to evaluate US OB/GYN residents' views on elective EF, decisions regarding family planning, and whether education on EF affects these views and self-reported comfort discussing EF with patients.

Methods: A 32 question survey was emailed to program directors at all US residency programs for distribution to residents. Chi-square tests were used to evaluate the relationship between educational factors and views on EF and comfort counselling patients.

Results: Of those surveyed, 106 residents and 7 fellows completed the survey (103 female). Almost three quarters of female respondents reported postponing pregnancy due to residency (71.8%). Non-exclusive reasons for this choice included career plans (54.4%) and concern for childcare (51.5%) and for fellow residents and their program (50.5%). Of the male and female residents who reported educational exposure to EF (57.5%), almost all of them (95.4%) received this in an REI rotation. Only half of female residents reported being comfortable counseling a patient on EF (49.5%). For female residents, education on EF (p = 0.03) and more advanced level of residency (p = 0.02) were significantly associated with comfort counseling a patient on EF.

Conclusions: Female OB/GYN residents are choosing to delay pregnancy during residency for career and social support reasons. Few residents feel comfortable counseling patients on EF, but appropriate curricular content on EF during residency could improve residents' comfort in assisting patients with reproductive planning.
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http://dx.doi.org/10.1186/s12958-019-0459-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352445PMC
January 2019

Birthweight in infants conceived through in vitro fertilization following blastocyst or cleavage-stage embryo transfer: a national registry study.

J Assist Reprod Genet 2018 Jun 10;35(6):1027-1037. Epub 2018 Apr 10.

Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA.

Purpose: In vitro fertilization (IVF) infants have lower birthweights than their peers, predisposing them to long-term health consequences. Blastocyst transfer (BT), at day 5-6 post-fertilization, is increasing in usage, partially due to improved pregnancy outcomes over cleavage-stage transfer (CT, day 2-3). Data to date, however, have been inconclusive regarding BT's effects on birthweight.

Methods: Participants included all US autologous, single-gestation, fresh embryo transfer cycles initiated from 2007 to 2014 that resulted in a term infant (N = 124,154) from the National Assisted Reproductive Technology Surveillance System. Generalized linear models including obstetric history, maternal demographics, and infant sex and gestational age were used to compare birthweight outcomes for infants born following BT (N = 67,169) with infants born following CT (N = 56,985) and to test for an interaction between transfer stage and single embryo transfer (SET).

Results: Infants born following BT were 6 g larger than those born following CT (p = 0.04), but rates of macrosomia (RR 1.00, 95% CI 0.96-1.04) and low birthweight (LBW, RR 1.00, 95% CI 0.93-1.06) were not different between the groups. The interaction between SET and transfer stage was significant (p = 0.02). Among SET infants, BT was associated with 19.26 g increased birthweight compared to CT (p = 0.008).

Conclusions: The increase in birthweights identified following BT is unlikely to be clinically relevant, as there were no differences in rates of macrosomia or LBW. These findings are clinically reassuring and indicate that the increasing use of BT is unlikely to further decrease the on average lower birthweights seen in IVF infants compared to their naturally conceived peers.
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http://dx.doi.org/10.1007/s10815-018-1168-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030018PMC
June 2018

Effect of frozen/thawed embryo transfer on birthweight, macrosomia, and low birthweight rates in US singleton infants.

Am J Obstet Gynecol 2018 04 29;218(4):433.e1-433.e10. Epub 2017 Dec 29.

Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA. Electronic address:

Background: Singleton infants conceived using assisted reproductive technology have lower average birthweights than naturally conceived infants and are more likely to be born low birthweight (<2500 gr). Lower birthweights are associated with increased infant and child mortality and poor adult health outcomes, including cardiovascular disease, hypertension, and diabetes. Data from registry and single-center studies suggest that frozen/thawed embryo transfer may be associated with larger birthweights. To date, however, a nationwide, full-population study on United States infants born using frozen/thawed embryo transfer has not been reported.

Objectives: The objective of this study was to compare the effect of frozen/thawed vs fresh embryo transfer on birthweight outcomes for singleton, term infants conceived using in vitro fertilization in the United States between 2007 and 2014, including average birthweight and the risks of both macrosomia (>4000 g) and low birthweight (<2500 g).

Study Design: We used data from the Centers for Disease Control and Prevention's National Assisted Reproductive Technology Surveillance System to compare birthweight outcomes of live-born singleton, autologous oocyte, term (37-43 weeks) infants. Generalized linear models for all infants and stratified by infant sex were used to assess the relationship between frozen/thawed embryo transfer and birthweight, in grams. Infertility diagnosis, year of treatment, maternal age, maternal obstetric history, maternal and paternal race, and infant gestational age and sex were included in the models. Missing race data were imputed. The adjusted relative risks for macrosomia and low birthweight were evaluated using multivariable predicted marginal proportions from logistic regression models.

Results: In total, 180,184 singleton, term infants were included, with 55,898 (31.02%) having been conceived from frozen/thawed embryos. Frozen/thawed embryo transfer was associated with, on average, a 142 g increase in birthweight compared with infants born after fresh embryo transfer (P < .001). An interaction between infant sex and embryo transfer type was significant (P < .0001), with frozen/thawed embryo transfer having a larger effect on male infants by 16 g. The adjusted risk of a macrosomic infant was 1.70 times higher (95% confidence interval, 1.64-1.76) following frozen/thawed embryo transfer than fresh embryo transfer. However, adjusted risk of low birthweight following frozen/thawed embryo transfer was 0.52 (95% confidence interval, 0.48-0.56) compared with fresh embryo transfer.

Conclusion: Frozen/thawed embryo transfer, in comparison with fresh embryo transfer, was associated with increased average birthweight in singleton, autologous oocytes, term infants born in the United States, with a significant interaction between frozen/thawed embryo transfer and infant sex. The risk of macrosomia following frozen/thawed embryo transfer was greater than that following fresh embryo transfer, but the risk of low birthweight among frozen/thawed embryo transfer infants was significantly decreased in comparison with fresh embryo transfer infants.
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http://dx.doi.org/10.1016/j.ajog.2017.12.223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5878119PMC
April 2018

Ultrastructure of cytoplasmic fragments in human cleavage stage embryos.

J Assist Reprod Genet 2016 Dec 10;33(12):1677-1684. Epub 2016 Sep 10.

Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, La Sapienza University of Rome, Rome, Italy.

Purpose: The goal of this study was to evaluate the ultrastructure of cytoplasmic fragments along with the effect of cytoplasmic fragment and perivitelline space coarse granulation removal (cosmetic microsurgery) from embryos before embryo transfer on ART outcomes.

Methods: One hundred and fifty intracytoplasmic sperm injection cycles with male factor infertility were included in this prospective study. Patients were divided into three groups of case (n = 50), sham (n = 50), and control (n = 50). Embryos with 10-50 % fragmentation were included in this study. Cosmetic microsurgery and zona assisted hatching were only performed in case and sham groups respectively. Extracted fragments were evaluated ultrastructurally by transmission electron microscopy (TEM). Rates of clinical pregnancy, live birth, miscarriage, multiple pregnancies, and congenital anomaly in the three groups were also compared.

Results: Micrographs from TEM showed that mitochondria were the most abundant structures found in the fragments along with mitochondria-vesicle complexes, Golgi apparatus, primary lysosomes, and vacuoles. There were no significant differences in demographic characteristics, laboratory and clinical data, or embryo morphological features between the groups. The rate of clinical pregnancy in control, sham, and case groups had no significant differences (24, 18, and 18 %, respectively). The rates of live birth, miscarriage, multiple pregnancy, and congenital anomaly were also similar between the different groups.

Conclusions: Our data demonstrated that cosmetic microsurgery on preimplantation embryos had no beneficial effect on ART outcomes in unselected groups of patients. As mitochondria are the most abundant organelles found in cytoplasmic fragments, fragment removal should be performed with more caution in embryos with moderate fragmentation.
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http://dx.doi.org/10.1007/s10815-016-0806-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171886PMC
December 2016

Human embryo mosaicism: did we drop the ball on chromosomal testing?

J Assist Reprod Genet 2016 Nov 30;33(11):1439-1444. Epub 2016 Aug 30.

Division of Reproductive Endocrinology and Infertility., Department of OB-GYN, School of Medicine, University of Toronto, Toronto, Canada.

There are newly recognized challenges presented by the occurrence of mosaicism in the context of trophectoderm (TE) biopsy for pre-implantation genetic screening (PGS) in in vitro fertilization (IVF) embryos. Chromosomal mosaicism, known to be significantly higher in IVF embryos than in later prenatal samples, may contribute to errors in diagnosis. In particular, PGS may result in discarding embryos diagnosed as aneuploid but in which the inner cell mass may be completely or mainly euploid, thus representing a false positive diagnosis. Although less likely, some embryos diagnosed as euploid could be mosaic and contain some aneuploid cells, possibly impacting their implantation potential. The ability of current diagnostic techniques to detect mosaicism is limited by the number and location of TE cells in the biopsy and by the methodology used for chromosomal assessment. The clinical consequences of mosaicism are dependent on the chromosome(s) involved, the developmental stage at which the mosaicism evolved, and whether TE biopsy accurately reflects the status of the inner cell mass that forms the fetus. Consequently, in patients with no euploid embryos identified on PGS, it may be appropriate to consider the transfer of diagnosed aneuploid embryos if the TE biopsy result is a non-viable chromosomal monosomy or triploidy that could not result in a birth. It should be acknowledged in consent forms that mosaicism has the potential to impact test results and that its detection may be below the resolution of the genetic tests being used. This concept represents a major shift in current IVF practice and ought to be considered given the data, or lack thereof, of the impact of mosaicism on IVF/PGS outcomes.
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http://dx.doi.org/10.1007/s10815-016-0797-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125153PMC
November 2016

A pilot study to evaluate a device for the intravaginal culture of embryos.

Reprod Biomed Online 2015 Dec 18;31(6):732-8. Epub 2015 Sep 18.

TCART Fertility Partners, Division of Reproductive Sciences, Department of Obstetrics and Gynecology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto M5S 2X9, Canada. Electronic address:

The aim of this comparative randomized embryology trial was to determine if an intravaginal culture device (IVC) can provide acceptable embryo development compared with conventional IVF. Ten women between the ages of 27 and 37 years with an indication for IVF treatment were included in this study. After ovarian stimulation, oocytes were randomized to fertilization in the IVC device or using conventional IVF. Fertilization rates were higher in the IVF group compared with the IVC device (68.7% ± 36 % versus 40.7% ± 27%), respectively, whereas cleavage rates were similar (93% ± 1.5% versus 97% ± 6%) for both groups. A significantly lower number of embryos of suitable quality for transfer was obtained from the IVC device compared with conventional IVF (OR, 0.47; 95% CI, 0.26 to 0.87). The clinical pregnancy rate from transfer of IVC device embryos was 30%. Satisfaction questionnaires were also completed by all participants. Most women (70%) placed high importance on having had fertilization and embryo development occur while carrying the device. Overall, the IVC device produced reasonable pregnancy rates suggesting this technology may have a place under certain circumstances. Cost-benefit analysis, psychological factors and future studies must be considered.
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http://dx.doi.org/10.1016/j.rbmo.2015.09.005DOI Listing
December 2015

Ongoing Pregnancies following Cosmetic Micromanipulation of Preimplantation Embryos in Patients with Implantation Failure.

Case Rep Med 2015 13;2015:734793. Epub 2015 Oct 13.

Division of Reproductive Endocrinology and Infertility, Department of Ob-Gyn, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.

Cosmetic micromanipulation is defined as fragment and coarse granulation removal from preimplantation embryos. We report two cases of pregnancies in patients with implantation failure following cosmetic micromanipulation.
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http://dx.doi.org/10.1155/2015/734793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621327PMC
November 2015

Large nuclear vacuoles in spermatozoa negatively affect pregnancy rate in IVF cycles.

Iran J Reprod Med 2015 Jul;13(7):425-32

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.

Background: Recently, motile sperm organelle morphology examination (MSOME) criteria as a new real time tool for evaluation of spermatozoa in intracytoplasmic sperm injection (ICSI) cycles has been considered.

Objective: The aim was to investigate the predictive value of MSOME in in vitro fertilization (IVF) in comparison to ICSI cycles and evaluation of the association between MSOME parameters and traditional sperm parameters in both groups.

Materials And Methods: This is a cross sectional prospective analysis of MSOME parameters in IVF (n=31) and ICSI cycles (n=35). MSOME parameters were also evaluated as the presence of vacuole (none, small, medium, large or mix); head size (normal, small or large); cytoplasmic droplet; head shape and acrosome normality. In sub-analysis, MSOME parameters were compared between two groups with successful or failed clinical pregnancy in each group.

Results: In IVF group, the rate of large nuclear vacuole showed significant increase in failed as compared to successful pregnancies (13.81±9.7vs7.38±4.4, respectively, p=0.045) while MSOME parameters were the same between successful and failed pregnancies in ICSI group. Moreover, a negative correlation was noticed between LNV and sperm shape normalcy. In ICSI group, a negative correlation was established between cytoplasmic droplet and sperm shape normalcy. In addition, there was a positive correlation between sperm shape normalcy and non-vacuolated spermatozoa.

Conclusion: The high rate of large nuclear vacuoles in sperm used in IVF cycles with failed pregnancies confirms that MSOME, is a helpful tool for fine sperm morphology assessment, and its application may enhance the assisted reproduction technology success rates.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609322PMC
July 2015

Non-synchronized endometrium and its correction in non-ovulatory cryopreserved embryo transfer cycles.

Reprod Biomed Online 2015 Apr 29;30(4):378-84. Epub 2014 Dec 29.

Toronto Centre for Advanced Reproductive Technology, M5X 2S9, Toronto, Ontario, Canada; Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. Electronic address:

The aim of this case series study was to investigate the effect of adjusting the length of progesterone exposure on clinical pregnancy rates in cryopreserved embryo transfer cycles of patients with out-of-phase classic endometrial dating. Eighty infertile women with previous implantation failure and good-quality embryos underwent endometrial biopsy before cryopreserved embryo transfer and were included in this study. The main outcome measures were clinical pregnancy rate and histologic endometrial dating. After adjusting the length of progesterone exposure according to endometrial dating, a significantly higher implantation rate was observed in blastocyst transfers (P = 0.02) and the clinical pregnancy rate for all cycles was 36.4%, similar to that in patients with in-phase endometrium (22.5%). In conclusion, the use of classic histologic endometrial dating to estimate the timing of the window of implantation and to adjust progesterone exposure accordingly may increase the implantation rate in frozen embryo transfer cycles.
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http://dx.doi.org/10.1016/j.rbmo.2014.12.005DOI Listing
April 2015

Coenzyme Q10 Supplementation and Oocyte Aneuploidy in Women Undergoing IVF-ICSI Treatment.

Clin Med Insights Reprod Health 2014 8;8:31-6. Epub 2014 Jun 8.

Toronto Centre for Advanced Reproductive Technology, Toronto, Ontario, Canada. ; Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada. ; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

Background: The age-related reduction in live-birth rate is attributed to a high rate of aneuploidy and follicle depletion. We showed in an animal model that treatment with Coenzyme Q10 (CoQ10) markedly improved reproductive outcome. The aim of this study was to compare the post-meiotic oocyte aneuploidy rate in in vitro fertilization (IVF) and intra cytoplasmic sperm injection (ICSI) patients treated with CoQ10 or placebo.

Methods: We conducted a double blind placebo controlled randomized trial that included IVF-ICSI patients 35-43 years of age. The patients were treated with either 600 mg of CoQ10 or an equivalent number of placebo caps. We compared the post-meiotic aneuploidy rate using polar body biopsy (PBBX) and comparative genomic hybridization (CGH). According to the power calculation, 27 patients were needed for each arm.

Results: Owing to safety concerns regarding the effects of polar body biopsy on embryo quality and implantation, the study was terminated before reaching the target number of participants. A total of 39 patients were evaluated and randomized (17 CoQ10, 22 placebo), 27 were given the study medication (12 CoQ10, 15 placebo), and 24 completed an IVF-ICSI cycle including PBBX and embryo transfer (10 CoQ10, 14 placebo). Average age, base line follicle stimulating hormone (FSH), peak estradiol and progesterone serum level, as well as the total number of human menopausal gonadotropin (hMG) units-did not differ between the groups. The rate of aneuploidy was 46.5% in the CoQ10 group compared to 62.8% in the control. Clinical pregnancy rate was 33% for the CoQ10 group and 26.7% for the control group.

Conclusion: No significant differences in outcome were detected between the CoQ10 and placebo groups. However, the final study was underpowered to detect a difference in the rate of aneuploidy.
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http://dx.doi.org/10.4137/CMRH.S14681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071761PMC
July 2014

A novel compound heterozygous mutation of the luteinizing hormone receptor -implications for fertility.

J Assist Reprod Genet 2014 Jul 22;31(7):787-94. Epub 2014 May 22.

Toronto Center for Advanced Reproductive Technology (TCART), Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Toronto, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 150 Bloor Street West, Suite 210, Toronto, ON, M5S 2X9, Canada,

The luteinizing hormone/chorionic gonadotropin receptor (LHCGR) belongs to the family of G-protein coupled receptors and binds both luteinizing hormone (LH) and human chorionic gonadotropin (hCG). Ligand-receptor interaction mediates a downstream cascade of events which is essential for ovulation in women, and expression of the male phenotype in men. The human LHCGR gene consists of 11exons and 10 introns. Homozygous and compound heterozygous mutations may inactivate the receptor by altering its structure and subsequent function. Herein we reported a novel, compound heterozgygous inactivating LHCGR mutation in a woman who presented with secondary infertility, having previously carried to term a donor oocyte pregnancy. A 27 bp deletion was detected in exon I at amino acid number 12. This mutation involved the signal peptide region, which is important for protein targeting, maturation and cellular expression. Another mutation involving a 2 base pair (thymine and cytosine) deletion was detected in exon 11 at amino acid number 586. This deletion produced a frameshift resulting in a premature stop codon and a truncated protein. An XY sibling with the same mutations was phenotypically female and misdiagnosed as complete androgen insensitivity syndrome. Other unaffected family members were genetically tested and carried one of the two mutations.
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http://dx.doi.org/10.1007/s10815-014-0249-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096877PMC
July 2014

Seminal hyperviscosity is not associated with semenogelin degradation or sperm deoxyribonucleic acid damage: a prospective study of infertile couples.

Fertil Steril 2014 Jun 26;101(6):1599-603. Epub 2014 Mar 26.

Division of Urology, Department of Surgery, Royal Victoria Hospital, McGill University Health Center, Montreal, Quebec, Canada. Electronic address:

Objective: To investigate the association between seminal hyperviscosity, the extent of semenogelin degradation, and sperm DNA integrity (DNA fragmentation index [DFI] and high DNA stainability [HDS]) in semen from infertile couples.

Design: Prospective study.

Setting: University-affiliated fertility center.

Patient(s): Twenty-four consecutive infertile couples with moderate or high seminal viscosity (hyperviscosity group) and 25 consecutive infertile couples with normal semen viscosity (control group) undergoing standard IVF.

Intervention(s): Semen volume and seminal hyperviscosity, sperm concentration, motility, and morphology, level of semenogelin degradation (by immunoblotting), and sperm chromatin damage (by sperm chromatin structure assay and expressed as %DFI and %HDS) were evaluated.

Main Outcome Measures(s): Sperm %DFI and %HDS in the hyperviscosity group and the control group and the relationship between the extent of semenogelin degradation and seminal viscosity.

Result(s): Semen volume in couples with moderate and high seminal viscosity was significantly lower as compared with the control group. In addition, total motility and normal morphology were significantly lower in the couples with high seminal viscosity as compared with the control group; however, there were no significant differences in sperm %DFI and %HDS between the hyperviscosity group and the control group. In addition, there was no relationship between the extent of semenogelin degradation and seminal viscosity.

Conclusion(s): Our data suggest that seminal hyperviscosity (a posttesticular factor) is not an important cause of sperm DNA damage. Moreover, seminal hyperviscosity is not related to the degree of semenogelin degradation.
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http://dx.doi.org/10.1016/j.fertnstert.2014.02.045DOI Listing
June 2014

Can cycle day 7 FSH concentration during controlled ovarian stimulation be used to guide FSH dosing for in vitro fertilization?

Reprod Biol Endocrinol 2013 Feb 22;11:12. Epub 2013 Feb 22.

Toronto Centre for Advanced Reproductive Technology, Toronto, ON, Canada.

Background: When stimulating a patient with poor ovarian response for IVF, the maximal dose of gonadotropins injected is often determined by arbitrary standards rather than a measured response. The purpose of this study was to determine if serum FSH concentration during an IVF stimulation cycle reflects follicular utilization of FSH and whether serum FSH values may inform dose adjustments of exogenous FSH.

Methods: In this retrospective cross sectional study we studied 155 consecutive IVF cycles stimulated only with recombinant human FSH. We only included long GnRH agonist protocols in which endogenous FSH levels were suppressed. We correlated the serum concentration of cycle day (CD) 7 FSH with the number of oocytes retrieved, cleaving embryos and pregnancy rate.

Results: We found that a CD7 FSH concentration above 22 IU/L was associated with poor response regardless of the daily dose of FSH injected and a lower pregnancy rate.

Conclusions: We concluded that CD7 FSH concentration during stimulation could be used to guide FSH dosing in poor responders. If the CD7 FSH concentration is above 22 IU/L increasing the dose of FSH in an attempt to recruit more growing follicles is unlikely to be successful.
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http://dx.doi.org/10.1186/1477-7827-11-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607851PMC
February 2013

Addition of low dose hCG to rFSh benefits older women during ovarian stimulation for IVF.

Reprod Biol Endocrinol 2012 Aug 6;10:55. Epub 2012 Aug 6.

Toronto Centre for Advanced Reproductive Technology, M5X 2 S9 Toronto, ON, Canada.

Background: To compare the outcome of IVF cycles in women receiving controlled ovarian stimulation with recFSH or recFSH plus low dose hCG.

Methods: A retrospective case control study, performed at a private practice affiliated with an academic institute. Patients were infertile women who were treated with IVF/ICSI and controlled ovarian stimulation in a long GnRH agonist protocol using either low dose hCG in addition to recFSH [N = 88] or recFSH alone [N = 99]. Primary outcomes were mean FSH dose, number of mature eggs, number of fertilized eggs, and serum levels of estradiol. Secondary outcomes were endometrial thickness, cycle cancellations and pregnancy rates.

Results: A significant increase in number of mature and fertilized eggs was observed in women over 40 years of age using low dose hCG in addition to recFSH. The estradiol level was significantly higher on the day of hCG administration and the serum level of FSH on cycle day 7 and on the day of hCG administration were lower.

Conclusion: Addition of low dose hCG to recFSH compared with recFSH alone significantly modified cycle characteristics in patients >/= 40 years and could be of potential benefit for IVF cycles in older infertile women.
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http://dx.doi.org/10.1186/1477-7827-10-55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464931PMC
August 2012

Effect of long-term combined oral contraceptive pill use on endometrial thickness.

Obstet Gynecol 2012 Aug;120(2 Pt 1):348-54

Reproductive Biology, Toronto Centre for Advanced Reproductive Technology, the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and the Department of Obstetrics and Gynecology, the Institute of Medical Sciences, and the Division of Reproductive Sciences, University of Toronto, Toronto, Ontario, Canada.

Objective: To estimate whether there is any association of long-term use of combined oral contraceptive pills (OCP) with adverse endometrial growth.

Methods: We reviewed the charts of 137 patients with history of OCP use undergoing endometrial preparation with estrogen for frozen embryo transfer. Endometrial thickness was measured by transvaginal ultrasonography on day 10 after menses and patients were divided into two groups (less than 7 mm and 7 mm or more).

Results: Thirty patients had endometrial thickness less than 7 mm and 107 had thickness of 7 mm or more. Mean years of combined OCP use in each group were 9.8±4.54 and 5.8±4.52, respectively (P<.001). With 10 years of combined OCP use as the threshold, the difference between the two groups (63.35% users in less than 7 mm group compared with 28.04% in the 7 mm or more thickness group) was highly significant (P<.001 by Fisher exact test), with an odds ratio of 4.43 (95% confidence interval 1.89-10.41). Past use of 5 years of OCPs was also associated with a significant (P=.002) difference in endometrial thickness. The mean endometrial thicknesses on cycle day 10 in patients using combined OCP for less than 10 years and 10 years or more were 9.54±1.88 mm and 8.48±2.33 mm, respectively, with P=.007. The mean endometrial thickness was 9.72±1.69 mm in less than 5 years and 8.81±2.23 mm in 5 or more years of use, respectively (P=.008). Cycle cancellation rates in the less than 7 mm group and 7 mm or greater endometrial thickness group were 23% and 4%, respectively (P=.002), but there was no difference in the clinical pregnancy rates between the two groups (13% compared with 27%, respectively; P=.15).

Conclusion: Long-term combined OCP use (5 years or more) can potentially affect optimal endometrial growth, leading to a higher cancellation rate and longer stimulation in frozen embryo transfer cycles. These findings suggest a previously unidentified adverse effect of long-term combined OCP use in women who are anticipating future fertility.

Level Of Evidence: II.
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http://dx.doi.org/10.1097/AOG.0b013e31825ec2eeDOI Listing
August 2012

Successful pregnancy following a novel endometrial preparation in a PCOS patient undergoing IVM: a case report.

J Assist Reprod Genet 2012 Apr 18;29(4):335-6. Epub 2012 Feb 18.

Yazd Institute for Reproductive Sciences, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

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http://dx.doi.org/10.1007/s10815-012-9723-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309990PMC
April 2012

Controlled aspiration and positioning of biological cells in a micropipette.

IEEE Trans Biomed Eng 2012 Apr 3;59(4):1032-40. Epub 2012 Jan 3.

Advanced Micro and Nanosystems Laboratory, University of Toronto, Toronto,ON,Canada.

Manipulating single cells with a micropipette is the oldest, yet still a widely used technique. This paper discusses the aspiration of a single cell into a micropipette and positioning the cell accurately to a target position inside the micropipette. Due to the small volume of a single cell (picoliter) and nonlinear dynamics involved, these tasks have high skill requirements and are labor intensive in manual operation that is solely based on trial and error and has high failure rates. We present automated techniques in this paper for achieving these tasks via computer vision microscopy and closed-loop motion control. Computer vision algorithms were developed to detect and track a single cell outside and inside a micropipette for automated single-cell aspiration. A closed-loop robust controller integrating the dynamics of cell motion was designed to accurately and efficiently position the cell to a target position inside the micropipette. The system achieved high success rates of 98% for cell detection and 97% for cell tracking (n = 100). The automated system also demonstrated its capability of aspirating a single cell into a micropipette within 2 s (versus 10 s by highly skilled operators) and accurately positioning the cell inside the micropipette within 8 s (versus 25 s by highly skilled operators).
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http://dx.doi.org/10.1109/TBME.2012.2182673DOI Listing
April 2012

The effects of low-level laser light exposure on sperm motion characteristics and DNA damage.

J Androl 2012 May-Jun;33(3):469-73. Epub 2011 Jul 14.

Toronto Centre for Advanced Reproductive Technology, Toronto, Ontario, Canada.

The objective of this study was to determine the effects of low-level laser light exposure on the motility of spermatozoa and on DNA damage. Thirty-three semen samples were collected for routine analysis and were classified as normospermic, oligospermic, or asthenospermic. After routine semen analysis was performed, residual semen was divided into treated and control aliquots. Treated samples were exposed to a 30-second infrared laser pulse of 50 mW/cm(2) at 905 nm, a wavelength thought to increase light-sensitive cytochrome c oxidase in the mitochondrial electron transport chain. Samples were then incubated at 37°C, and aliquots were analyzed at 30 minutes and 2 hours using computerassisted semen analysis. After incubation, 250 μL of each sample was frozen at 280°C until DNA fragmentation analysis by flow cytometry. A significant increase in motility, most prominent in oligospermic and asthenospermic samples (85% increase), was observed 30 minutes after the treatment (P < .0001). No significant increase in DNA damage compared with control samples was observed. Significant changes in sperm motion kinetics were observed. Low-level laser light exposure appears to have a positive short-term effect on the motility of treated spermatozoa and did not cause any increase in DNA damage measured at 2 hours. We conclude that some cases of asthenospermia may be related to mitochondrial dysfunction. The implications of this study in terms of future clinical applications needs further investigation.
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http://dx.doi.org/10.2164/jandrol.111.013458DOI Listing
October 2012

The contribution of mitochondrial function to reproductive aging.

J Assist Reprod Genet 2011 Sep 27;28(9):773-83. Epub 2011 May 27.

Toronto Centre for Advanced Reproductive Technology, University of Toronto, Toronto, Ontario, Canada.

Purpose: The number of women attempting to conceive between the ages of 36 and 44 has increased significantly in the last decade. While it is well established that women's reproductive success dramatically declines with age, the underlying physiological changes responsible for this phenomenon are not well understood. With assisted reproductive technologies, it is clear that oocyte quality is a likely cause since women over 40 undergoing in vitro fertilization (IVF) with oocytes donated by younger women have success rates comparable to young patients. Apart from oocyte donation, there is no known intervention to improve the pregnancy outcome of older patients. The aim of this paper was the review the relevant data on the potential role of mitochondria in reproductive aging.

Method: Review of current literature on the subject.

Results: We present the current evidence that associate mitochondrial dysfunction with age related decrease in female reproductive outcome.

Conclusions: The aging process is complex, driven by a multitude of factors thought to modulate cellular and organism life span. Although the factors responsible for diminished oocyte quality remain to be elucidated, the present review focuses on the potential role of impaired mitochondrial function.
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http://dx.doi.org/10.1007/s10815-011-9588-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169682PMC
September 2011

Robotic ICSI (intracytoplasmic sperm injection).

IEEE Trans Biomed Eng 2011 Jul 25;58(7):2102-8. Epub 2011 Apr 25.

Advanced Micro and Nanosystems Laboratory, University of Toronto, 5 King’s College Road, Toronto, ON M5S 3G8 Canada.

This paper is the first report of robotic intracytoplasmic sperm injection (ICSI). ICSI is a clinical procedure performed worldwide in fertility clinics, requiring pick-up of a single sperm and insertion of it into an oocyte (i.e., egg cell). Since its invention 20 years ago, ICSI has been conducted manually by a handful of highly skilled embryologists; however, success rates vary significantly among clinics due to poor reproducibility and inconsistency across operators. We leverage our work in robotic cell injection to realize robotic ICSI and aim ultimately, to standardize how clinical ICSI is performed. This paper presents some of the technical aspects of our robotic ICSI system, including a cell holding device, motion control, and computer vision algorithms. The system performs visual tracking of single sperm, robotic immobilization of sperm, aspiration of sperm with picoliter volume, and insertion of sperm into an oocyte with a high degree of reproducibility. The system requires minimal human involvement (requiring only a few computer mouse clicks), and is human operator skill independent. Using the hamster oocyte-human sperm model in preliminary trials, the robotic system demonstrated a high success rate of 90.0% and survival rate of 90.7% (n=120).
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http://dx.doi.org/10.1109/TBME.2011.2146781DOI Listing
July 2011

Use of letrozole challenge test to adjust gonadotropin dose in non-down-regulated cycles.

Fertil Steril 2011 Jun 9;95(8):2492-3. Epub 2011 Apr 9.

Toronto Centre for Advanced Reproductive Technology, Toronto, Ontario, Canada.

The use of a letrozole challenge test to predict ovarian response is described. The authors show that a ratio of cycle day 7 to cycle day 3 post-letrozole FSH level >1.5 is associated with poor ovarian response.
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http://dx.doi.org/10.1016/j.fertnstert.2011.03.042DOI Listing
June 2011

Automated sperm immobilization for intracytoplasmic sperm injection.

IEEE Trans Biomed Eng 2011 Apr 13;58(4):935-42. Epub 2010 Dec 13.

Advanced Micro and Nanosystems Laboratory, University of Toronto, Toronto M5S 3G8, Canada.

Sperm immobilization is a requisite step in intracytoplasmic sperm injection (ICSI). Conventionally, sperm immobilization is performed manually, which entails long training hours and stringent skills. Manual sperm immobilization also has the limitation of low success rates and poor reproducibility due to human fatigue and skill variations across operators. This paper presents a system for fully automated sperm immobilization to eliminate limitations in manual operation. Integrating computer vision and motion control algorithms, the automated system is able to visually track a sperm and control a micropipette to immobilize the sperm. A robust sperm tail tracking algorithm is developed to locate the optimal position on the sperm tail for sperm immobilization. The system demonstrates: 1) an average sperm tail tracking error of 0.95 μm; 2) a sperm tail visual tracking success rate of 96%; 3) a sperm immobilization success rate of 88.2% (based on 1000 trials); and 4) a speed of 6-7 s per successful immobilization.
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http://dx.doi.org/10.1109/TBME.2010.2098875DOI Listing
April 2011