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The present study was undertaken to examine the effect of circulating oestradiol on serum levels of 25-hydroxyvitamin D3 (25-OHD3), 24,25-dihydroxyvitamin D3[24,25-(OH)2D3], and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] during gonadotrophin-induced ovarian stimulation in 10 healthy women undergoing in-vitro fertilization and embryo transfer (IVF). The presence of these metabolites in the follicular fluid was also investigated. Plasma oestradiol increased from 25 +/- 3.2 (mean +/- SE) pg/ml before initiation of treatment to 2563 +/- 328 pg/ml on the day of injection of human chorionic gonadotrophin (HCG) and 1641 +/- 299 pg/ml on the day of ovum retrieval (P < 0.01). Serum levels of 1,25-(OH)2D3 increased from 32.0 +/- 1.9 (mean +/- SE) pg/ml to 46.6 +/- 8.1 and 48.5 +/- 7.7 pg/ml (P < 0.05) on the day of HCG and ovum retrieval, respectively. No changes in blood levels of 25-OHD3 and 24,25-(OH)2D3 were found. The presence of vitamin D metabolites in follicular fluid is documented herein for the first time. All three metabolites were present in the follicular fluid but were significantly lower than in the concurrent serum (P < 0.01). A highly significant correlation was found between serum and follicular fluid levels: r = 0.787, P < 0.001 for 1,25-(OH)2D3; r = 0.738, P < 0.01 for 25-OHD3; and r = 0.751, P < 0.01 for 24,25-(OH)2D3. Our results suggest that raised levels of circulating oestradiol during gonadotrophin-induced ovarian stimulation are associated with a significant increase of serum 1,25-(OH)2D3. [ABSTRACT FROM AUTHOR]

Purpose: Intrapartum fetal death is devastating for both parents and medical caregivers. The purpose of this study was to evaluate the risk factors for intrapartum fetal death, which often influence management in subsequent pregnancies., Methods: This population-based cohort study included all singleton deliveries between the years 1991-2016 at Soroka University Medical Center. Trends over the years, risk factors for intrapartum fetal death and the effect of day of the week were examined. A generalized estimation equation (GEE) model was used to control for confounders., Results: During the study period 344,536 deliveries were recorded, of which 251 (0.1%) suffered intrapartum fetal death. Rates did not change significantly over the years (p = 0.130, using the chi-square test for trends). Preterm delivery, placental abruption, uterine rupture, shoulder dystocia, congenital malformations, severe preeclampsia and fetal malpresentation were significantly more common in pregnancies complicated by intrapartum death. Using a GEE model; shoulder dystocia (aOR 23.8, 95% CI 9.9-57.3, p < 0.005), uterine rupture (aOR 19.0, 95% CI 7.0-51.4, p < 0.05), preterm delivery (aOR 11.9, 95% CI 8.6-16.5, p < 0.001), placental abruption (aOR 6.2, 95% CI 4.1-9.4, p < 0.001), fetal malpresentation (aOR 3.6, 95% CI 2.6-4.9, p < 0.005) and congenital malformations (aOR 2.6, 95% CI 1.9-3.5, p < 0.05) were all independent risk factors for intrapartum fetal death. Weekend deliveries were not at increased risk of intrapartum fetal death., Conclusion: Several risk factors were identified for intrapartum fetal death, with shoulder dystocia demonstrating the highest risk. Unfortunately most factors are neither preventable nor predictable and interventions to decrease the rate of intrapartum fetal death remain elusive., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Blastocyst selection is primarily based on morphological scoring systems and morphokinetic data. These methods involve subjective grading and time-consuming techniques. Artificial intelligence allows for objective and quick blastocyst selection. In this study, 608 blastocysts were selected for transfer using morphokinetics and Gardner criteria. Retrospectively, morphometric parameters of blastocyst size, inner cell mass (ICM) size, ICM-to-blastocyst size ratio, and ICM shape were automatically measured by a semantic segmentation neural network model. The model was trained on 1506 videos with 102 videos for validation with no overlap between the ICM and trophectoderm models. Univariable logistic analysis found blastocyst size and ICM-to-blastocyst size ratio to be significantly associated with implantation potential. Multivariable regression analysis, adjusted for woman age, found blastocyst size to be significantly associated with implantation potential. The odds of implantation increased by 1.74 for embryos with a blastocyst size greater than the mean (147 ± 19.1 μm). The performance of the algorithm was represented by an area under the curve of 0.70 (p < 0.01). In conclusion, this study supports the association of a large blastocyst size with higher implantation potential and suggests that automatically measured blastocyst morphometrics can be used as a precise, consistent, and time-saving tool for improving blastocyst selection., (© 2023. Springer Nature Limited.)

This cohort study investigated whether letrozole versus hormone replacement therapy (HRT) results in higher live birth rate among anovulatory and oligoovulatory women in frozen-thawed embryo transfer (FET) cycles. It was conducted from 1st February 2018 to 31st January 2019 and included 261 anovulatory and oligoovulatory women. Since letrozole has become an effective alternative to HRT cycles, 121 patients received letrozole in 121 cycles from 1st February 2018 to 31st January 2019 and were compared to 140 HRT FET cycles among 140 women from 1st February 2017 to 31st January 2018. The primary outcome was live birth rate. Secondary outcomes were clinical pregnancy, multiple pregnancy and miscarriage rates. Clinical pregnancy and live birth rates of transferred cleavage embryos were higher in the letrozole compared to the HRT group (36/65 (55.3%) vs. 20/110 (18.1%), p  < 0.001) and (25/65 (38.4%) vs. 17/110 (15.4%), p  < 0.001) respectively, whilst these rates were similar for transferred blastocyst embryos. Miscarriage and multiple pregnancy rates were similar between groups. The letrozole group was older than the HRT group (31.8 ± 5.1 vs. 29.9 ± 5.1 years, p  = 0.002) and more smoked cigarettes ( p  = 0.035). Groups were similar regarding BMI, male versus non-male indication for fertility treatment, peak oestradiol levels, and numbers of oocytes retrieved, blastocysts, frozen and transferred embryos. Letrozole compared to HRT might improve live birth and clinical pregnancy rates among anovulatory and oligoovulatory women undergoing FET cycles.

Purpose: To assess the impact of post-thawing embryo culture on frozen embryo transfer (FET) outcomes., Methods: A retrospective cohort study including 678 consecutive FET cycles performed between the years 2004 and 2017 was conducted. Patients older than 45 years old were excluded. FET cycles were stratified as follows: (1) two-day (2d) embryos thawed and cultured to three-day (3d) versus 3d embryos thawed and transferred; (2) 2d or 3d embryos thawed and cultured to blastocysts versus blastocysts thawed and transferred. A p -value <.05 was considered statistically significant., Results: Maternal age, BMI, smoking, and basal FSH of the 2d and 3d cultured embryo group ( n  = 110) and the 3d non-cultured embryo group ( n  = 189) were comparable. Endometrium preparation protocols and the achieved endometrial thickness did not differ between groups. Pregnancy rate, implantation rate, clinical pregnancy, live birth rate, abortions, multiple pregnancies, perinatal outcomes, and birth weight were comparable.The 2d and 3d embryos cultured to blastocyst ( n  = 41) compared to non-cultured blastocyst ( n  = 338) showed that the non-cultured blastocyst patients had higher smoking rates and longer follicular phase. Endometrial thickness was comparable. The 2d and 3d embryos cultured to blastocyst stage had higher multiple pregnancies rate compared to the blastocyst non-cultured group, whereas pregnancy rate, implantation rate, live birth rate, miscarriages, perinatal outcomes, and birth weight were comparable., Conclusion: We could not demonstrate that the post-thaw culture had a significant impact on the outcome of FET cycles.

A time-lapse monitoring system provides a complete picture of the dynamic embryonic development process and simultaneously supplies extensive morphokinetic data. The objective of this study was to investigate whether the use of the morphokinetic parameter of time of starting blastulation (tSB) can improve the implantation rate of day-5 transferred blastocyst selected based on morphological parameters. In this retrospective study we analyzed the morphokinetics of 196 day-5 transferred blastocysts, selected solely based on morphological parameters. The interval time from intracytoplasmic sperm injection (ICSI) to time of starting blastocyst formation (tSB) was calculated for each embryo. The overall implantation rate of transferred blastocyst, selected based only on morphological parameters, was 49.2%. Implantation rate, determined retrospectively, was significantly higher (58.8% versus 42.6%, P = 0.02) for embryos with a short interval time to tSB (78-95.9 h) compared with embryos with a longer timeframe (96-114 h). Time of expanded blastocyst (tEB) post-ICSI was also significantly associated with implantation; however, this parameter was not available for all the embryos at time of transfer. When we tested only high ranked KIDScore day-3 sub-group embryos, the implantation rate was significantly higher in short interval time embryos compared with longer interval time embryos (62.2% vs. 45.5%, respectively, P = 0.02).These observations emphasize the importance of the timing of starting blastulation over blastocyst morphological parameters and may provide a preferable criterion for good morphology day-5 blastocyst selection.

Objective: To compare pregnancy outcomes between pregnancies following day 2, day 3, and days 5/6 fresh embryo transfer (ET)., Methods: A retrospective cohort study including all pregnancies following fresh IVF/intracytoplasmic sperm injection (ICSI) ET cycles performed between January 2014 and December 2015 at Fertility and In Vitro Fertilization (IVF) Unit of the tertiary Soroka University Medical Center. The study groups consisted of 48, 72, 120, and 144 hours embryos. Pregnancies were confirmed by a serum beta-human chorionic gonadotropin measurement. Data regarding patients' medical history, infertility workup, fertility treatment characteristics, and outcome, as well as obstetrical outcome, were collected from patients' medical records and IVF Laboratory database. Multiple regression models were constructed to control for confounders. Patients who underwent fertility preservation treatment, cycles of oocyte donation or in vitro maturation oocytes, and cases of preimplantation genetic testing were excluded., Results: A total of 534 pregnancies following fresh IVF/ICSI ET on day 2 ( n  = 189, 35.4%), day 3 ( n  = 200, 37.5%), and days 5 or 6 ( n  = 145, 27.2%) were included. Live birth rate demonstrated a linear association to the developmental stage at ET with the highest rates in blastocysts and gradually lower in day 3 and day 2 ET (79.2, 65.8, and 60.6%, respectively, p  = .001). A positive linear association was also observed between ET age and clinical pregnancy rate (77.3, 87.5, and 90.3% for days 2, 3, and 5/6, respectively, p  = .002), as well as with combined pregnancy complication rate (29, 37.3, and 43.3%, p  = .026). However, using multivariate logistic regression model controlling for ET age, maternal age, smoking, obesity, initial HCG level and peak E2 level, live birth rate was comparable between the study groups regardless of ET age. Pregnancy complications were comparable between the groups; however, a composite pregnancy complications variable was higher in the blastocyst pregnancies compared to cleavage embryos pregnancies., Conclusions: The common approach of blastocyst transfer, as high quality of the embryo, has not proven beneficial in terms of live birth rate. Moreover, cleavage stage embryos were not associated with adverse perinatal outcomes. The current data suggest maternal age has an independent effect on live birth.

Infertility affects one in six couples, half of which are caused by a male factor. Male infertility can be caused by both, qualitative and quantitative defects, leading to Oligo- astheno-terato-zoospermia (OAT; impairment in ejaculate sperm cell concentration, motility and morphology). Azoospermia defined as complete absence of sperm cells in the ejaculation. While hundreds of genes are involved in spermatogenesis the genetic etiology of men's infertility remains incomplete.We identified a hemizygous stop gain pathogenic variation (PV) in the X-linked Germ Cell Nuclear Acidic Peptidase (GCNA), in an Azoospermic patient by exome sequencing. Assessment of the prevalence of pathogenic variations in this gene in infertile males by exome sequence data of 11 additional unrelated patients identified a probable hemizygous causative missense PV in GCNA in a severe OAT patient. Expression of GCNA in the patients' testes biopsies and the stage of spermatogonial developmental arrest were determined by immunofluorescence and immunohistochemistry. The Azoospermic patient presented spermatogenic maturation arrest with an almost complete absence of early and late primary spermatocytes and thus the complete absence of sperm. GCNA is critical for genome integrity and its loss results in genomic instability and infertility in Drosophila, C. elegans, zebrafish, and mouse. PVs in GCNA appear to be incompatible with male fertility in humans as well: A stop-gain PV caused Azoospermia and a missense PV caused severe OAT with very low fertilization rates and no pregnancy in numerous IVF treatments., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)

Purpose: To assess the effect of high ovarian response on oocyte quality and ovarian stimulation cycle outcomes., Methods: A retrospective cohort study conducted at three IVF units. The high ovarian response (HOR) and polycystic ovary syndrome (PCOS) with HOR (PCOS HOR) groups included 151 and 13 women who underwent controlled ovarian stimulation (COS) resulting in more than 15 retrieved oocytes, for a total of 1863 and 116 cultured embryos, respectively. The normal ovarian response (NOR) group comprised 741 women with 6-15 retrieved oocytes, resulting in 4907 cultured embryos. Data collected included fresh cycle data and pregnancy rates, in addition to annotation of morphokinetic events from time of pronuclei fading to time of initiation of blastocyst formation of embryos cultured in a time lapse incubator, including occurrence of direct unequal cleavage at first cleavage (DUC-1) (less than 5 h from two to three blastomeres). Comparison was made between morphokinetic parameters between the 3 groups. Cycle outcomes were compared in the high vs. normal ovarian response groups., Results: Oocyte maturation rate was significantly lower in the HOR vs. NOR groups (56.5% vs. 90.0%, p < 0.001), while the fertilization rates were similar (60.2% vs. 58.1%, p = 0.397). The prevalence of DUC-1 embryos was higher in the PCOS HOR and the HOR groups as compared to the NOR group (22.7% vs. 16.2% and 12.0%, respectively, p < 0.001). After exclusion of DUC-1 embryos, remaining embryos from the NOR and HOR groups reached the morphokinetic milestones at similar rates, with comparable implantation and clinical pregnancy rates, while the PCOS HOR showed shorter time to 5 blastomeres compared to the NOR and HOR groups., Conclusions: High ovarian response might be associated with decreased oocyte quality, manifested as a higher proportion of immature oocytes and higher rate of direct uneven cleavage embryos, while embryos exhibiting normal first cleavage have similar temporal milestones and implantation potential., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Methylphenidate (MPH) is the most widely prescribed therapy for attention deficit hyperactivity disorder. Animal studies have shown a potential adverse effect of MPH exposure on male fertility. We examined the impact of MPH on human male sperm parameters., Design: Sperm parameters of 9769 samples from patients 18 years of age or older, collected as part of the basic evaluation of couples referred to the Infertility Clinic were analyzed retrospectively. We divided the study population into three groups according to MPH purchasing information: MPH purchased ≤ 90 days prior to sperm analysis-current users (n = 83), MPH purchased > 90 days prior to sperm analysis-past users (n = 293), and MPH-naïve patients (n = 9393)., Methods: All sperm samples were analyzed by the same laboratory technician team for the following routine parameters: semen volume, sperm concentration, percentage of motile sperm, and percentage of normal morphology according to World Health Organization. The analysis of the samples was completed by evaluation of total sperm count, total sperm motility, and percentage of fast and slow motile cells. Sperm morphology was evaluated by a laboratory technician using methodological examination according to the strict Kruger-Tygerberg criteria., Results: Methylphenidate exposure did not affect sperm morphology but was associated with increased sperm concentration as well as increased total sperm count and total sperm motility among current and past users compared with MPH-naïve patients. In particular, progressive motility and total motile sperm count were significantly increased following MPH use. A multivariate analysis adjusting for age and current smoking was conducted, further supporting a positive correlation between current MPH use and increased values of total sperm count and total sperm motility., Limitations: Our study has several inherent weaknesses, foremost of which is its retrospective nature. Another notable weakness is that medication purchasing data may not accurately reflect MPH exposure in the study population. Patients may be purchasing MPH and not taking it as prescribed., Conclusions: In the present study, we could not demonstrate a negative impact of methylphenidate treatment on sperm parameters in adults with ADHD. Hence, we may assume that methylphenidate does not negatively affect male fertility., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Objective: To study the association among fertility treatments, treatment protocol, and offspring neoplasm risk up to the age of 18 years., Design: A population-based retrospective cohort., Setting: Soroka University Medical Center (SUMC), the single tertiary medical center and in vitro fertilization (IVF) unit in southern Israel., Patient(s): All offspring born at the SUMC between the years 1995 and 2018 after IVF treatment (the exposed group) and offspring conceived spontaneously (the unexposed group)., Intervention(s): The study was performed at the SUMC, the single tertiary medical center and IVF unit in southern Israel. The exposed and unexposed were matched with a ratio of 1:4, based on maternal age and calendar month of delivery. Data collection included a summary of the couple's medical records, delivery data, and offspring neoplasm diagnoses., Main Outcome Measure(s): Offspring neoplasm of any kind and time to diagnosis in each of the groups., Result(s): A total of 1,583 exposed and 5,874 offspring were included in the study. The incidences of offspring benign neoplasm were 14 (0.9%) versus 21 (0.4%), and the incidences of malignancies were 17 (1.1%) versus 29 (0.5%) among offspring of the IVF and spontaneous groups, respectively. The association between mode of conception and offspring neoplasm risk remained significant after adjusting for confounders, including mode of delivery and pregnancy complications such as hypertensive disorder, gestational diabetes mellitus, and preterm delivery compared with spontaneously conceived offspring. Among the IVF group, the increased risk for neoplasm was found among offspring who were transferred as fresh embryos, at an earlier stage of development (cleavage stage), or after three or more aspirated oocytes., Conclusion(s): IVF treatment is associated with offspring neoplasm risk; specifically, the risk was greater among offspring who were returned as fresh embryos, at an earlier embryotic stage (cleavage stage), or after three or more aspirated oocytes., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Mutation in S-phase cyclin A-associated protein rin the endoplasmic reticulum ( SCAPER ) have been found across ethnicities and have been shown to cause variable penetrance of an array of pathological traits, including intellectual disability, retinitis pigmentosa and ciliopathies., Methods: Human clinical phenotyping, surgical testicular sperm extraction and testicular tissue staining. Generation and analysis of short spindle 3 ( ssp3 ) ( SCAPER orthologue) Drosophila CAS9-knockout lines. In vitro microtubule (MT) binding assayed by total internal reflection fluorescence microscopy., Results: We show that patients homozygous for a SCAPER mutation lack SCAPER expression in spermatogonia (SPG) and are azoospermic due to early defects in spermatogenesis, leading to the complete absence of meiotic cells . Interestingly, Drosophil a null mutants for the ubiquitously expressed ssp3 gene are viable and female fertile but male sterile. We further show that male sterility in ssp3 null mutants is due to failure in both chromosome segregation and cytokinesis. In cells undergoing male meiosis, the MTs emanating from the centrosomes do not appear to interact properly with the chromosomes, which remain dispersed within dividing spermatocytes (SPCs). In addition, mutant SPCs are unable to assemble a normal central spindle and undergo cytokinesis. Consistent with these results, an in vitro assay demonstrated that both SCAPER and Ssp3 directly bind MTs., Conclusions: Our results show that SCAPER null mutations block the entry into meiosis of SPG, causing azoospermia. Null mutations in ssp3 specifically disrupt MT dynamics during male meiosis, leading to sterility. Moreover, both SCAPER and Ssp3 bind MTs in vitro. These results raise the intriguing possibility of a common feature between human and Drosophila meiosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: It is unclear whether sperm origin, either ejaculated or testicular, in couples diagnosed with male factor infertility, affects the timing of the embryo's developmental events evaluated by time-lapse monitoring and implantation rates., Objective: To examine the effect of sperm origin on embryo morphokinetics in couples diagnosed with male factor infertility., Materials and Methods: This study included a retrospective analysis of morphokinetic parameters performed by time-lapse monitoring between 2013 and 2017. The developmental processes and morphokinetic parameters of 419 embryos obtained from couples with male factor infertility attributed to oligo-astheno-teratozoospermia, 158 embryos derived from surgically extracted testicular spermatozoa from couples diagnosed with non-obstructive azoospermia, and 190 embryos from couples with normal ejaculated spermatozoa and female mechanical factor-related infertility, were evaluated. A comparison of morphokinetic parameters, implantation, and clinical pregnancy rates was performed between the groups with additional analysis in accordance with implantation status., Results: Embryos from the normal ejaculated spermatozoa and oligo-astheno-teratozoospermia patients reached the later morphokinetic milestones-synchronous division (S3) and time to morula (tM)-faster than embryos obtained from testicular spermatozoa. Implantation rate was similar in the normal ejaculated spermatozoa and oligo-astheno-teratozoospermia groups (41.9% vs. 45.8%, NS), with higher implantation rate in the oligo-astheno-teratozoospermia group compared to the testicular spermatozoa group (45.8% vs. 33.6%, p = 0.02). Comparison of Known Implantation Data (KID) positive (KIDp) and KID negative (KIDn) embryos in each group revealed more rapid development in KIDp embryos in the normal ejaculated spermatozoa and the oligo-astheno-teratozoospermia groups, while in the testicular spermatozoa group implanted embryos reached the late morphokinetic milestones (time to 8 cell stage-t8, ECC3, S3, and tM) significantly faster than embryos that failed to implant. In a multivariate logistic regression analysis of the male factor infertility population, (oligo-astheno-teratospermia) (OR = 2.54, p = 0.003) and t8 (OR = 0.95, p = 0.027) were predictive of successful implantation. Male factor infertility embryos that reached the t8 milestone within 48-56 h had favorable implantation rates (p < 0.001)., Discussion: The study results may highlight another pathophysiology by means of which sperm origin affects embryo developmental kinetics. Selecting embryos demonstrating a faster developmental rate at t8 and specifically the 48- to 56 h interval following time of pronuclei fading (tPNf) may improve implantation rates in cases of male factor infertility., Conclusion: This study showed that ejaculated spermatozoa is associated with faster late cell divisions, more rapid compaction, and higher implantation rates compared to testicular spermatozoa. Additionally, t8 is an important predictor for implantation in the male factor infertility population., (© 2020 American Society of Andrology and European Academy of Andrology.)

Research Question: Are obstetric and perinatal complications associated with morphokinetic parameters of embryo development?, Design: This proof-of-concept pilot study included a retrospective analysis of embryo morphokinetic parameters of 85 live births following day 5 single blastocyst transfer. Kinetic variables included time interval (hours) from time of pronuclei fading (tPNf) to: time of 2 cells (tPNf-t2), 9 cells (tPNf-t9), morula (tPNf-tM), start of blastulation (tPNf-tSB), full blastocyst (tPNf-tB) and expanded blastocyst (tPNf-tEB). Multivariable logistic models were used to calculate the risk of perinatal complications after adjustment for confounders., Results: The mean interval of tPNf-tSB was significantly longer for newborns with congenital anomalies compared with healthy newborns (79.49 ± 5.78 versus 71.7 ± 6.3, respectively, P = 0.01) and for embryos of women who had gestational diabetes mellitus compared with normoglycemic women (76.56 ± 7.55 versus 71.5 ± 6.13, respectively, P = 0.015). The mean interval of tPNf-t9 was significantly longer for low-birthweight newborns compared with normal weight (49.25 ± 5.54 versus 45.47 ± 4.77, respectively, P = 0.01). Preterm delivery was associated with several longer intervals of cell divisions compared with delivery at term (tPNf-t5: 28.76 ± 3.13 versus 26.64 ± 2.40, respectively, P = 0.01; tPNf-t6: 30.10 ± 3.05 versus 27.68 ± 2.30, respectively, P < 0.001; tPNf-t7: 32.08 ± 4.11 versus 28.70 ± 2.67, respectively, P < 0.001; tPNf-t8: 34.75 ± 4.95 versus 30.70 ± 4.10, respectively, P < 0.001; tPNf-t9: 50.23 ± 5.87 versus 45.44 ± 4.67, respectively, P < 0.001). For each of the outcomes, the association remained significant after adjusting for confounders., Conclusion: This study indicates that there may be a possible association between adverse perinatal outcomes and morphokinetic parameters. Larger studies are needed to establish this association., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)