Information Visualization and Innovative Research

STUDY QUESTION:Which mechanisms of action and candidate drugs can be used to treat endometrial failure caused by molecular alterations rather than endometrial timing?SUMMARY ANSWER:Genistein, pioglitazone, alprostadil, flunisolide, and tenoxicam emerged as potential therapies to treat two molecular causes of endometrial failure not originating in endometrial timing.WHAT IS KNOWN ALREADY:Several studies have described molecular profiles of endometrial failure unrelated to endometrial timing and proposed diagnostic tools based on clinical and transcriptomic data, but effective therapeutic options remain lacking. Hence, there is a pressing need for tailored treatments to enable personalised medicine in endometrial-factor infertility.STUDY DESIGN, SIZE, DURATION:This multicentre prospective study, conducted at 5 fertility clinics in Spain between January 2019 and August 2022, included 192 patients undergoing in vitro fertilisation with hormone replacement therapy, whose endometrial biopsies were collected during the mid-secretory phase.PARTICIPANTS/MATERIALS, SETTING, METHODS:Of 291 endometrial biopsies, 192 met the quality criteria and 161 were classified according to clinical and transcriptomic data using a semi-supervised learning model for prognosis. Before classification, transcriptomic variation related to endometrial timing was corrected using our validated transcriptomic endometrial-dating model. Profiles were analysed using systems pharmacology approaches combining network analysis and reversal signature matching to identify therapeutic drugs capable of reversing molecular disruption. Candidate drugs were grouped by mechanism of action and prioritised by side-effect profile. Selected drugs were validated in endometrial cells through RT-PCR, F-actin staining, and enzyme-linked immunosorbent assays.MAIN RESULTS AND THE ROLE OF CHANCE:Four transcriptomic profiles were identified using artificial intelligence models, each with distinct clinical implications. Two profiles were associated with poor prognosis: clinical miscarriage-associated (CMA, n = 27) and biochemical miscarriage-associated (BMA, n = 16). CMA was characterised by upregulation of differentiation-related genes and BMA by upregulation of immune-related genes. The 4 profiles were homogeneous in demographic and embryological parameters (age, BMI, and embryo quality), reinforcing their biological relevance. Approved drugs capable of reversing these disrupted expression patterns were identified. Both BMA and CMA were linked to abnormal decidualisation, while BMA also showed immune dysregulation. Genistein and pioglitazone promoted decidualisation in vitro, whereas alprostadil, flunisolide, and tenoxicam inhibited immune responses in endometrial cell cultures, supporting their potential therapeutic role in endometrial failure not originating in endometrial timing.LIMITATIONS, REASONS FOR CAUTION:Although our artificial intelligence-based stratification model revealed clinical and functional differences among profiles, it was designed for drug repurposing rather than predictive diagnosis. A larger, specifically designed study would be required to validate predictive performance and generalisability. Further clinical trials are needed to evaluate the proposed drugs as personalised treatments for this condition.WIDER IMPLICATIONS OF THE FINDINGS:This is the first application of a systems-based drug repurposing strategy in IVF to develop tailored therapeutic interventions. We propose genistein, pioglitazone, alprostadil, flunisolide, and tenoxicam as approved, safe drugs identified through an evidence-based approach that could prevent loss of good-quality embryos and miscarriage due to maternal endometrial factors. These findings, supported by functional in vitro validation, pave the way for future clinical trials advancing personalised medicine in endometrial-factor infertility.TRIAL REGISTRATION NUMBER:Not applicable

Background: Embryo selection in in vitro fertilization (IVF) aims to prioritize embryos with the highest reproductive potential. While preimplantation genetic testing for aneuploidy (PGT-A) remains the gold standard for identifying euploid embryos, it is invasive and not universally applicable. Deep learning (DL)-based models, such as the intelligent data analysis (iDA) score, have emerged as non-invasive alternatives for embryo assessment. This review critically evaluates the relationship between iDAScore (versions 1.0 and 2.0), embryo euploidy, and clinical outcomes, including live birth and miscarriage rates. Methods: A narrative review was performed using PubMed and Google Scholar, covering studies published from January 2020 to May 2025. The search included terms such as “iDAScore,” “deep learning,” “euploidy,” and “live birth.” Only English-language full-text studies assessing the predictive performance of iDAScore relative to chromosomal status or reproductive outcomes were included. Results: Six retrospective studies met the inclusion criteria. All reported a statistically significant association between higher iDAScore values and embryo euploidy. AUC values for euploidy prediction ranged from 0.60 to 0.68. In several studies, iDAScore was also positively associated with live birth rates and negatively with miscarriage rates. However, the predictive accuracy was moderate when restricted to euploid embryo cohorts, indicating that iDAScore may be more effective in broader populations where chromosomal status is unknown. Conclusions: iDAScore represents a promising adjunct to traditional embryo assessment. Although it cannot replace PGT-A, it may aid in embryo prioritization when genetic testing is not feasible. Larger prospective studies are warranted to further validate its clinical utility.

The time at which embryo developmental velocity variations occur remains unknown. Therefore, we analysed the morphokinetic trajectory of human early fertilisation from the extrusion of the second polar body (PB2) to pronuclear breakdown (PNBD) and retrospectively compared its alterations during the fertilisation of day 4-7 blastocysts. Patients (n = 905) who underwent oocyte retrieval and blastocyst expansion between October 2019 and December 2020 were included. This study involved time-lapse technology monitoring of day 4 (n = 29), 5 (n = 1181), 6 (n = 244), and 7 (n = 12) blastocysts generated over 1009 intracytoplasmic sperm injection cycles. Morphokinetics during fertilisation were compared among the day 4-7 blastocyst groups. The timing of fertilisation events in the cytoplasm and pronuclei (PN) differed among the day 4-7 blastocyst groups from the outset. PB2 extrusion occurred significantly earlier in day 4 blastocysts than in day 5 blastocysts. The duration of the cytoplasmic halo was shortened in day 4 blastocysts and prolonged in day 6 blastocysts compared with that in day 5 blastocysts. Paternal PN appeared earlier in day 4 blastocysts than in day 5 blastocysts, whereas their appearance was delayed in day 6 blastocysts. In paternal and maternal PN, the time interval from PN appearance to PNBD was shortened in day 4 blastocysts but was prolonged in day 6 and 7 blastocysts. Embryos that reached the blastocyst stage between days 4 and 7 displayed different morphokinetic speeds throughout fertilisation and as early as PB2 extrusion. Aberrant cytoplasmic granules, organelles, and PN rearrangement may contribute to these differences.

Triploid and haploid conceptions are not viable and are a common occurrence in humans, where they account for 10% of all pregnancy losses. Despite the parent-of-origin being important in the etiology of the pregnancy, our knowledge of their causes is limited, especially at the point of conception. Using a dataset of 96,660 biopsies and a validation dataset of 44,324 from human blastocysts embryos gener-ated by intracytoplasmic sperm injection (ICSI), we estimate that 1.1% of human conceptions (n=1,063) contain extra or missing chromosome sets in zygotes. We identify a maternal age effect, with a 1.059 per year increased risk in triploi-dy/haploidy (p=0.0008). In 0.03% of couples, we identified three or more trip-loid/haploid embryos, suggesting a personal risk effect (p=0.03). Genotype analysis of 55 triploid embryo biopsies and their parents show that one third of maternal triploid conceptions originate in meiosis I and two thirds in meiosis II. Seven of these embryos are inferred to have entirely failed to initiate meiotic recombination genome-wide, suggesting that human oocytes with pervasive meiotic recombina-tion failure that are formed during fetal development are capable of ovulation in adult life. Finally, we identify a new type of genome-wide maternal isodiploidy (two maternal chromosome sets) in 0.05% of embryos (41 of 74,009). Collectively, our findings shed light on the biology of meiosis and the formation of human oo-cytes with the number of chromosome sets.

Caseinolytic peptidase P (CLPP) plays a central role in mitochondrial unfolded protein response (mtUPR) by promoting the breakdown of misfolded proteins and setting in motion a cascade of reactions to re-establish protein homeostasis. Global germline deletion of Clpp in mice results in female infertility and accelerated follicular depletion. Telomeres, on the other hand, are tandem repeats of 5’-TTAGGG-3’ sequences found at the ends of the chromosomes. Telomeres are essential for maintaining chromosome stability during somatic cell division and their shortening is associated with cellular senescence and aging. In this study, we asked whether the infertility and ovarian aging phenotype caused by global germline deletion of Clpp is associated with somatic aging, and tested telomere length in tissues of young and aging mice. We found that impaired mtUPR caused by the lack of CLPP is associated with accelerated telomere shortening in both oocytes and somatic cells of aging mice. In addition, expression of several genes that maintain telomere integrity were decreased, and double strand DNA breaks were increased in telomeric regions. Our results highlight how impaired mtUPR can affect telomere integrity and demonstrate a link between loss of mitochondrial protein hemostasis, infertility, and somatic aging.

With the incessant growth of the ‘data-driven economy’ have come calls for the introduction of a novel property right in data, particularly in response to the demands of the automotive industry regarding machine-generated data. As it is still unclear who owns these data, the European Commission has advanced the idea of creating at EU level a ‘data producer’s right’ to establish data ownership rules. Although the scope of this novel data right and its subject matter are still quite obscure, this new right would most likely bring the protection of industrial data in the EU to a much higher level than the existing – and already controversial – database right. This chapter wonders whether there is an actual need for creating a property right in industrial data. It therefore enquires into existing intellectual property regimes, asks to what extent these may cover data, and, conversely, speculates how a property right in data might affect these regimes. In addition, the introduction of ownership in data is critically examined as to its likely impact on fundamental rights, in particular on freedom of information and communication. The chapter then concludes against introducing a right of property in data.

Technik-Gesellschaft/Wem-gehoeren-Daten-im-Auto.The German industry coalition BDI (Bundesverband der deutschen Industrie) does not however support the idea of a

I also appreciate the time dedicated by all respondents who took their time to tell a little of their histories.