Instituto Bernabeu

Can sperm selection through cumulus cells improve embryo quality compared to conventional methods, and is its effectiveness influenced by parental age? This prospective clinical trial included 99 ICSI cycles from 95 couples. Sibling oocytes were randomly allocated at the oocyte level to either the study group (cumulus cell-mediated sperm selection after conventional density gradients centrifugation (DGC), 554 oocytes) or the control group (only sperm selection by DGC, 543 oocytes), using a dish designed to facilitate sperm interaction with cumulus cells. The inclusion criteria for this study were patients using their own oocytes, with a medical indication for ICSI, who had at least 6 mature oocytes (MII) in that cycle. For semen samples, inclusion required the ability to adjust the concentration to 10 million/mL. Exclusion criteria included the use of vitrified oocytes, donated oocytes, and semen samples obtained by testicular biopsy or aspiration. Embryo quality was assessed at the blastocyst stage on day 5 according to ASEBIR. A subanalysis evaluated the influence of parental age on outcomes. The study group showed a significantly higher proportion of good-quality day-5 blastocysts compared to controls (55.2% vs. 45.3%, p = 0.028). No statistically significant differences were observed in overall blastocyst formation or pregnancy rates, although favourable trends were noted. In an age-stratified analysis, a significant improvement in day-5 blastocyst quality among evaluable blastocysts was observed in women aged 40-45 (51.4% vs. 30.4%, p = 0.017), with a non-significant trend toward improved outcomes in men aged 40-53 (44.7% vs. 32.6%, p = 0.083). No differences were seen in younger age groups. Cumulus cell-mediated sperm selection after DGC using a specialized Oosafe® ICSI Dish with Sperm Selection Channels was associated with an increased proportion of good-quality day 5 blastocysts compared with conventional sperm preparation. While clinical outcomes did not differ significantly, these findings suggest a potential benefit in specific ART subpopulations, particularly those of advanced maternal age. Further adequately powered studies are required to confirm these observations and to determine their impact on clinical outcomes.

BackgroundBictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single-tablet regimen recommended as first-line HIV treatment in international guidelines. This analysis aimed to assess the effectiveness and safety of B/F/TAF in real-world Spanish clinical practice.MethodsThis was an analysis of the Spanish subset from the BICSTaR study in treatment-naïve (TN) and treatment-experienced (TE) people with HIV who started treatment between November 2019 and July 2021 (European study registration: EUPAS22185). The primary endpoint was virologic suppression (HIV-1 RNA <50 copies/mL); additional endpoints included CD4 cell count changes, treatment persistence, adverse events, weight changes, and the 36-Item Short Form Survey mental and physical component summary (MCS/PCS) scores at 12 months.ResultsIn total, 249 people with HIV initiated B/F/TAF treatment (62 TN, 187 TE). At 12 months, virologic suppression was achieved by 86% of TN and 98% of TE participants, with 91% of those TE participants with baseline HIV-1 RNA ≥50 copies/µL achieving suppression. Median CD4 count increased by 296 cells/µL in TN (p<0.001) and 12 cells/µL in TE (p=0.302) participants. Persistence at 12 months was high in all participants, with 95% still on treatment. Overall, none of TN and less than 3% of TE participants discontinued B/F/TAF due to drug-related adverse events, all of which were mild or moderate. Median weight increase was 2.9 kg in TN (p<0.001) and 1.0 kg in TE (p<0.001) participants. Median MCS scores improved in the TN group (8.4-point increase, p<0.001) but not in the TE group (0.4-point increase, p=0.767), while PCS scores remained stable both among TN and TE.ConclusionThese real-world findings strongly support B/F/TAF use in TN and TE people with HIV in Spain, demonstrating high 12-month persistence and effectiveness, and mental health benefits in TN participants, with minimal adverse events.

Summary Sotos syndrome is associated with hypergrowth, macrocephaly, intellectual disability and characteristic facial features, the diagnosis of which becomes more evident during childhood. We present the case of a full-term newborn, who was admitted to the Neonatology Unit with early hypoglycaemia, hypotonia, a peculiar phenotype and joint hyperlaxity, with dislocation of both wrists. An interventricular communication with haemodynamic repercussions was detected. During his hospitalisation, he presented with feeding difficulties and cholestasis of multifactorial aetiology. Genetic testing detected a pathogenic variant in heterozygosity in the NSD1 gene (c.5990A&gt;G p.Tyr1997Cys) with an autosomal dominant de novo inheritance pattern. Therefore, in a newborn with hypotonia associated with typical facial features, together with joint hyperlaxity, jaundice, hypoglycaemia and feeding difficulties, this syndrome should be suspected and a genetic study requested. In more than 95% of cases, Sotos syndrome is caused by mutations or microdeletions in the NSD1 gene. Given the associated complications, multidisciplinary follow-up is recommended.

Abstract Study question Do granulosa cells enhance sperm selection and embryo quality in advanced maternal age patients undergoing intracytoplasmic sperm injection? Summary answer Sperm selection via granulosa cells enhances embryo quality in patients over 40 years old. What is known already Numerous studies have highlighted that spermatozoa capable of traversing the oocyte’s granulosa cells exhibit enhanced motility and capacitation. For successful in vivo fertilization, sperm must penetrate the granulosa-oocyte complex, where hyaluronic acid serves as a key component. Mature sperm show an affinity for hyaluronic acid, demonstrating superior motility and facilitating the acrosome reaction. Optimising sperm selection has been shown to improve outcomes in in vitro fertilisation treatments. However, advanced maternal age adversely affects oocyte and embryo quality, leading to reduced success rates in assisted reproductive technologies (ART). Study design, size, duration A prospective randomised multicenter study was conducted between July 2022 and December 2024, analysing data from 1,097 oocytes obtained from 99 autologous oocyte treatments. Participants were divided into two groups: granulosa cells and control. Additionally, three subgroups were established based on maternal age: 26–35, 36–39, and 40–45 years. The sample size was determined to detect a 10% difference in blastocyst formation rates between the two groups. Participants/materials, setting, methods A total of 99 autologous oocyte cycles were analyzed. Sibling oocytes were randomized into study (granulosa cells, 554 oocytes) and control groups (543 oocytes). Sperm samples (10 million/ml motile spermatozoa) were prepared using the “Supersperm” ICSI dish (Oosafe® ICSI Dish with Sperm Selection Channels, CE mark pending). Fertilized oocytes were cultured in Geri dishes with 80 µL Global Total medium until day 5 and evaluated using Gardner’s criteria. Statistical analysis was performed using R (v4.4.2). Main results and the role of chance No statistically significant differences were observed between the study and control groups in fertilisation rate (74.9% vs 78.1%, p = 0.689) or blastocyst formation rate (62.8% vs 58.3%, p = 0.178), respectively. However, the study group exhibited a significantly higher proportion of good-quality embryos compared to the control group (55.2% vs 45.3%, p = 0.028). Subgroup analysis revealed no significant differences in the 26–35 age group for fertilisation rate (79.7% vs 84.3%, p = 0.529), blastocyst formation rate (66.2% vs 68.1%, p = 0.726), or good-quality embryos (60.9% vs 54.1%, p = 0.344). Similarly, in the 36–39 age group, no significant differences were found in fertilisation (73.3% vs 77.9%, p = 0.408), blastocyst formation (61.3% vs 52.9%, p = 0.137), or good-quality embryos (52.3% vs 45.1%, p = 0.334). Conversely, the 40–45 age group showed a significantly higher rate of good-quality embryos in the granulosa cell group compared to the control group (51.4% vs 30.4%, p = 0.017). However, no statistically significant differences were observed in fertilisation (70.9% vs 70.1%, p = 0.734) or blastocyst formation (59.8% vs 50.5%, p = 0.174) for this subgroup. Our data suggest that sperm selection using granulosa cells in the “Supersperm” ICSI dish could benefit patients of advanced maternal age by obtaining better quality embryos, since these oocytes have less capacity to repair sperm damage. Limitations, reasons for caution Although the results indicate promising improvements in achieving higher rates of good-quality embryos, further research is necessary to better characterise the properties of the selected spermatozoa. Wider implications of the findings Our findings suggest that sperm selection using granulosa cells may benefit patients of advanced maternal age by improving embryo quality, as oocytes from this group have a reduced ability to repair sperm damage. This method offers a simple and reliable approach during ICSI, demonstrating superior laboratory outcomes in this population. Trial registration number No

A diet rich in polyphenols and other types of phytonutrients can reduce the occurrence of chronic diseases. However, a well-established cause—and—effect association has not been clearly demonstrated and several other issues will need to be fully understood before general recommendations will be carried out In the present review, some of the future challenges that the research on phenolic compounds will have to face in the next years are discussed: toxicological aspects of polyphenols and safety risk assessment; synergistic effects between different polyphenols; metabotype-based nutritional advice based on a differential gut microbial metabolism of polyphenols (precision nutrition); combination of polyphenols with other bioactive compounds; innovative formulations to improve the bioavailability of phenolic compounds; and polyphenols in sports nutrition and recovery.Other aspects related to polyphenol research that will have a boost in the next years are: polyphenol and gut microbiota crosstalk, including prebiotic effects and biotransformation of phenolic compounds into bioactive metabolites by gut microorganisms; molecular docking, molecular dynamics simulation, and quantum and molecular mechanics studies on the protein–polyphenol complexes; and polyphenol-based coating films, nanoparticles, and hydrogels to facilitate the delivery of drugs, nucleic acids and proteins.In summary, this article provides some constructive inspirations for advancing in the research of the applications, risk assessment and metabolic effects of dietary polyphenols in humans.

Abstract Study question Is it possible to score the mosaic embryos in order to prioritise them according to their pregnancy potencial? Summary answer The machine-learning score underscores the crucial role of embryo quality over mosaicism, prioritizing high-quality, day-5 biopsied embryos for enhanced live birth outcomes in ART. What is known already After embryo biopsy and PGT-A analysis, embryos can be classified as euploid, aneuploid, or mosaic, wherein a combination of chromosomally normal and altered cells is detected. The transfer of mosaic embryos has been controversial, but currently, the recommendations of international scientific societies, including ESHRE, advocate for their transfer. In case of pregnancy, a prenatal test is advised to rule out any chromosomal aberration. The non-transfer of these embryos reduces ART success chances, as chromosomally normal children may be born from them. Study design, size, duration The study design is observational and retrospective. A total of 8346 embryos from 2583 PGT-A cycles were considered (January-2017 to January-2023). Only transferred mosaic embryos (n = 263) were included in the study. The trophectoderm biopsies of D5, D6, or D7 blastocysts were analyzed by NGS using the Illumina platform (VeriSeq Illumina®, San Diego, CA, USA). The biopsied embryos were vitrified and transferred in a subsequent cycle. Participants/materials, setting, methods The primary indications for PGT-A included advanced maternal age, abnormal sperm FISH, and recurrent miscarriage or implantation failure. Clinical outcomes, along with variables related to progenitors, embryos, biopsy, ovarian stimulation, and adjuvant treatments, were recorded in a database. Machine learning models were conducted using R statistical software (v.4.3.1), and the ‘Caret’ library was utilized to implement different algorithms. ‘Autoscore,’ as an interpretable scoring tool, combined machine learning and regression modeling. Main results and the role of chance The mean maternal and paternal ages were 34.95±6.38 and 39.13±6.74 years. Biopsies were predominantly performed on day 5 (61%). Additionally, 44% of embryos were of A quality, and 49% were of B quality. Regarding clinical outcomes for mosaic embryos, biochemical, clinical pregnancy, and live birth rates were 51%, 41%, and 36%, respectively. The features used to generate the score included those related to embryo quality, biopsy, and mosaicism. Through 10-fold cross-validation, the study identified top-ranking predictors maximizing the AUC of the predictive model. The highest weight in the score was assigned to embryo quality (42%) and day of biopsy (34%), with lower weights for factors related to mosaicism: monosomy and/or trisomy (18%) and mosaicism level (6%). The machine-learning score indicates that, in transferring embryos with mosaicism, priority should be given to high-quality embryos biopsied on day 5. The type and level of mosaicism have a minor impact on the embryo’s gestational capacity, becoming relevant only when prioritizing embryos of identical quality. In such cases, embryos with lower mosaicism degrees and no monosomy demonstrate higher implantation potential. Limitations, reasons for caution The inherent limitations of a retrospective analysis highlight the need for prospective randomized studies to confirm the validity and usefulness of the mosaic embryo transfer score. Wider implications of the findings A scoring system has been developed to prioritize the transfer of mosaic embryos. The crucial variables are associated with embryo quality and the day of biopsy, reflecting the progression of embryonic development. Conversely, variables related to mosaicism play a secondary role. Trial registration number Not applicable

Women undergoing IVF who have had a previous c-section (CS) have a lower live birth rate than those with a previous vaginal delivery. However, the precise underlying mechanisms need clarification. Does a previous CS affect the pattern of uterine contractility?. Prospective evaluation in patients undergoing frozen blastocyst embryo transfer in medicated endometrial preparation cycles. Twenty patients were included in groups: A/nulliparous. B/previous vaginal delivery. C/ previous CS without a niche, whereas fifteen patients were recruited in group D (CS and a niche). Patients employed estradiol compounds and 800 mg vaginal progesterone. A 3D-scan was performed the transfer-day where uterine contractility/minute was recorded. Baseline characteristics (age, BMI, smoking, endometrial thickness) were similar. Mean frequency of uterine contractions/minute was similar between groups (1.15, 1.01, 0.92, and 1.21 for groups A, B, C, and D, respectively). There was a slight increase in the number of contractions in patients with a sonographic niche versus controls, not reaching statistical significance (p=0.48). No differences were observed when comparing patients with a previous C-section (regardless of the presence of a niche) to those without a C-section, either nulliparous (p=0.78) or with a previous vaginal delivery (p=0.80). The frequency of uterine contractions was similar between patients who achieved a clinical pregnancy and those who did not (1.19 vs. 1.02 UC/min, p=0.219, respectively). Our study found no significant difference in the frequency of uterine contractility between patients with or without a previous C-section or sonographic diagnosed niche. Further investigation is necessary to understand the physiological mechanisms affecting implantation in patients with isthmocele.

The present study compares two protocols for ovarian controlled stimulation in terms of number of cumulus-oocyte complexes and metaphase II oocytes. We employed a single injection of 150mcg of corifollitropin alfa after a 7-day oral contraceptive pill-free interval for TAIL group and a conventional administration of corifollitropin alfa after a 5-day OCP-free interval with additional rFSH from 8th of ovarian controlled stimulation. Prospective, randomized, comparative, non-inferiority, opened and controlled trial carried out in 180 oocyte donors 31 were excluded, 81 were randomized to the control group and 68 to the TAIL group. No differences were found in the number of follicles larger than 14 and 17 mm at triggering day. However, a lower number of cumulus-oocyte complexes and metaphase II oocytes were obtained in TAIL group compared to the control group, expressed as median (interquartile range): 10.5 (5.5–19) vs. 14 [11–21] and 9 (4–13) vs. 12 (9–17) respectively. Additionally, the incidence of failed retrieval or metaphase II oocytes = 0 was higher in TAIL group 7(10.3%) vs. 1(1.2%) p = 0.024. The use of a single injection of corifollitropin alfa after a 7-day oral contraceptive pill-free interval in oocyte donors resulted in a lower number of cumulus-oocyte complexes and metaphase II oocytes. No additional rFSH was administered in this group.Clinical Trial Registration:https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-001343-44/results.

BackgroundDouble ovarian stimulation is one of the most used strategies in poor-prognosis patients. There is a high heterogeneity between the studies regarding the execution of this stimulation protocol. The aim of this study was to investigate whether the day on which luteal phase stimulation begins after the first oocyte retrieval affects ovarian response in DuoStim cycles.MethodsThis observational and retrospective study included 541 DuoStim cycles between January 2018 and December 2021 in a private fertility clinic. Patients were assigned to 4 groups according to the timing of the onset of luteal phase stimulation after oocyte retrieval (0-2nd day, 3rd day, 4th day and 5th-6th day). The primary outcome was the number of oocytes retrieved in the luteal phase in each group.ResultsNo differences were found between groups in the number of oocytes collected (5.12 ± 3.56 vs. 5.39 ± 3.74 vs. 5.61 ± 3.94 vs. 5.89 ± 3.92; p=0,6), MII or number of follicles. An increase in the duration of stimulation was found when stimulation started on the 4th day (10.42 ± 2.31 vs. 10.68 ± 2.37 vs. 11.27 ± 2.40 vs. 10.65 ± 2.37 days, p=0,033). A lower number of fertilized oocytes was observed when stimulation began before the fourth day (3.36 ± 2.80 vs. 3.95 ± 2.53 vs. 4.03 ± 2.73 vs. 4.48 ± 3.11; p=0,036). The number of blastocysts was higher when the stimulation started 5-6 days after retrieval (1.82 ± 1.74 vs. 2.13 ± 1.61 vs. 2.33 ± 2.06 vs. 2.91 ± 2.39; p= 0,030).DiscussionThe number of oocytes retrieved does not differ depending on the day that stimulation begins. However, oocytes competence in terms of fertilized oocytes and blastulation, appears to be lower when the second stimulation starts before the fourth day after oocyte retrieval.