Human Implantation Research Articles

APOE polymorphism status (E4) may help in predicting the risk of recurrent implantation failure.

To examine the association between apolipoprotein E (APOE) gene polymorphisms and incidence of recurrent implantation failure (RIF). In a case-control study, 100 women with RIF were compared with 100 women with at least one live child. DNA was extracted from the peripheral blood and APOE genotyping was performed through polymerase chain reaction, followed by restriction fragment length polymorphism. Statistical analysis was performed using Pearson's χ2 test. Our data revealed a significantly higher frequency for the E3/E4genotype and E4 allele in the RIF group compared with controls. Significant differences in frequencies of the E4 allele (odds ratio [OR] 2.176; 95% confidence interval [CI] 1.131-4.185; P=0.026) and E3/E4genotype (OR 2.203; 95% CI 1.092-4.443; P=0.038) were observed between the groups. The E4 polymorphism is correlated with RIF occurrence in women undergoing assisted reproductive treatment and potentially can be considered as a risk factor to the human implantation process.

Insights into the Regulation of Implantation and Placentation in Humans, Rodents, Sheep, and Pigs.

Precise cell-specific spatio-temporal molecular signaling cascades regulate the establishment and maintenance of pregnancy. Importantly, the mechanisms regulating uterine receptivity, conceptus apposition and adhesion to the uterine luminal epithelia/superficial glandular epithelia and, in some species, invasion into the endometrial stroma and decidualization of stromal cells, are critical prerequisite events for placentation which is essential for the appropriate regulation of feto-placental growth for the remainder of pregnancy. Dysregulation of these signaling cascades during this critical stage of pregnancy can lead to pregnancy loss, impaired growth and development of the conceptus, and alterations in the transplacental exchange of gasses and nutrients. While many of these processes are conserved across species, significant variations in the molecular mechanisms governing maternal recognition of pregnancy, conceptus implantation, and placentation exist. This review addresses the complexity of key mechanisms that are critical for the establishment and maintenance of a successful pregnancy in humans, rodents, sheep, and pigs. Improving understanding of the molecular mechanisms governing these processes is critical to enhancing the fertility and reproductive health of humans and livestock species.

The role of epithelial progesterone receptor isoforms in embryo implantation

The loss of uterine epithelial progesterone receptor (PGR) is crucial for successful embryo implantation in both humans and mice. The two major isoforms PGRA and PGRB have divergent functions under both physiological and pathological conditions. The present study compares phenotypes and gene signatures of PGRA and PGRB in uterine epithelium using uterine epithelial-specific constitutively expressed PGRA or PGRB mouse models. The cistrome and transcriptome analysis reveals substantial overlap between epithelial PGRA and PGRB, and both disrupt embryo implantation through FOXO1 pathways. Constitutive epithelial PGRA and PGRB expression impairs ESR1 occupancy at the promoter of Lif leading to reduced Lif transcription and further exaggerates SGK1 expression leading to enhanced PI3K-SGK1 activities, and both contribute to the decline of nuclear FOXO1 expression. Our study demonstrates that PGRA and PGRB in the uterine epithelium act on a similar set of target genes and commonly regulate the LIF-SGK1-FOXO1 signaling pathway for embryo implantation.

Effect of Autologous Platelet-Rich Plasma (PRP) Treatment on Endometrial Receptivity in ICSI cases

The crosstalk between a receptive endometrium and a functional blastocyst during human embryo implantation is crucial for conception. Because platelets rich plasma (PRP) with concentrated platelets 4-5 times higher than normal, when release of granules containing growth factors including VEGF, TGF, PDGF, IGF, and EGF, these factors involved for sub endometrial angiogenesis and endometrial receptivity. 44 women under the age of 40 were given antagonist ovarian stimulation treatments, the oocytes were harvested utilizing 2-D power doppler ultrasound guidance, then ICSI done for them. On the hCG day all had an intrauterine autologous PRP infusion. Power Doppler is utilized to measure endometrial thickness (EnT), pulsatility index (PI), and resistance index (RI) of sub endometrial arteries, as well as serum levels of VEGF and EGF were measured on the hCG day and ovum pickup (OPU). The ultrasound findings, on the hCG day compared to those of OPU in all women with intrauterine infused autologous PRP were highly significant (HS). The mean EnT, RI, PI, VEGF and EGF at OPU day was lower than that on hCG day in a HS manner, with (p < 0.001), (p < 0.001), (p = 0.047), (p < 0.001), and (p < 0.001) respectively. These characteristics were shown to be significantly and independently associated to intrauterine PRP infusion. After PRP injection, both growth factors serum levels (VEGF and EGF) increased, and ultrasonography sub-endometrial metrics such as EnT, RI, and PI changed as the thickness grew while vascular resistance decreased, and all considered as predictors of endometrial receptivity.

TNF-α Regulated Endometrial Stroma Secretome Promotes Trophoblast Invasion

Successful implantation requires the coordinated migration and invasion of trophoblast cells from out of the blastocyst and into the endometrium. This process relies on signals produced by cells in the maternal endometrium. However, the relative contribution of stroma cells remains unclear. The study of human implantation has major technical limitations, therefore the need of in vitro models to elucidate the molecular mechanisms. Using a recently described 3D in vitro models we evaluated the interaction between trophoblasts and human endometrial stroma cells (hESC), we assessed the process of trophoblast migration and invasion in the presence of stroma derived factors. We demonstrate that hESC promotes trophoblast invasion through the generation of an inflammatory environment modulated by TNF-α. We also show the role of stromal derived IL-17 as a promoter of trophoblast migration through the induction of essential genes that confer invasive capacity to cells of the trophectoderm. In conclusion, we describe the characterization of a cellular inflammatory network that may be important for blastocyst implantation. Our findings provide a new insight into the complexity of the implantation process and reveal the importance of inflammation for embryo implantation.

1-Nitropyrene exposure impairs embryo implantation through disrupting endometrial receptivity genes expression and producing excessive ROS

Haze problem is an important factor threatening human health. PM2.5 is the main culprit haze. 1-Nitropyrene (1-NP) is the main nitrated polycyclic aromatic hydrocarbon, the toxic component of PM2.5 particles. The effects of 1-NP on various organs and reproductive health have been extensively and deeply studied, but the effects of 1-NP on embryo implantation and endometrial receptivity remain to be determined. The purpose of this study was to investigate the adverse effects of 1-NP on mouse embryo implantation and human endometrial receptivity. In early pregnancy, CD1 mice were given 2 mg/kg 1-NP by oral gavage, which resulted in a decreased embryo implantation number on day 5, inhibited leukemic inhibitory factor (LIF)/STAT3 pathway, decreased expression of estrogen receptor and progesterone receptor, and disrupted regulation of uterine cell proliferation. In addition, in a human in vitro implantation model, 1-NP was found to significantly inhibit the adhesion rate between trophoblast spheroids and endometrial epithelial cells, possibly by inhibiting the expression of receptivity molecules in Ishikawa cells. Promoting reactive oxygen species (ROS) production may be an additional mechanism by which it inhibits trophoblast spheroid adhesion. In this study, we used an in vivo mouse pregnancy model and an in vitro human embryo implantation model to demonstrate that 1-NP can impair endometrial receptivity and compromise embryo implantation.

Cell-assembled extracellular matrix (CAM): a human biopaper for the biofabrication of pre-vascularized tissues able to connect to the host circulation in vivo

When considering regenerative approaches, the efficient creation of a functional vasculature, that can support the metabolic needs of bioengineered tissues, is essential for their survival after implantation. However, it is widely recognized that the post-implantation microenvironment of the engineered tissues is often hypoxic due to insufficient vascularization, resulting in ischemia injury and necrosis. This is one of the main limitations of current tissue engineering applications aiming at replacing significant tissue volumes. Here, we have explored the use of a new biomaterial, the cell-assembled extracellular matrix (CAM), as a biopaper to biofabricate a vascular system. CAM sheets are a unique, fully biological and fully human material that has already shown stable long-term implantation in humans. We demonstrated, for the first time, the use of this unprocessed human ECM as a microperforated biopaper. Using microvalve dispensing bioprinting, concentrated human endothelial cells (30 millions ml−1) were deposited in a controlled geometry in CAM sheets and cocultured with HSFs. Following multilayer assembly, thick ECM-based constructs fused and supported the survival and maturation of capillary-like structures for up to 26 d of culture. Following 3 weeks of subcutaneous implantation in a mice model, constructs showed limited degradative response and the pre-formed vasculature successfully connected with the host circulatory system to establish active perfusion.This mechanically resilient tissue equivalent has great potential for the creation of more complex implantable tissues, where rapid anastomosis is sine qua non for cell survival and efficient tissue integration.

Does descending health resources reform impact patient low-level hospital selection behavior? Evidence from Zhejiang, China

BackgroundSince 2013, China launched descending resources reform, which is a new attempt to correct unbalanced allocation of health resources through human capital spillovers and brand implantation from high-level hospitals. The purpose of this paper is to explore the patients’ hospital selection response to this reform with the focus of low-level hospitals to better understand the effect of this reform on correcting regional inequality of health resources allocation.MethodsThe European Consumer Satisfaction Index model (ECSI) was used to design a questionnaire, and cross-sectional data from 17 hospitals were collected through 1287 questionnaires from Zhejiang Province. Patient hospital selection (loyalty) is measured using ordinary variables by considering patient willingness to choose a low-level hospital when suffering an illness or severe illness. Analysis of variance (ANOVA) and the structure equation model are applied to examine the effect of reforms on patient behavior.ResultsThe descending resources reform promotes improvements in the capabilities and medical environment of low-level hospitals, and descending doctors also have high accessibility. Perceived quality, patient expectations, and hospital image have significant positive effects on patient satisfaction, and the explanatory power of brand implantation from cooperative high-level hospitals and descending doctors is stronger than the image of the low-level hospital itself. And descending resources reform and patient satisfaction have significant positive impacts on patient’s choice for low-level hospitals with the existence of mediating effect of satisfaction.ConclusionsThis paper provides supporting empirical evidence of the descending resources reform’s impact on patients’ low-level hospital selection. This reform has been effective in improving the capabilities of low-level hospitals, and brand implantation of high-level hospitals shows strong explanatory power. China’s reform offers a distinct and valuable approach to correcting the uneven allocation of health resources. Besides, the findings also suggest that policymakers could pay more attention to the importance of information channels in impacting patient awareness, responses, and hospital selection.

Biocompatible reference electrodes to enhance chronic electrochemical signal fidelity in vivo.

In vivo electrochemistry is a vital tool of neuroscience that allows for the detection, identification, and quantification of neurotransmitters, their metabolites, and other important analytes. One important goal of in vivo electrochemistry is a better understanding of progressive neurological disorders (e.g., Parkinson's disease). A complete understanding of such disorders can only be achieved through a combination of acute (i.e., minutes to hours) and chronic (i.e., days or longer) experimentation. Chronic studies are more challenging because they require prolonged implantation of electrodes, which elicits an immune response, leading to glial encapsulation of the electrodes and altered electrode performance (i.e., biofouling). Biofouling leads to increased electrode impedance and reference electrode polarization, both of which diminish the selectivity and sensitivity of in vivo electrochemical measurements. The increased impedance factor has been successfully mitigated previously with the use of a counter electrode, but the challenge of reference electrode polarization remains. The commonly used Ag/AgCl reference electrode lacks the long-term potential stability in vivo required for chronic measurements. In addition, the cytotoxicity of Ag/AgCl adversely affects animal experimentation and prohibits implantation in humans, hindering translational research progress. Thus, a move toward biocompatible reference electrodes with superior chronic potential stability is necessary. Two qualifying materials, iridium oxide and boron-doped diamond, are introduced and discussed in terms of their electrochemical properties, biocompatibilities, fabrication methods, and applications. In vivo electrochemistry continues to advance toward more chronic experimentation in both animal models and humans, necessitating the utilization of biocompatible reference electrodes that should provide superior potential stability and allow for unprecedented chronic signal fidelity when used with a counter electrode for impedance mitigation.

New TiTaNbZrMo high-entropy alloys for metallic biomaterials

The advantages of high entropy alloy with good comprehensive properties provide a potential opportunity to explore and develop new alloys suitable for human implantation. In this experiment, TiTaNbZrMo high entropy alloy was designed and prepared by alloy design and first principle. The calculation results predict that the phase composition of each high entropy alloy is BCC structure, and the designed high entropy alloy has structural stability; the non-equal atomic ratio TiNbTaZrMo high-entropy alloy has higher ductility than the equal atomic ratio TiNbTaZrMo high-entropy alloy; the B/G, Poisson’s ratio υ and (C 12-C 44) values of Ti30(NbTaZr)60Mo10 alloy are the largest, indicating that the toughness of this alloy is the best, and the Young’s modulus value is the smallest. The experimental results show that the yield strength of Ti30(NbTaZr)60Mo10 alloy is 1132 MPa, the plastic strain is 33%, and the wear resistance and corrosion resistance are good. The potential of Ti30(NbTaZr)60Mo10 in biological field is proved by calculation and experimental test, which provides an important basis for its industrial application in biomedical alloy.

Human menstrual blood-derived mesenchymal stem cells regulation of the EGF/Ras p21 pathway as a potential therapeutic target for thin endometrium.

BackgroundHuman infertility is caused by many factors, among which thin endometrium is the main reason for poor embryo implantation. Currently, stem cell therapy could be a potential approach in treating human endometrial disorder like thin endometrium. In this study, we aimed to explore the influence of menstrual stem cells from non-thin endometrium (NTE-MenSCs) and thin endometrium (TE-MenSCs) on the phenotype of endometrial epithelial cells (EECs).MethodsThe MenSCs were isolated from women with and without thin endometria, characterized and co-cultured with the EECs. The expression of cytokeratin 7 (CK7) was verified by immunofluorescence while the detection stem cell markers was determined flow cytometry. Osteogenic and adipogenic differentiation were induced in appropriate media. The quantitative real-time PCR and western blotting were respectively used for detecting the mRNA and protein expression levels, respectively. The CCK-8 assay was used for cell viability analysis whereas ELISA was used for the detection of cytokine levels.ResultsThe results showed that the co-culture of NTE-MenSCs or TE-MenSCs and EECs promoted the proliferation, migration, and angiogenesis of endothelial progenitor cells differently. Furthermore, the TE-MenSCs promoted the expression of inflammation, vascularized adipose, and extracellular matrix related proteins. The epidermal growth factor (EGF)/Ras p21 pathway was found to mediate the influence of MenSCs on EECs.ConclusionsThese findings are vital in that they may promote stem cell therapy of thin endometrium and enable embryo implantation in humans with thin endometrium.

The Role of the Adhesion Receptor CD146 and Its Soluble Form in Human Embryo Implantation and Pregnancy.

CD146 is an adhesion molecule essentially located in the vascular system, which has been described to play an important role in angiogenesis. A soluble form of CD146, called sCD146, is detected in the bloodstream and is known as an angiogenic factor. During placental development, CD146 is selectively expressed in extravillous trophoblasts. A growing body of evidence shows that CD146 and, in particular, sCD146, regulate extravillous trophoblasts migration and invasion both in vitro and in vivo. Hereby, we review expression and functions of CD146/sCD146 in the obstetrical field, mainly in pregnancy and in embryo implantation. We emphasized the relevance of quantifying sCD146 in the plasma of pregnant women or in embryo supernatant in the case of in vitro fertilization (IVF) to predict pathological pregnancy such as preeclampsia or implantation defect. This review will also shed light on some major results that led us to define CD146/sCD146 as a biomarker of placental development and paves the way toward identification of new therapeutic targets during implantation and pregnancy.

An in vitro Model for Human Blastocyst Implantation

An in vitro Model for Human Blastocyst Implantation

Minimally invasive fully ROBOT‐assisted cochlear implantation in humans: Preliminary results in five consecutive patients

- Cochlear implants are medical devices indispensable for the treatment of severe-to-profound bilateral sensorineural hearing loss - The most commonly used surgical procedure for cochlear implantation involves temporal bone drilling associating mastoidectomy with a facial recess approach - Improvements in robot-assisted surgery since 2010 have raised questions about the possibility of "simplifying" cochlear implant surgery - This study showed that the use of robotic assistance coupled to CT guidance for cochlear implantation is possible and apparently safe for the entire procedure using a Robot that is already available worldwide. - Several improvements are required to optimize this procedure.

P–368 Dynamic metabolomic profiling during early implantation period

Abstract Study question To investigate the different metabolomic profiling in serum between pregnant and non-pregnant women during early implantation period. Summary answer Metabolomics of progesterone-related hormones enhances from ET day3 for pregnancy women compared with non-pregnancy women. What is known already Metabolomics is based on high-throughput analytical methods to identify and quantify metabolites. Compared to other omics study, metabolomics is the closest one to the phenotype, allowing the observation of dynamic changes in phenotype at specific timepoints. So far there is no published work about the metabolomics profile in human early implantation period. Study design, size, duration: Study design: comparative study. Size: 14 pregnancy women and 14 non-pregnancy women. duration: time-course. Participants/materials, setting, methods Participants: pregnancy women and unpregnancy women after embryo transfer (ET). Setting: university-based study. Methods: Peripheral blood were collected at ET day0, 3, 6 and 9. metabolomic profiling in serum by platforms of capillary electrophoresis-mass spectrometry (CE-MS) and liquid chromatography–mass spectrometry (LC-MS). Main results and the role of chance There were no statistical difference of the age, BMI, basal FSH level, endometrium thickness on the day of embryo transfer, distribution of primary and secondary fertility, embryo transfer cycle as well as the infertile types between the two groups. After deleting those with over 50% missing data, we finally have 310 metabolites into statistical analysis. Among the 310 metabolite, lipid metabolites account the largest percentage, nearly half of all metabolites. The second biggest class of metabolites in our data was organic acids. Combined results in repeated measurement ANOVA (RM-ANOVA) and ANOVA-simultaneous component analysis (ASCA) as well as multivariate empirical Bayes time-series analysis (MEBA), we finally found that progesterone-related hormones were the most important metabolites for the whole time-series data. Those significant metabolites showed a significant down regulation from ET day0 to ET day3 and up regulation from ET day3 to ET day9. Limitations, reasons for caution we have limited sample size for this study and further validation is necessary for confirmation. Wider implications of the findings: The phenomenon of upregulation of progesterone-related hormones from day3 in pregnancy group might be related to the embryo-originated hcg. Because the embryo has entered into endometrium at day3 and produced cytokines, hcg and other interaction with endometrium. Trial registration number NA

O-031 Importance of blood flow to human implantation

Abstract text The success of embryo implantation depends on a plethora of factors, with embryo quality and endometrial receptivity belonging to the most important ones. The receptive phenotype of endometrium develops in reaction to appropriate estrogen stimulation in the proliferative phase and embryo-synchronized maturation warranted by the action of progesterone. Uterine blood supply, myometrial contractions and the activity of local immune cells also belong to important factors affecting the outcome of both natural and assisted reproduction. Endometrial perfusion was shown to be an independent receptivity parameter, showing a direct association with pregnancy outcomes. Historically, the use of Doppler parameters of uterine vessels was studied as a reflection of blood flow to the endometrium. Although some authors showed a correlation between blood flow in uterine arteries and success rates in IVF cycles, it might not reflect the actual endometrial flow as most of the blood volume goes through myometrium, not endometrium. Currently, using available ultrasound tools – 2D/3D Power Doppler with VOCAL (Virtual Organ Computer-Aided Analysis) software enables clinicians to evaluate parameters of endometrial perfusion in a matter of minutes. In this method, ultrasound system can calculate indices reflecting endometrial blood flow - vascularity index (VI), endometrial flow index (FI), and endometrial vascularity flow index (VFI) which are based on the total and relative amounts of Power Doppler signal (corresponding to the blood flow) within the volume of interest. Endometrial blood flow parameters can be altered in implantation limiting conditions such as endometriosis or chronic intrauterine inflammation. It was also shown to be influenced by implantation-related hormones such as oxytocin. Oxytocin receptor antagonists were shown to decrease uterine contractions in non-pregnant uteri of women being prepared for embryo transfer procedure. This class of medications has been extensively studied as potential candidates for medications promoting embryo implantation in IVF-ET treatments. In several studies, it was shown that mixed oxytocin/vasopressin V1A receptor antagonist atosiban, which is currently registered in Europe for the tocolysis in preterm labour, had the potential of improving implantation rates. Interestingly, this effect was confirmed also in women without pronounced contractions. Additionally, it has been demonstrated that oxytocin antagonism enhances endometrial decidualization and influences other parameters necessary for the acquisition of the endometrial receptivity phenotype. Considering that atosiban and other oxytocin antagonists relax uterine blood vessels and increase endometrial blood flow, it was hypothesized that improvement in endometrial perfusion could be an additional mechanism for observed support of embryo implantation. A similar finding was confirmed in our study on nolasiban – a non-peptide, orally active, oxytocin receptor-specific antagonist. In the 1st phase study on volunteers undergoing estrogen/progesterone endometrial preparation reflecting the synchronization for embryo transfer, it was confirmed that application of nolasiban decreased uterine contractions and improved FI and VFI parameters of endometrial perfusion. Such an effect lasted for more than 24 hours after dosing. The study results suggested that oxytocin antagonism could have an effect on endometrial perfusion, and its potential clinical significance requires further investigation. In a longer perspective, once confirmed it would mean that, apart from the possibility of observation of endometrial blood flow, we could have a tool for improving it, which would hopefully lead to improved outcomes of assisted reproduction treatments.

O-199 Proof of concept: implantation window must be wider than proposed. Report of seven twins after asynchronous double embryo transfer

Abstract Study question Can simultaneous transfer of two embryos that were cryopreserved at different stages (D3 and Blastocyst) be appropriate to enhance success in women with more than three failed embryo transfers? Summary answer Double asynchronous embryo transfer offered excellent results in RIF. Unexpectedly high twin rate suggests that embryo-endometrium synchrony is overemphasized. Implantation window must be wider. What is known already Transcriptomic signature of the endometrium has been investigated in the last few years trying to understand the best moment for embryo implantation. Nevertheless, the optimal period has not been well established yet in humans. Simultaneous transfer of two human embryos at different developmental stages (D3 and Blastocyst) on Day 4 was proposed to help couples who have had RIF. Study design, size, duration Observational case-control study. From April 2016 to January 2021, we offered double asynchronous embryo transfer only after Recurrent Implantation Failure (RIF). Two requirements were necessary: 1) Double embryo transfer was acceptable by the couple due to poor reproductive outcome. 2) Availability of two embryos cryopreserved at different stage (D3 and Blastocyst). Results were compared with good prognosis patients (all patients under 35 years in that period who had elected to transfer two day 3 cryopreserved embryos). Participants/materials, setting, methods Forty-five patients accepted to participate in the study. Results were compared with all patients (237) under 35 years where two D3 thawed embryos were transferred. All cases received same protocol (oral estradiol 6mg/d or vaginal estradiol 4mg/d until ultrasound showed endometrial growth) LH, P4 and E2 were monitored in all patients to detect spontaneous LH surge. All cases received transvaginal micronized progesterone 800 mg/d. Embryo transfers were ultrasound guided and Wallace Embryosure catheter was employed. Main results and the role of chance Limitations, reasons for caution Multiple pregnancy rate was unacceptably high. Therefore, it should not be suggested for good prognosis couples where single embryo transfer is clearly advidsed. Our main limitation was the combination of D3 embryos with blastocysts. The retrospective design make the results to be considered as a proof of concept. Wider implications of the findings Double asynchronic embryo transfer can offer new insights in the understanding of human implantation. The concept of implantation window is clearly challenged. Aiming to the center of the window is fine, but we still dońt know how wide is that center. Trial registration number not applicable

Decellularised Human Umbilical Artery as a Vascular Graft Elicits Minimal Pro-Inflammatory Host Response Ex Vivo and In Vivo.

Small diameter (<6 mm) vessel grafts still pose a challenge for scientists worldwide. Decellularised umbilical artery (dUA) remains promising as small diameter tissue engineered vascular graft (TEVG), yet their immunogenicity remains unknown. Herein, we evaluated the host immune responses, with a focus on the innate part, towards human dUA implantation in mice, and confirmed our findings in an ex vivo allogeneic human setup. Overall, we did not observe any differences in the number of circulating white blood cells nor the number of monocytes among three groups of mice (1) dUA patch; (2) Sham; and (3) Mock throughout the study (day −7 to 28). Likewise, we found no difference in systemic inflammatory and anti-inflammatory cytokine levels between groups. However, a massive local remodelling response with M2 macrophages were observed in the dUA at day 28, whereas M1 macrophages were less frequent. Moreover, human monocytes from allogeneic individuals were differentiated into macrophages and exposed to lyophilised dUA to maximize an eventual M1 response. Yet, dUA did not elicit any immediate M1 response as determined by the absence of CCR7 and CXCL10. Together this suggests that human dUA elicits a minimal pro-inflammatory response further supporting its use as a TEVG in an allogeneic setup.

Podocalyxin inhibits human embryo implantation in vitro and luminal podocalyxin in putative receptive endometrium is associated with implantation failure in fertility treatment

To study whether endometrial epithelial podocalyxin (PCX) inhibits implantation of human embryos invitro and in patients undergoing in vitro fertilization (IVF). We have recently identified PCX as a key negative regulator of endometrial epithelial receptivity. Podocalyxin is expressed in all epithelial cells in the nonreceptive endometrium, but is selectively downregulated in the luminal epithelium (LE) for receptivity. In the current study, we first investigated whether high levels of PCX in Ishikawa monolayer inhibit attachment and/or penetration of human blastocysts in invitro models. We then examined PCX by immunohistochemistry in putative receptive endometrial tissues biopsied from 81 IVF patients who underwent frozen embryo transfer in the next natural cycle and retrospectively analyzed the association between PCX staining in LE and clinical pregnancy as a proxy of successful implantation. RMIT University, Australia; Vrije Universiteit Brussel, Belgium. In vitro fertilization patients undergoing frozen/thawed embryo transfer. N/A. Endometrial epithelial PCX inhibits implantation of human embryos invitro and in IVF patients. High levels of PCX in Ishikawa monolayer significantly inhibited blastocyst attachment and penetration. Among the 81 putative receptive tissues, 73% were negative, but 27% were heterogeneously positive for PCX in LE. The clinical pregnancy rate was 53% in those with a PCX-negative LE but only 18% in those with a PCX-positive LE. If LE was positive for PCX, the odds ratio of no clinical pregnancy was 4.95 (95% Confidence interval, 1.48-14.63). Podocalyxin inhibits embryo implantation. Assessment of PCX may aid the evaluation and optimization of endometrial receptivity in fertility treatment.

Defining the Clinical, Emotional, Social, and Financial Burden of Congenital Athymia.

IntroductionCharacterize the burden of illness in pediatric patients with congen̄ital athymia who were receiving supportive care.MethodsThis cross-sectional study of adult caregivers of patients with congenital athymia used both a quantitative survey and qualitative interviews. Caregivers of patients currently receiving supportive care responded to questions about the past 12 months and completed the parent proxy version of the Pediatric Quality of Life Inventory Generic instrument (PedsQL) for patients aged 2–4 years. For caregivers of patients who had received supportive care in the past, questions were asked about the period when they were receiving supportive care only.ResultsThe sample included caregivers of 18 patients, 5 who were currently receiving supportive care and 13 who received investigational cultured human thymus tissue implantation before study enrollment and had received supportive care in the past. The impact of congenital athymia was substantial. Reports included the need to live in isolation (100% of respondents); caregiver emotional burden such as fear of death, infection, and worries about the future (100%); financial hardship (78%); and the inability to meet family/friends (72%). Patients had frequent and prolonged hospitalizations (78%) and had high utilization of procedures, medications, and home medical supplies. Caregiver-reported PedsQL scores for patients currently receiving supportive care (n = 4) indicated low health-related quality of life.ConclusionsCaregivers of patients with congenital athymia reported high clinical, emotional, social, and financial burden on patients and their families.