Centromeric AA motif in KIR as an optimal surrogate marker for precision definition of alloimmune reproductive failure.

Throughout pregnancy, the decidua is predominantly populated by NK lymphocytes expressing Killer immunoglobulin-like receptors (KIR) that recognize human leukocyte antigen-C (HLA-C) ligands from trophoblast cells. This study aims to investigate the association of KIR-HLA-C phenotypes in couples facing infertility, particularly recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF), in comparison to a reference population and fertile controls. This observational, non-interventional retrospective case-control study included patients consecutively referred to our Reproductive Immunology Unit from 2015 to 2019. We analyzed the frequencies of KIR and HLA-C genes. As control groups, we analyzed a reference Spanish population for KIR analysis and 29 fertile controls and their male partners for KIR and HLA-C combinations. We studied 397 consecutively referred women with infertility and their male partners. Among women with unexplained RPL (133 women) and RIF (176 women), the centromeric (cen)AA KIR genotype was significantly more prevalent compared to the reference Spanish population (p = 0.001 and 0.02, respectively). Furthermore, cenAA was associated with a 1.51-fold risk of RPL and a 1.2-fold risk of RIF. Conversely, the presence of BB KIR showed a lower risk of reproductive failure compared to non-BB KIR (OR: 0.12, p < 0.001). Women and their partners with HLA-C1C1/C1C1 were significantly less common in the RPL-Group (p < 0.001) and RIF-Group (p = 0.002) compared to the control group. Moreover, the combination of cenAA/C1C1 in women with C1C1 partners was significantly higher in the control group than in the RPL (p = 0.009) and RIF (p = 0.04) groups, associated with a 5-fold increase in successful pregnancy outcomes. In our cohort, the cenAA KIR haplotype proved to be a more accurate biomarker than the classic AA KIR haplotype for assessing the risk of RPL and RIF, and might be particularly useful to identify women at increased risk among the heterogeneous KIR AB or Bx population. The classification of centromeric KIR haplotypes outperforms classical KIR haplotypes, making it a better indicator of potential maternal-fetal KIR-HLA-C mismatch in patients.

Impact of Ovarian Endometrioma and Surgery on Reproductive Outcomes: A Single-Center Spanish Cohort Study.

Anti-Müllerian hormone (AMH) and antral follicular count (AFC) decrease in women with ovarian endometrioma (OMA) and in vitro fertilization (IVF). In addition, these parameters drop even further when women with OMA undergo surgery. In this study, the primary aim was to compare the reproductive variables in IVF-treated women with and without endometriosis. The secondary aim was to explore if the reproductive variables were modified by endometrioma surgery. In this retrospective study, 244 women undergoing IVF were enrolled at the Hospital Universitario La Paz (Madrid, Spain). Women were categorized as OMA not surgically treated (OMA; n = 124), OMA with surgery (OMA + S; n = 55), and women with infertility issues not related to OMA (control; n = 65). Demographic and clinical variables, including age, body mass index (BMI), and reproductive (AMH, AFC, number of extracted oocytes, and transferred embryos) and obstetrical data (biochemical pregnancy and fetal heart rate at 6 weeks) were collected. Adjusted logistic regression models were built to evaluate reproductive and pregnancy outcomes. The models showed that women with OMA (with and without surgery) had significantly decreased levels of AMH and AFC and numbers of cycles and C + D embryos. Women with OMA + S had similar rates of pregnancy to women in the control group. However, women with OMA had lower biochemical pregnancy than controls (aOR = 0.08 [0.01; 0.50]; p-value = 0.025). OMA surgery seems to improve pregnancy outcomes, at least until 6 weeks of gestation. However, it is important to counsel the patients about surgery expectations due to the fact that endometrioma itself reduces the quality of oocytes.

Ligilactobacillus salivarius PS11610 exerts an effect on the microbial and immunological profile of couples suffering unknown infertility.

PROBLEM: Unknown or idiopathic infertility has been associated with urogenital tract dysbiosis, reducing pregnancy and delivery ratios during assisted reproductive treatments (ART). The Ligilactobacillus salivarius PS11610 strain has shown extraordinary antimicrobial activity in vitro against urogenital pathogens as well as other probiotic characteristics. Therefore, an intervention study was performed to evaluate the effect of L. salivarius PS11610 on the microbial composition of urogenital tract in infertile couples with bacterial dysbiosis. METHOD OF STUDY: Seventeen couples undergoing ART diagnosed with unknown infertility were selected. After confirming urogenital dysbiosis, they started a 6-month treatment with L. salivarius PS11610 (1 dose/12 h for female and 1 dose/24 h for male). Vaginal, seminal, glans, uterine and plasma samples were collected for determination of the microbiome and immune profile at the beginning and the end of the treatment. RESULTS: Supplementation with L. salivarius PS11610 significantly modified the urogenital microbiome composition in male and female samples, solving dysbiosis of 67% of the couples. Pathogens disappeared from the vaginal samples whereas Lactobacilli percentage increased after 3 and 6 months of treatment. Moreover, L. salivarius PS11610 changed the uterine microbiome that could be associated with a change of the uterine immune profile. Additionally, the probiotic intake could be associated with the observed change in the systemic immunological profile of couples. Finally, the pregnant and delivery ratio were improved. CONCLUSIONS: Probiotic supplementation with L. salivarius PS11610 improved the male and female urogenital tract microbiome, modulating the immune system and increasing pregnancy success in couples undergoing ART.

Originator recombinant human follitropin alfa versus recombinant human follitropin alfa biosimilars in Spain: A cost-effectiveness analysis of assisted reproductive technology related to fresh embryo transfers.

This study compared the cost per live birth and cost-effectiveness of the originator recombinant human follicle-stimulating hormone follitropin alfa (r-hFSH-alfa) and r-hFSH-alfa biosimilars for ovarian stimulation prior to assisted reproductive technology treatment in Spain. A decision tree model was developed, comprising pregnancy and live birth for one treatment cycle with fresh embryo transfer. Clinical inputs were based on a recent meta-analysis by Chua et al. [4]. Cost inputs were extracted from publicly available Spanish sources. The costs per live birth were lower with originator r-hFSH-alfa (€18,138) versus r-hFSH-alfa biosimilars (€20,377). The incremental cost-effectiveness ratio was €7208 for originator r-hFSH-alfa versus biosimilars. Drug acquisition costs for originator r-hFSH-alfa represented 10.5% of total costs in the base case analysis, and 6.2% in a treatment cycle resulting in live birth with one fresh embryo transfer. Results from the sensitivity analyses confirmed the robustness of the findings.

Use of steroid pre-treatments in IVF-ICSI cycles with GnRH antagonist protocol and their impact on gestational outcomes.

Different steroid pre-treatments have been used to schedule the start of the ovarian stimulation in IVF cycles. Currently, there is controversy about their effects on gestational outcomes. We designed a three-armed randomised controlled trial (RCT). Eighty-six normoresponder patients undergoing IVF treatment with antagonist GnRH protocol were allocated to three different groups. In the group 1, 34 patients received oral contraceptive pill (OCP) from the first day of the cycle to five days before starting ovarian stimulation, in the group 2, 25 patients received 2 mg/12 hours of oral E2 valerate from day 25 of the previous cycle until the day before starting stimulation, and finally, in the group 3, 27 patients did not receive any treatment. There are no statistically significant differences neither in clinical pregnancy rate (CPR) (40.9% OCP vs. 28.6% E2 vs. 53.3% no treatment group, p=.388) nor live birth rate (LBR) (31.8% OCP vs. 28.6% E2 vs. 46.7% no treatment group, p=.537) between groups in fresh embryo transfer. Likewise, no differences were found in the cumulative CPR, nor in cumulative LBR. However, there is a tendency to worst outcomes in the E2 group. In this E2 group, we observed better results with longer exposition, although no significant differences are reached (E2 mean days in the pregnant group 8.29 vs. 6.83 in the non-pregnant group, p=.08). Our study shows no significant differences in pregnancy rates between groups, but the E2 group is trending at worse gestational results. Trial registration number: Eudra-CT registration number is 2014-001809-40.Impact StatementWhat is already known on this subject? Nowadays, there is much controversy about how pregnancy rates could be affected by the selection of steroid pre-treatments used in order to schedule IVF cycles. However, these treatments are widely utilised in clinical practice.What the results of this study add? The results support the clinical findings of most of the studies previously published. No significant differences in gestational outcomes were found between the groups treated with steroid pre-treatments and the control group. Additionally, oestrogen pre-treatment seems to be related to better pregnancy outcomes when the exposition is longer. Thus, an earlier start of this treatment in the luteal phase could be the optimal approach.What the implications are of these findings for clinical practice and/or further research? This study pretends to provide clarity about the treatment guidelines of steroid pre-treatments to schedule the clinical work without impact on gestational outcomes.

Effects of progesterone variation on IVF Progesterone variation during controlled ovarian stimulation: effects on in vitro results.

The objective of this study was to investigate the impact of the progesterone variation (PV) between early progesterone and preovulatory progesterone on pregnancy rate (PR), number of oocytes, and embryo quality. Three hundred and thirty-eight cycles of in vitro fertilisation were included and progesterone was measured on 5th day of stimulation GnRH as well as on the day of induction of ovulation. Fresh embryo transfer (ET) on the second-third day after follicular puncture was made in 152/338 cycles, with positive pregnancies in 61/152 (40%). In the cycles in which ET was cancelled (186/338) higher levels of estradiol and P2 were detected, as well as greater PV and number of oocytes obtained than those made in with fresh transfer. A greater PV was not associated with a worse clinical PR but with a minor embryo quality in the group of 35-37 years old patients.Impact StatementWhat is already known on this subject? Preovulatory progesterone (P2) elevation has been linked to worse results in IVF cycles. It has also been described been reported that there is a lower pregnancy rate (PR) in patients with high progesterone in the early follicular phase (P1). In our study, we measured P1 and P2 to evaluate the possible repercussion of progesterone variation (PV) (ratio of P2 to P1) on PR, a variable that has not previously been analysed.What do the results of this study add? Negative correlation between preovulatory progesterone and embryo quality was found, according to the literature. In the present study, a negative significant correlation between PV and embryo quality was also found, however, only in the group of 35-37 years old women.What are the implications of these findings for clinical practice and/or further research? This could indicate that a rapid increase in progesterone levels after the early follicular phase is related to a lower quality of the obtained embryos, although further studies are required to achieve greater statistical significance.

Breast relapse after metastatic alveolar rhabdomyosarcoma: Is it an incurable entity?

Metastatic breast disease is a very rare condition in children. Rhabdomyosarcoma (RMS) is the most common solid primary tumor in children, but only a few cases of breast metastases have been described. We present the case of a young female with a primary pelvic metastatic alveolar RMS, which metastasized to the breast twice and achieved prolonged complete remission with a multimodal approach.

Drug levels, immunogenicity and assessment of active sacroiliitis in patients with axial spondyloarthritis under biologic tapering strategy.

The aim of the study was to assess drug levels, immunogenicity and sacroiliitis on MRI in patients with axial spondyloarthritis under biologic tapering strategy. Consecutive patients with axial spondyloarthritis who remained in low disease activity more than 1 year after dose tapering of infliximab and adalimumab were included. Plasma drug concentrations of TNF inhibitors and anti-drug antibodies were determined, and MRI of sacroiliac joints was evaluated. Of twenty patients included, eighteen had therapeutic drug levels, no patient had anti-drug antibodies, and no patient had active sacroiliitis on MRI. These data could support the biologic tapering strategy and their maintenance over time.

Cardiac Tamponade Associated with the Presentation of Anaplastic Large Cell Lymphoma in a 2-Year-Old Child.

The anaplastic large cell lymphoma is a rare entity in pediatric patients. We present an unusual case of pericardial involvement, quite uncommon as extranodal presentation of this type of disorder, that provoked a life-risk situation requiring an urgent pericardiocentesis. To our knowledge, this is the first report on a child with pericardial involvement without an associated cardiac mass secondary to anaplastic large cell lymphoma in pediatric age. We report the case of a 21-month-old Caucasian male infant with cardiac tamponade associated with the presentation of anaplastic large cell lymphoma. Initially, the child presented with 24-day prolonged fever syndrome, cutaneous lesions associated with hepatomegaly, inguinal adenopathies, and pneumonia. After a 21-day asymptomatic period, polypnea and tachycardia were detected in a clinical check-up. Chest X-ray revealed a remarkable increase of the cardiothoracic index. The anaplastic large cell lymphoma has a high incidence of extranodal involvement but myocardial or pericardial involvements are rare. For this reason, we recommend a close monitoring of patients with a differential diagnosis of anaplastic large cell lymphoma.

Safety profile of biological intravenous therapy in a rheumatoid arthritis patients cohort. Clinical nursing monitoring (Sebiol study).

INTRODUCTION: The Biologics used in the management of rheumatoid arthritis (RA) in recent years, have comprehensively permitted to understand its security, as shown in registries such as BIOBADASER. The present manuscript represents an observational cohort study to describe the safety perinfusional profile of those intravenous treatments. OBJECTIVES: To confirm the safety profile of biological therapies in routine clinical practice, after the administration of intravenous drugs and 24 hours post-administration. MATERIAL AND METHODS: We evaluated a cross-sectional cohort of 114 patients with RA (according to the American College of Rheumatology ACR criteria), attending within one month in 2009 the nursing clinics of day care hospital of 12 Catalonian hospitals. All patients were treated with intravenous biological agents. We recorded the age, sex, current and previous drug treatments, we also collected data about previous vaccination and premedication received and any adverse event occurring at the time of drug administration or within 24 hours. If an adverse event occurred, was categorized by MedDRAv11.0 International Dictionary, and categorized in terms of intensity (mild, moderate, severe), relationship to drug administration according to Karch and Lasagna algorithm (unrelated, unlikely, possible, probable, definite) and the further measures taken. RESULTS: 111 patients met the inclusion criteria, with a mean age of 56.06 years (SD: 12.12), 90 of them women (81.1%) and mean time since diagnosis of the disease of 11.97 years (SD: 7.95). 24 patients (21.6%) had a history of allergy. 12 adverse events were observed in 7 patients, 9 of which at the time of administration and 3 in 24 hours after. There were no serious adverse events and only one of the adverse events (AEs) was rated as moderate (urticaria). The remaining AA were mild.

Tibolone and risk of endometrial polyps: a prospective, comparative study with hormone therapy.

OBJECTIVE: To assess the incidence of endometrial polyps during postmenopausal replacement therapy with tibolone, using an appropriate control group. DESIGN: A total of 485 postmenopausal women were included in this open, prospective, comparative study for a duration of 36 months. Of this group, 249 women received 2.5 mg/day of tibolone and 244 women served as controls, receiving continuous-combined estrogen-progestogen therapy (HT). Transvaginal ultrasound, hysteroscopy, and directed biopsies were performed before treatment was initiated and at the end of the study. RESULTS: Two hundred twenty-one of the women receiving tibolone and 203 receiving continuous-combined HT completed the study. Endometrial polyps were detected in 74 women (33.4%) from the tibolone group and in 22 women (10.8%) from the HT group (P < 0.01). The vaginal bleeding rate did not differ between the groups. The frequency of atrophic polyps was significantly higher in the tibolone group (P < 0.01). No difference was found in the size of the polyps. CONCLUSIONS: Tibolone increases by threefold the risk for endometrial polyps.

Endometrial intraepithelial neoplasia diagnosed at endometrial resection.

The literature has no reported cases of isolated endometrial intraepithelial neoplasia found at endometrial resection. If endometrial cancer is occult it might not be detected at diagnostic hysteroscopy or during resection, especially if destructive techniques are used. A 51-year-old woman had history of menorrhagia, with diagnostic hysteroscopy showing benign functional endometrium and diagnosed as dysfunctional uterine bleeding. Endometrial resection was performed and the pathologic examination in one stripe of resected tissue found focal, isolated endometrial intraepithelial neoplasia. This case reinforces the importance of pathologic tissue examination after endometrial ablation. Care must be taken when performing second-generation nonhysteroscopic ablation techniques, as even with direct visualization a premalignant lesion can be missed.