Pile-Up Mitigation using Attention

Particle production from secondary proton-proton collisions, commonly referred to as pile-up, impair the sensitivity of both new physics searches and precision measurements at LHC experiments. We propose a novel algorithm, PUMA, for identifying pile-up objects with the help of deep neural networks based on sparse transformers. These attention mechanisms were developed for natural language processing but have become popular in other applications. In a realistic detector simulation, our method outperforms classical benchmark algorithms for pile-up mitigation in key observables. It provides a perspective for mitigating the effects of pile-up in the high luminosity era of the LHC, where up to 200 proton-proton collisions are expected to occur simultaneously

Effect of embryo vitrification on the steroid biosynthesis of liver tissue in rabbit offspring

[EN] Preimplantation embryo manipulations during standard assisted reproductive technologies (ART) have significant repercussions on offspring. However, few studies to date have investigated the potential long-term outcomes associated with the vitrification procedure. Here, we performed an experiment to unravel the particular effects related to stress induced by embryo transfer and vitrification techniques on offspring phenotype from the foetal period through to prepuberal age, using a rabbit model. In addition, the focus was extended to the liver function at prepuberal age. We showed that, compared to naturally conceived animals (NC), offspring derived after embryo exposure to the transfer procedure (FT) or cryopreservation-transfer procedure (VT) exhibited variation in growth and body weight from foetal life to prepuberal age. Strikingly, we found a nonlinear relationship between FT and VT stressors, most of which were already present in the FT animals. Furthermore, we displayed evidence of variation in liver function at prepuberal age, most of which occurred in both FT and VT animals. The present major novel finding includes a significant alteration of the steroid biosynthesis profile. In summary, here we provide that embryonic manipulation during the vitrification process is linked with embryo phenotypic adaptation detected from foetal life to prepuberal age and suggests that this phenotypic variation may be associated, to a great extent, with the effect of embryo transfer.This research was funded by Conselleria d'Educacio, Investigacio, Cultura i Esport, Spain, grant number AICO/2019/272. Ximo Garcia-Dominguez was supported by a research grant from the Ministry of Economy, Industry and Competitiveness of Spain (BES-2015-072429).Marco-Jiménez, F.; Garcia-Dominguez, X.; Domínguez-Martínez, M.; Viudes-De-Castro, MP.; Diretto, G.; Peñaranda, D.; Vicente Antón, JS. (2020). Effect of embryo vitrification on the steroid biosynthesis of liver tissue in rabbit offspring. International Journal of Molecular Sciences. 21(22):1-17. https://doi.org/10.3390/ijms21228642S1172122Novakovic, B., Lewis, S., Halliday, J., Kennedy, J., Burgner, D. P., Czajko, A., … Saffery, R. (2019). Assisted reproductive technologies are associated with limited epigenetic variation at birth that largely resolves by adulthood. Nature Communications, 10(1). doi:10.1038/s41467-019-11929-9Roseboom, T. J. (2018). Developmental plasticity and its relevance to assisted human reproduction. Human Reproduction, 33(4), 546-552. doi:10.1093/humrep/dey034Fleming, T. P., Watkins, A. J., Velazquez, M. A., Mathers, J. C., Prentice, A. M., Stephenson, J., … Godfrey, K. M. (2018). Origins of lifetime health around the time of conception: causes and consequences. The Lancet, 391(10132), 1842-1852. doi:10.1016/s0140-6736(18)30312-xDulioust, E., Toyama, K., Busnel, M. C., Moutier, R., Carlier, M., Marchaland, C., … Auroux, M. (1995). Long-term effects of embryo freezing in mice. Proceedings of the National Academy of Sciences, 92(2), 589-593. doi:10.1073/pnas.92.2.589Auroux, M., Cerutti, I., Ducot, B., & Loeuillet, A. (2004). Is embryo-cryopreservation really neutral? Reproductive Toxicology, 18(6), 813-818. doi:10.1016/j.reprotox.2004.04.010Vicente, J. S., Saenz-de-Juano, M. D., Jiménez-Trigos, E., Viudes-de-Castro, M. P., Peñaranda, D. S., & Marco-Jiménez, F. (2013). Rabbit morula vitrification reduces early foetal growth and increases losses throughout gestation. Cryobiology, 67(3), 321-326. doi:10.1016/j.cryobiol.2013.09.165Saenz-de-Juano, M. D., Marco-Jimenez, F., Schmaltz-Panneau, B., Jimenez-Trigos, E., Viudes-de-Castro, M. P., Peñaranda, D. S., … Vicente, J. S. (2014). Vitrification alters rabbit foetal placenta at transcriptomic and proteomic level. REPRODUCTION, 147(6), 789-801. doi:10.1530/rep-14-0019Saenz-de-Juano, M. D., Vicente, J. S., Hollung, K., & Marco-Jiménez, F. (2015). Effect of Embryo Vitrification on Rabbit Foetal Placenta Proteome during Pregnancy. PLOS ONE, 10(4), e0125157. doi:10.1371/journal.pone.0125157Berntsen, S., & Pinborg, A. (2018). Large for gestational age and macrosomia in singletons born after frozen/thawed embryo transfer (FET) in assisted reproductive technology (ART). Birth Defects Research, 110(8), 630-643. doi:10.1002/bdr2.1219Maheshwari, A., Pandey, S., Amalraj Raja, E., Shetty, A., Hamilton, M., & Bhattacharya, S. (2017). Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer? Human Reproduction Update, 24(1), 35-58. doi:10.1093/humupd/dmx031Garcia-Dominguez, X., Vicente, J. S., & Marco-Jiménez, F. (2020). Developmental Plasticity in Response to Embryo Cryopreservation: The Importance of the Vitrification Device in Rabbits. Animals, 10(5), 804. doi:10.3390/ani10050804Kohda, T. (2013). Effects of embryonic manipulation and epigenetics. Journal of Human Genetics, 58(7), 416-420. doi:10.1038/jhg.2013.61Canovas, S., Ross, P. J., Kelsey, G., & Coy, P. (2017). DNA Methylation in Embryo Development: Epigenetic Impact of ART (Assisted Reproductive Technologies). BioEssays, 39(11), 1700106. doi:10.1002/bies.201700106Canovas, S., Ivanova, E., Romar, R., García-Martínez, S., Soriano-Úbeda, C., García-Vázquez, F. A., … Coy, P. (2017). DNA methylation and gene expression changes derived from assisted reproductive technologies can be decreased by reproductive fluids. eLife, 6. doi:10.7554/elife.23670Ivanova, E., Canovas, S., Garcia-Martínez, S., Romar, R., Lopes, J. S., Rizos, D., … Coy, P. (2020). DNA methylation changes during preimplantation development reveal inter-species differences and reprogramming events at imprinted genes. Clinical Epigenetics, 12(1). doi:10.1186/s13148-020-00857-xGarcía-Martínez, S., Sánchez Hurtado, M. A., Gutiérrez, H., Sánchez Margallo, F. M., Romar, R., Latorre, R., … López Albors, O. (2018). Mimicking physiological O2 tension in the female reproductive tract improves assisted reproduction outcomes in pig. MHR: Basic science of reproductive medicine, 24(5), 260-270. doi:10.1093/molehr/gay008Ng, K. Y. B., Mingels, R., Morgan, H., Macklon, N., & Cheong, Y. (2017). In vivo oxygen, temperature and pH dynamics in the female reproductive tract and their importance in human conception: a systematic review. Human Reproduction Update, 24(1), 15-34. doi:10.1093/humupd/dmx028Marchesi, D., Qiao, J., & Feng, H. (2012). Embryo Manipulation and Imprinting. Seminars in Reproductive Medicine, 30(04), 323-334. doi:10.1055/s-0032-1320013Ramos‐Ibeas, P., Heras, S., Gómez‐Redondo, I., Planells, B., Fernández‐González, R., Pericuesta, E., … Gutiérrez‐Adán, A. (2019). Embryo responses to stress induced by assisted reproductive technologies. Molecular Reproduction and Development, 86(10), 1292-1306. doi:10.1002/mrd.23119Vrooman, L. A., & Bartolomei, M. S. (2017). Can assisted reproductive technologies cause adult-onset disease? Evidence from human and mouse. Reproductive Toxicology, 68, 72-84. doi:10.1016/j.reprotox.2016.07.015Chen, M., & Heilbronn, L. K. (2017). The health outcomes of human offspring conceived by assisted reproductive technologies (ART). Journal of Developmental Origins of Health and Disease, 8(4), 388-402. doi:10.1017/s2040174417000228Duranthon, V., & Chavatte-Palmer, P. (2018). Long term effects of ART: What do animals tell us? Molecular Reproduction and Development, 85(4), 348-368. doi:10.1002/mrd.22970Leibo, S. P., & Sztein, J. M. (2019). Cryopreservation of mammalian embryos: Derivation of a method. Cryobiology, 86, 1-9. doi:10.1016/j.cryobiol.2019.01.007Sparks, A. (2015). Human Embryo Cryopreservation—Methods, Timing, and other Considerations for Optimizing an Embryo Cryopreservation Program. Seminars in Reproductive Medicine, 33(02), 128-144. doi:10.1055/s-0035-1546826De Geyter, C., Calhaz-Jorge, C., Kupka, M. S., Wyns, C., Mocanu, E., Motrenko, T., … Goossens, V. (2020). ART in Europe, 2015: results generated from European registries by ESHRE†. Human Reproduction Open, 2020(1). doi:10.1093/hropen/hoz038Saenz-de-Juano, M., Marco-Jimenez, F., Viudes-de-Castro, M., Lavara, R., & Vicente, J. (2014). Direct Comparison of the Effects of Slow Freezing and Vitrification on Late Blastocyst Gene Expression, Development, Implantation and Offspring of Rabbit Morulae. Reproduction in Domestic Animals, 49(3), 505-511. doi:10.1111/rda.12320Garcia-Dominguez, X., Marco-Jiménez, F., Peñaranda, D. S., & Vicente, J. S. (2020). Long-Term Phenotypic and Proteomic Changes Following Vitrified Embryo Transfer in the Rabbit Model. Animals, 10(6), 1043. doi:10.3390/ani10061043Lavara, R., Baselga, M., Marco-Jiménez, F., & Vicente, J. S. (2015). Embryo vitrification in rabbits: Consequences for progeny growth. Theriogenology, 84(5), 674-680. doi:10.1016/j.theriogenology.2015.04.025Lavara, R., Baselga, M., Marco-Jiménez, F., & Vicente, J. S. (2014). Long-term and transgenerational effects of cryopreservation on rabbit embryos. Theriogenology, 81(7), 988-992. doi:10.1016/j.theriogenology.2014.01.030Garcia-Dominguez, X., Marco-Jiménez, F., Peñaranda, D. S., Diretto, G., García-Carpintero, V., Cañizares, J., & Vicente, J. S. (2020). Long-term and transgenerational phenotypic, transcriptional and metabolic effects in rabbit males born following vitrified embryo transfer. Scientific Reports, 10(1). doi:10.1038/s41598-020-68195-9Feuer, S., & Rinaudo, P. (2016). From Embryos to Adults: A DOHaD Perspective on In Vitro Fertilization and Other Assisted Reproductive Technologies. Healthcare, 4(3), 51. doi:10.3390/healthcare4030051Zandstra, H., Brentjens, L. B. P. M., Spauwen, B., Touwslager, R. N. H., Bons, J. A. P., Mulder, A. L., … Van Montfoort, A. P. A. (2018). Association of culture medium with growth, weight and cardiovascular development of IVF children at the age of 9 years. Human Reproduction, 33(9), 1645-1656. doi:10.1093/humrep/dey246Chen, L., Yang, T., Zheng, Z., Yu, H., Wang, H., & Qin, J. (2018). Birth prevalence of congenital malformations in singleton pregnancies resulting from in vitro fertilization/intracytoplasmic sperm injection worldwide: a systematic review and meta-analysis. Archives of Gynecology and Obstetrics, 297(5), 1115-1130. doi:10.1007/s00404-018-4712-xZhang, W. Y., Selamet Tierney, E. S., Chen, A. C., Ling, A. Y., Fleischmann, R. R., & Baker, V. L. (2019). Vascular Health of Children Conceived via In Vitro Fertilization. The Journal of Pediatrics, 214, 47-53. doi:10.1016/j.jpeds.2019.07.033Guo, X.-Y., Liu, X.-M., Jin, L., Wang, T.-T., Ullah, K., Sheng, J.-Z., & Huang, H.-F. (2017). Cardiovascular and metabolic profiles of offspring conceived by assisted reproductive technologies: a systematic review and meta-analysis. Fertility and Sterility, 107(3), 622-631.e5. doi:10.1016/j.fertnstert.2016.12.007Feuer, S. K., Liu, X., Donjacour, A., Simbulan, R., Maltepe, E., & Rinaudo, P. (2017). Transcriptional signatures throughout development: the effects of mouse embryo manipulation in vitro. Reproduction, 153(1), 107-122. doi:10.1530/rep-16-0473Feuer, S. K., & Rinaudo, P. F. (2017). Physiological, metabolic and transcriptional postnatal phenotypes ofin vitrofertilization (IVF) in the mouse. Journal of Developmental Origins of Health and Disease, 8(4), 403-410. doi:10.1017/s204017441700023xEcker, D. J., Stein, P., Xu, Z., Williams, C. J., Kopf, G. S., Bilker, W. B., … Schultz, R. M. (2004). Long-term effects of culture of preimplantation mouse embryos on behavior. Proceedings of the National Academy of Sciences, 101(6), 1595-1600. doi:10.1073/pnas.0306846101Fauque, P., Mondon, F., Letourneur, F., Ripoche, M.-A., Journot, L., Barbaux, S., … Vaiman, D. (2010). In Vitro Fertilization and Embryo Culture Strongly Impact the Placental Transcriptome in the Mouse Model. PLoS ONE, 5(2), e9218. doi:10.1371/journal.pone.0009218Fernandez-Gonzalez, R., Ramirez, M. A., Pericuesta, E., Calle, A., & Gutierrez-Adan, A. (2010). Histone Modifications at the Blastocyst Axin1Fu Locus Mark the Heritability of In Vitro Culture-Induced Epigenetic Alterations in Mice1. Biology of Reproduction, 83(5), 720-727. doi:10.1095/biolreprod.110.084715Fernandez-Gonzalez, R., Moreira, P., Bilbao, A., Jimenez, A., Perez-Crespo, M., Ramirez, M. A., … Gutierrez-Adan, A. (2004). Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression of imprinting genes, development, and behavior. Proceedings of the National Academy of Sciences, 101(16), 5880-5885. doi:10.1073/pnas.0308560101Winick, M., & Noble, A. (1965). Quantitative changes in DNA, RNA, and protein during prenatal and postnatal growth in the rat. Developmental Biology, 12(3), 451-466. doi:10.1016/0012-1606(65)90009-6Saenz-de-Juano, M. D., Marco-Jiménez, F., & Vicente, J. S. (2016). Embryo transfer manipulation cause gene expression variation in blastocysts that disrupt implantation and offspring rates at birth in rabbit. European Journal of Obstetrics & Gynecology and Reproductive Biology, 207, 50-55. doi:10.1016/j.ejogrb.2016.10.049Delle Piane, L., Lin, W., Liu, X., Donjacour, A., Minasi, P., Revelli, A., … Rinaudo, P. F. (2010). Effect of the method of conception and embryo transfer procedure on mid-gestation placenta and fetal development in an IVF mouse model. Human Reproduction, 25(8), 2039-2046. doi:10.1093/humrep/deq165Wale, P. L., & Gardner, D. K. (2015). The effects of chemical and physical factors on mammalian embryo culture and their importance for the practice of assisted human reproduction. Human Reproduction Update, 22(1), 2-22. doi:10.1093/humupd/dmv034Charni-Natan, M., Aloni-Grinstein, R., Osher, E., & Rotter, V. (2019). Liver and Steroid Hormones—Can a Touch of p53 Make a Difference? Frontiers in Endocrinology, 10. doi:10.3389/fendo.2019.00374Yakar, S., Liu, J.-L., Stannard, B., Butler, A., Accili, D., Sauer, B., & LeRoith, D. (1999). Normal growth and development in the absence of hepatic insulin-like growth factor I. Proceedings of the National Academy of Sciences, 96(13), 7324-7329. doi:10.1073/pnas.96.13.7324Juul, A. (2003). Serum levels of insulin-like growth factor I and its binding proteins in health and disease. Growth Hormone & IGF Research, 13(4), 113-170. doi:10.1016/s1096-6374(03)00038-8Miles, H. L., Hofman, P. L., Peek, J., Harris, M., Wilson, D., Robinson, E. M., … Cutfield, W. S. (2007). In Vitro Fertilization Improves Childhood Growth and Metabolism. The Journal of Clinical Endocrinology & Metabolism, 92(9), 3441-3445. doi:10.1210/jc.2006-2465Belva, F., Bonduelle, M., Provyn, S., Painter, R. C., Tournaye, H., Roelants, M., & De Schepper, J. (2018). Metabolic Syndrome and Its Components in Young Adults Conceived by ICSI. International Journal of Endocrinology, 2018, 1-8. doi:10.1155/2018/8170518Fournier, N., Atger, V., Paul, J.-L., Sturm, M., Duverger, N., Rothblat, G. H., & Moatti, N. (2000). Human ApoA-IV Overexpression in Transgenic Mice Induces cAMP-Stimulated Cholesterol Efflux From J774 Macrophages to Whole Serum. Arteriosclerosis, Thrombosis, and Vascular Biology, 20(5), 1283-1292. doi:10.1161/01.atv.20.5.1283Liang, Y., Jiang, X.-C., Liu, R., Liang, G., Beyer, T. P., Gao, H., … Cao, G. (2004). Liver X Receptors (LXRs) Regulate Apolipoprotein AIV-Implications of the Antiatherosclerotic Effect of LXR Agonists. Molecular Endocrinology, 18(8), 2000-2010. doi:10.1210/me.2003-0477Lin, Q., Cao, Y., & Gao, J. (2015). Decreased expression of the APOA1–APOC3–APOA4 gene cluster is associated with risk of Alzheimer’s disease. Drug Design, Development and Therapy, 5421. doi:10.2147/dddt.s89279Qin, W., Li, X., Xie, L., Li, S., Liu, J., Jia, L., … Chen, Z. (2016). A long non-coding RNA,APOA4-AS, regulatesAPOA4expression depending on HuR in mice. Nucleic Acids Research, 44(13), 6423-6433. doi:10.1093/nar/gkw341Leese, H. J., Guerif, F., Allgar, V., Brison, D. R., Lundin, K., & Sturmey, R. G. (2016). Biological optimization, the Goldilocks principle, and how much islagomin the preimplantation embryo. Molecular Reproduction and Development, 83(9), 748-754. doi:10.1002/mrd.22684Kohda, T., & Ishino, F. (2013). Embryo manipulation via assisted reproductive technology and epigenetic asymmetry in mammalian early development. Philosophical Transactions of the Royal Society B: Biological Sciences, 368(1609), 20120353. doi:10.1098/rstb.2012.0353Garcia-Dominguez, X., Juarez, J. D., Vicente, J. S., & Marco-Jiménez, F. (2020). Impact of embryo technologies on secondary sex ratio in rabbit. Cryobiology, 97, 60-65. doi:10.1016/j.cryobiol.2020.10.008Viudes-de-Castro, M. P., Marco-Jiménez, F., Cedano-Castro, J. I., & Vicente, J. S. (2017). Effect of corifollitropin alfa supplemented with or without LH on ovarian stimulation and embryo viability in rabbit. Theriogenology, 98, 68-74. doi:10.1016/j.theriogenology.2017.05.005Marco-Jiménez, F., Lavara, R., Jiménez-Trigos, E., & Vicente, J. S. (2013). In vivo development of vitrified rabbit embryos: Effects of vitrification device, recipient genotype, and asynchrony. Theriogenology, 79(7), 1124-1129. doi:10.1016/j.theriogenology.2013.02.008Vicente, J.-S., Viudes-de-Castro, M.-P., & García, M.-L. (1999). In vivo survival rate of rabbit morulae after vitrification in a medium without serum protein. Reproduction Nutrition Development, 39(5-6), 657-662. doi:10.1051/rnd:19990511Garcia-Dominguez, X., Marco-Jimenez, F., Viudes-de-Castro, M. P., & Vicente, J. S. (2019). Minimally Invasive Embryo Transfer and Embryo Vitrification at the Optimal Embryo Stage in Rabbit Model. Journal of Visualized Experiments, (147). doi:10.3791/58055Besenfelder, U., Strouhal, C., & Brem, G. (1998). A Method for Endoscopic Embryo Collection and Transfer in the Rabbit. Journal of Veterinary Medicine Series A, 45(1-10), 577-579. doi:10.1111/j.1439-0442.1998.tb00861.

The relationship between maximal left ventricular wall thickness and sudden cardiac death in childhood onset hypertrophic cardiomyopathy

Background: Maximal left ventricular wall thickness (MLVWT) is a risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). In adults, the severity of left ventricular hypertrophy has a nonlinear relationship with SCD, but it is not known whether the same complex relationship is seen in childhood. The aim of this study was to describe the relationship between left ventricular hypertrophy and SCD risk in a large international pediatric HCM cohort. Methods: The study cohort comprised 1075 children (mean age, 10.2 years [±4.4]) diagnosed with HCM (1–16 years) from the International Paediatric Hypertrophic Cardiomyopathy Consortium. Anonymized, noninvasive clinical data were collected from baseline evaluation and follow-up, and 5-year estimated SCD risk was calculated (HCM Risk-Kids). Results: MLVWT Z score was <10 in 598 (58.1%), ≥10 to <20 in 334 (31.1%), and ≥20 in 143 (13.3%). Higher MLVWT Z scores were associated with heart failure symptoms, unexplained syncope, left ventricular outflow tract obstruction, left atrial dilatation, and nonsustained ventricular tachycardia. One hundred twenty-two patients (71.3%) with MLVWT Z score ≥20 had coexisting risk factors for SCD. Over a median follow-up of 4.9 years (interquartile range, 2.3–9.3), 115 (10.7%) had an SCD event. Freedom from SCD event at 5 years for those with MLVWT Z scores <10, ≥10 to <20, and ≥20 was 95.6%, 87.4%, and 86.0, respectively. The estimated SCD risk at 5 years had a nonlinear, inverted U-shaped relationship with MLVWT Z score, peaking at Z score +23. The presence of coexisting risk factors had a summative effect on risk. Conclusions: In children with HCM, an inverted U-shaped relationship exists between left ventricular hypertrophy and estimated SCD risk. The presence of additional risk factors has a summative effect on risk. While MLVWT is important for risk stratification, it should not be used either as a binary variable or in isolation to guide implantable cardioverter defibrillator implantation decisions in children with HCM