Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance.

Mitofusin 2 (MFN2) plays critical roles in both mitochondrial fusion and the establishment of mitochondria-endoplasmic reticulum (ER) interactions. Hypothalamic ER stress has emerged as a causative factor for the development of leptin resistance, but the underlying mechanisms are largely unknown. Here, we show that mitochondria-ER contacts in anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus are decreased in diet-induced obesity. POMC-specific ablation of Mfn2 resulted in loss of mitochondria-ER contacts, defective POMC processing, ER stress-induced leptin resistance, hyperphagia, reduced energy expenditure, and obesity. Pharmacological relieve of hypothalamic ER stress reversed these metabolic alterations. Our data establish MFN2 in POMC neurons as an essential regulator of systemic energy balance by fine-tuning the mitochondrial-ER axis homeostasis and function. This previously unrecognized role for MFN2 argues for a crucial involvement in mediating ER stress-induced leptin resistance.

Ovarian response and embryo ploidy following oral micronized progesterone-primed ovarian stimulation versus GnRH antagonist protocol. A prospective study with repeated ovarian stimulation cycles.

STUDY QUESTION: Is there any difference in ovarian response and embryo ploidy following progesterone-primed ovarian stimulation (PPOS) using micronized progesterone or GnRH antagonist protocol? SUMMARY ANSWER: Pituitary downregulation with micronized progesterone as PPOS results in higher number of oocytes retrieved and a comparable number of euploid blastocysts to a GnRH antagonist protocol. WHAT IS KNOWN ALREADY: Although the GnRH antagonist is considered by most the gold standard protocol for controlling the LH surge during ovarian stimulation (OS) for IVF/ICSI, PPOS protocols are being increasingly used in freeze-all protocols. Still, despite the promising results of PPOS protocols, an early randomized trial reported potentially lower live births in recipients of oocytes resulting following downregulation with medroxyprogesterone acetate as compared with a GnRH antagonist protocol. The scope of the current prospective study was to investigate whether PPOS with micronized progesterone results in an equivalent yield of euploid blastocysts to a GnRH antagonist protocol. STUDY DESIGN, SIZE, DURATION: In this prospective study, performed between September 2019 to January 2022, 44 women underwent two consecutive OS protocols within a period of 6 months in a GnRH antagonist protocol or in a PPOS protocol with oral micronized progesterone. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 44 women underwent two OS cycles with an identical fixed dose of rFSH (225 or 300 IU) in both cycles. Downregulation in the first cycles was performed with the use of a flexible GnRH antagonist protocol (0.25 mg per day as soon as one follicle of 14 mm) and consecutively, after a washout period of 1 month, control of LH surge was performed with 200 mg of oral micronized progesterone from stimulation Day 1. After the completion of both cycles, all generated blastocysts underwent genetic analysis for aneuploidy screening (preimplantation genetic testing for aneuplody, PGT-A). MAIN RESULTS AND THE ROLE OF CHANCE: Comparisons between protocols did not reveal differences between the duration of OS. The hormonal profile on the day of trigger revealed statistically significant differences between protocols in all the tested hormones except for FSH: with significantly higher serum E2 levels, more elevated LH levels and higher progesterone levels in PPOS cycles as compared with antagonist cycles, respectively. Compared with the GnRH antagonist protocol, the PPOS protocol resulted in a significantly higher number of oocytes (12.7 ± 8.09 versus 10.3 ± 5.84; difference between means [DBM] -2.4 [95% CI -4.1 to -0.73]), metaphase II (9.1 ± 6.12 versus 7.3 ± 4.15; DBM -1.8 [95% CI -3.1 to -0.43]), and 2 pronuclei (7.1 ± 4.99 versus 5.7 ± 3.35; DBM -1.5 [95% CI -2.6.1 to -0.32]), respectively. Nevertheless, no differences were observed regarding the mean number of blastocysts between the PPOS and GnRH antagonist protocols (2.9 ± 2.11 versus 2.8 ± 2.12; DBM -0.07 [95% CI -0.67 to 0.53]) and the mean number of biopsied blastocysts (2.9 ± 2.16 versus 2.9 ± 2.15; DBM -0.07 [95% CI -0.70 to 0.56]), respectively. Concerning the euploidy rates per biopsied embryo, a 29% [95% CI 21.8-38.1%] and a 35% [95% CI 26.6-43.9%] were noticed in the PPOS and antagonist groups, respectively. Finally, no difference was observed for the primary outcome, with a mean number of euploid embryos of 0.86 ± 0.90 versus 1.00 ± 1.12 for the comparison of PPOS versus GnRh antagonist. LIMITATIONS, REASONS FOR CAUTION: The study was powered to detect differences in the mean number of euploid embryos and not in terms of pregnancy outcomes. Additionally, per protocol, there was no randomization, the first cycle was always a GnRH antagonist cycle and the second a PPOS with 1 month of washout period in between. WIDER IMPLICATIONS OF THE FINDINGS: In case of a freeze-all protocol, clinicians may safely consider oral micronized progesterone to control the LH surge and patients could benefit from the advantages of a medication of oral administration, with a potentially higher number of oocytes retrieved at a lower cost, without any compromise in embryo ploidy rates. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by an unrestricted grant from Theramex. N.P.P. has received Research grants from Merck Serono, Organon, Ferring Pharmaceutical, Roche, Theramex, IBSA, Gedeon Richter, and Besins Healthcare; honoraria for lectures from: Merck Serono, Organon, Ferring Pharmaceuticals, Besins International, Roche Diagnostics, IBSA, Theramex, and Gedeon Richter; consulting fees from Merck Serono, Organon, Besins Healthcare, and IBSA. M.d.M.V., F.M., and I.R. declared no conflicts of interest. TRIAL REGISTRATION NUMBER: The study was registered at Clinical Trials Gov. (NCT04108039).

Prenatal screening after preimplantation genetic testing for aneuploidy: time to evaluate old strategies.

RESEARCH QUESTION: How does first-trimester aneuploidy screening perform in pregnancies achieved through IVF with preimplantation genetic testing for aneuploidy (PGT-A) in a medical setting? DESIGN: This retrospective cohort study was undertaken in a single tertiary care centre between January 2013 and June 2022. In total, 20,237 women had prenatal follow-up at the study centre and were included in the study. The women were divided into three groups: singleton pregnancies conceived through the transfer of a PGT-A-screened euploid embryo (n = 510); singleton pregnancies conceived through IVF without PGT-A (n = 3291); and singleton pregnancies conceived naturally (n = 16,436). RESULTS: The conventional combined screening test for pregnancies conceived through IVF with PGT-A had specificity of 91%; sensitivity could not be calculated as there were no cases of fetal aneuploidy in this group. In 89.1% of pregnancies conceived through IVF with PGT-A with high risk for trisomy 21, 18 or 13, the result was related to advanced maternal age (>35 years at time of screening). CONCLUSIONS: The current screening strategy for trisomies 21, 18 and 13 can generate unnecessary tests in pregnancies achieved through IVF with PGT-A. A new protocol is needed for these patients, with greater weight given to ultrasound markers.

Predicting the likelihood of live birth: an objective and user-friendly blastocyst grading system.

RESEARCH QUESTION: Can day-5 blastocysts be ranked according to their likelihood of live birth using an objective and user-friendly grading system? DESIGN: A retrospective multicentre study conducted between 2017 and 2019, including 1044 day-5 blastocysts. Blastocyst expansion degree, trophectoderm and inner cell mass quality were assessed morphologically and morphometrically. Several analyses were conducted: the association between the qualitative and quantitative assessment for the blastocyst expansion degree and the number of trophectoderm cells; the effect of the embryo quality on day 3 and the contribution of the three blastocyst parameters to live birth, with logistic regression; and a decision tree with the most significant variables to create the new scoring system. RESULTS: Cut-off points were found to discriminate between expanding and expanded blastocysts (165 µm for blastocyst diameter) and between trophectoderm grades (A: ≥14 cells; B: 11-13 cells; C: ≤10 cells). When the embryos reached the blastocyst stage, their quality on day 3 did not add predictive value for implantation and live birth. In the logistic regression analysis, the only parameter capable of significantly predicting the live birth likelihood was the trophectoderm grade: A versus C (OR 1.95, 95% CI 1.26 to 3.0); B versus C (OR 1.71, 95% CI 1.22 to 2.4). The decision tree supported the finding that the trophectoderm grade had the highest predictive value for a live birth, followed by the blastocyst expansion degree in a second step. CONCLUSIONS: This new method makes objective blastocyst assessment feasible, allowing for standardization and exportation to other laboratories worldwide.

Analyzing multiple acoustic diffraction over a wide barrier using equivalent knife-edge geometries and Babinet's principle (L).

We present a new method for the calculation of the multiple acoustic diffraction caused by the presence of a wide barrier. Our solution decomposes the initial scenario into an equivalent sum of geometries that only consider knife-edges. Then, by applying Babinet's principle, the total acoustic field that reaches the receiving point, which can be located at an arbitrary position, can be calculated via the uniform theory of diffraction. This method is mathematically less complex and computationally more efficient than most existing techniques. The results are validated (with and without ground reflection) by the solid agreement obtained with other solutions that solve the problem by considering the wide barrier as such, with our proposed method yielding a lower computational time (except against semi-empirical formulations) and better accuracy when compared with measurements. The presented solution can be applied in urban environments where the impact of traffic noise on residential buildings located along roads or highways needs to be evaluated, as well as in scenarios in which the insertion loss caused by a rectangular obstacle, such as a noise barrier, is to be calculated.

Characterization of a Piezoelectric Acoustic Sensor Fabricated for Low-Frequency Applications: A Comparative Study of Three Methods.

Piezoelectric transducers are widely used for generating acoustic energy, and choosing the right radiating element is crucial for efficient energy conversion. In recent decades, numerous studies have been conducted to characterize ceramics based on their elastic, dielectric, and electromechanical properties, which have improved our understanding of their vibrational behavior and aided in the manufacturing of piezoelectric transducers for ultrasonic applications. However, most of these studies have focused on the characterization of ceramics and transducers using electrical impedance to obtain resonance and anti-resonance frequencies. Few studies have explored other important quantities such as acoustic sensitivity using the direct comparison method. In this work, we present a comprehensive study that covers the design, manufacturing, and experimental validation of a small-sized, easy-to-assemble piezoelectric acoustic sensor for low-frequency applications, using a soft ceramic PIC255 from PI Ceramic with a diameter of 10 mm and a thickness of 5 mm. We present two methods, analytical and numerical, for sensor design, followed by experimental validation, allowing for a direct comparison of measurements with simulated results. This work provides a useful evaluation and characterization tool for future applications of ultrasonic measurement systems.

Constrained IoT-Based Machine Learning for Accurate Glycemia Forecasting in Type 1 Diabetes Patients.

Individuals with diabetes mellitus type 1 (DM1) tend to check their blood sugar levels multiple times daily and utilize this information to predict their future glycemic levels. Based on these predictions, patients decide on the best approach to regulate their glucose levels with considerations such as insulin dosage and other related factors. Nevertheless, modern developments in Internet of Things (IoT) technology and innovative biomedical sensors have enabled the constant gathering of glucose level data using continuous glucose monitoring (CGM) in addition to other biomedical signals. With the use of machine learning (ML) algorithms, glycemic level patterns can be modeled, enabling accurate forecasting of this variable. Constrained devices have limited computational power, making it challenging to run complex machine learning algorithms directly on these devices. However, by leveraging edge computing, using lightweight machine learning algorithms, and performing preprocessing and feature extraction, it is possible to run machine learning algorithms on constrained devices despite these limitations. In this paper we test the burdens of some constrained IoT devices, probing that it is feasible to locally predict glycemia using a smartphone, up to 45 min in advance and with acceptable accuracy using random forest.

Fetal Megacystis: Associated Structural Abnormalities and Obstetric Outcomes.

Purpose: We evaluated the obstetrical outcomes, ultrasonographic characteristics, and final diagnosis in pregnancies with fetal megacystis (FM). Methods: We evaluated the obstetrical outcomes and associated structural abnormalities of fetuses with FM detected between FM between 2000 and 2021. Results: 17 FM were diagnosed, 16 had follow up. 16 were early megacystis. 14/16 (87.5%) of pregnancies were terminated, 1/16 (6.25%) resulted in intrauterine death, and 1/16 (6.25%) survived. FM was associated with 13 other abnormal sonographic findings in 12/16 (75%) pregnancies. The most common associated ultrasound abnormality was umbilical cord cyst in 3/16 (18.75%). Recognized etiologies included posterior urethral valves (2), trisomy 18 (2), trisomy 13 (1), Prune Belly syndrome (1), and Megacystis-Microcolon-Hypoperistalsis syndrome (1). Conclusion: Most FM are detected in the 2nd trimester, most are electively terminated, are associated with other ultrasonic abnormalities in 75%, most commonly umbilical cord cyst, and have an identifiable cause in 44%.

Blastocyst versus cleavage embryo transfer improves cumulative live birth rates, time and cost in oocyte recipients: a randomized controlled trial.

RESEARCH QUESTION: Does embryo transfer day (day 5 versus day 3) affect cumulative live birth rates (CLBR), time to live birth (TLB) and cost per live birth (CPL) in recipients of donated oocytes? STUDY DESIGN: A single-centre RCT conducted between April 2017 and August 2018. Recipients of donated oocytes were randomized to cleavage-stage (day 3) or to blastocyst-stage (day 5) embryo transfer. Eligible recipients were aged 18-50 years and in their first or second synchronous cycle. Primary outcome was CLBR (12 months from first embryo transfer), and fresh and subsequent cryopreserved transfers were considered; TLB and CPL were also analysed. RESULTS: Recipients (n = 134) were randomized to the day-3 group (n = 69) or to the day-5 group (n = 65). Day-5 transfer resulted in a 15.9% relative increase in CLBR and a significant shorter TLB compared with day-3 transfer. To reach a 50% CLBR, the day-3 group required 6 months more than the day-5 group (15.3 versus 8.9 months, respectively). The average CPL in the day-3 strategy cost 24% more than the day-5 strategy (€14817.10 versus €10959.20). Clinical pregnancy rate was 25% less in the day-3 group. The trial was prematurely stopped after poor initial results in the day-3 arm led to unplanned interim analysis. CONCLUSIONS: The transfer of blastocyst-stage embryos in recipients of donated oocytes is preferred as it leads to a higher clinical pregnancy rate, live birth rate, shorter time to pregnancy and lower costs to achieve live birth, compared with cleavage-stage embryo transfer.

Relevance of biometals during neuronal differentiation and myelination: in vitro and in vivo studies.

Biometals are essential during the development of the central nervous system (CNS) since they participate in the organization and regulation of multiple processes related with the proper organization and functioning of brain structures. Neuronal differentiation is a specialized and complex process that occurs actively from embryonic development to the first years of life and is even maintained in specific areas of the mammalian adult brain. In this review, we focus on describing the cellular and molecular mechanisms of trace biometals such as iron (Fe), zinc (Zn), copper (Cu), and manganese (Mn) on neuronal specialization, comprising from brain uptake to effects on synaptogenesis, axonal outgrowth, myelination, and cellular and neurochemical phenotype determination. We highlight the relevance of biometals in the proper brain functioning by discussing some of the potentially detrimental effects when biometal dyshomeostasis occurs in the brain. Finally, future directions are proposed for exploring the relevance of biometals in brain function using pharmacological, molecular, and analytical approaches.

Recurrence Rate and Morbidity after Ultrasound-guided Transvaginal Aspiration of Ultrasound Benign-appearing Adnexal Cystic Masses with and without Sclerotherapy: A Systematic Review and Meta-analysis.

OBJECTIVE: To determine the pooled recurrence rate of benign adnexal masses/cysts (namely simple cyst, endometrioma, hydrosalpinx, peritoneal cyst) after transvaginal ultrasound-guided aspiration, with or without sclerotherapy. DATA SOURCES: Search of studies published in PubMed and Web of Science databases between January 1990 and December 2020. METHODS OF STUDY SELECTION: A systematic search strategy was done using Medical Subject Heading terms. Only randomized trials and prospective studies published in English language were included. TABULATION, INTEGRATION, AND RESULTS: A total of 395 articles were screened. After applying inclusion and exclusion criteria, 20 studies were included in this review comprising data from 1386 patients with a mean follow-up of 11.4 months (range 0.5-26.5 months). The overall pooled rate of recurrence of adnexal masses was 27%, (95% confidence interval [CI], 18%-39%). Recurrence rate was significantly higher after only aspiration than after sclerotherapy (53%; 95% CI, 46%-60% vs 14%; 95% CI, 8%-22%; p <.001). However, a high heterogeneity across the studies was found. A total of 10 major complications were recorded in the different publications. CONCLUSION: In a selected population, aspiration with sclerotherapy had a lower recurrence rate than aspiration without sclerotherapy. However, these results should be interpreted with caution given the heterogeneity of the studies and the paucity of randomized controlled trials. Regarding the adoption of this procedure in routine clinical practice, we believe that aspiration should be considered an experimental procedure as there are few studies addressing long-term recurrence rate, and data comparing this technique with surgical cystectomy are lacking.

The Reproducibility of Ultrasonographic Findings of Rectosigmoid Endometriosis Among Examiners With Different Level of Expertise.

OBJECTIVE: To analyze the reproducibility of ultrasonographic (US) findings of rectosigmoid endometriosis among examiners with different level of expertise using stored three-dimensional (3D) volumes of the posterior compartment of the pelvis as a part of SANABA (Sardinia-Navarra-Barcelona) collaborative study. MATERIALS AND METHODS: Six examiners in 3 academic Department of Obstetrics and Gynecology, with different levels of experience and blinded to each other, evaluated 60 stored 3D volumes from the posterior compartment of the pelvis and looked for the presence or absence of features of rectosigmoid endometriotic lesions defined as an irregular hypoechoic nodule with or without hypoechoic foci at the level of the muscularis propria of the anterior wall rectum sigma. Multiplanar view and virtual navigation were used. All examiners had to assess the 3D volume of posterior compartment of the pelvis and classify it as present or absent disease. To analyze intra-observer and the inter-observer agreements, each examiner performed the assessment twice with a 2-week interval between the first and second assessments. Reproducibility was assessed by calculating the weighted Kappa index. RESULTS: Intra-observer reproducibility was moderate to very good for all observers (Kappa index ranging from 0.49 to 0.96) associated with a good diagnostic accuracy of each reader. Inter-observer reproducibility was fair to very good (Kappa index range: 0.21-0.87). CONCLUSIONS: The typical US sign of rectosigmoid endometriosis is reasonably recognizable to observers with different level of expertise when assessed in stored 3D volumes.

Maternal and perinatal outcomes in women ≥40 years undergoing induction of labor compared with women <35 years: Results from 4027 mothers.

AIM: Cesarean section is known to be increased with advanced maternal age in women undergoing induction of labor (IOL), but there is less information regarding other possible adverse maternal and fetal outcomes. METHODS: Retrospective cohort study of singleton, nulliparous, at-term women undergoing IOL between January 2007 and September 2020. Outcomes studied were: cesarean section, failed induction rate, fetal distress, post-partum hemorrhage, post-partum hysterectomy, and need of transfusion. Neonatal variables analyzed were: Apgar score, umbilical cord pH, need of admission to neonatal intensive care unit, and mortality. RESULTS: A total of 4027 women met the inclusion criteria; 1968 (48.9%) of mothers were <35 years, 1283 (31.9%) were 35-39 years, 658 (16.3%) were 40-44 years, and 118 (2.9%) were ≥45 years. Results showed a significantly increased incidence of c-section in women ≥35 years, with an OR 1.79 (95% CI 1.50-2.14) for women 40-44 years and OR 3.95 (95% CI 2.66-5.98) for women ≥45 years. The main indication for cesarean delivery was failed IOL, and this risk was also significantly increased in women ≥40 years. These differences remained significant after adjustment for confounding factors. No other adverse maternal or fetal outcomes showed an association with age. CONCLUSION: Maternal age ≥40 years was associated with an increased risk of c-section after IOL at term compared with younger women, mainly because of failed induction, but no association with other adverse maternal or neonatal outcomes were found in our population. Risks and benefits of IOL in older women should be individually evaluated and adequately discussed with mothers.

The effect of trophectoderm biopsy technique and sample handling on artefactual mosaicism.

PURPOSE: To determine whether embryo mosaicism prevalence in preimplantation genetic testing for aneuploidy (PGT-A) cycles is associated with the trophectoderm biopsy technique used (a. number of laser pulses or b. the use of flicking or pulling) or the time to tubing. METHODS: Prospective observational study performed in a single IVF-PGT-A setting from May 2019 to May 2021. Trophectoderm biopsies were analysed by next-generation sequencing. Mosaicism was analysed in relation to the biopsy methodology (number of laser pulses and pulling vs flicking), time elapsed from biopsy to tubing (min), and time of sample cryostorage from tubing to amplification (days). As a secondary objective, the number of laser pulses and biopsy methodology were studied in relation to clinical outcomes of transferred euploid blastocysts. RESULTS: None of the analysed variables were associated to mosaicism prevalence. Multivariable regression analysis demonstrated that mosaicism prevalence was comparable either when  > 3 laser pulses were used as compared to ≤ 3 (13.9% vs 13.8%, aOR = 0.8726 [0.60-1.28]) and pulling compared to flicking (13.1% vs 14.0%, aOR = 0.86 [0.60-1.23]). Moreover, neither the number of laser pulses during biopsy (> 3 vs ≤ 3) nor the technique used (pulling vs flicking) were associated with clinical pregnancy after the transfer of frozen-thawed euploid blastocysts (54.9% vs 55.2%, aOR = 1.05 [0.53-2.09]; 61.1% vs 52.9%, aOR = 1.11 [0.55-2.25], respectively). CONCLUSION: Our results suggest that, as long as the biopsy and tubing procedures are performed following standardized high quality procedures, no specific approach would increase the generation of artefactual mosaicism as a result of trophectoderm biopsy. Trophectoderm biopsies should be performed regardless of the methodology but always aiming on minimising blastocyst manipulation.

Individualised luteal phase support in artificially prepared frozen embryo transfer cycles based on serum progesterone levels: a prospective cohort study.

STUDY QUESTION: Does an individualised luteal phase support (iLPS), according to serum progesterone (P4) level the day prior to euploid frozen embryo transfer (FET), improve pregnancy outcomes when started on the day previous to embryo transfer? SUMMARY ANSWER: Patients with low serum P4 the day prior to euploid FET can benefit from the addition of daily subcutaneous P4 injections (Psc), when started the day prior to FET, and achieve similar reproductive outcomes compared to those with initial adequate P4 levels. WHAT IS KNOWN ALREADY: The ratio between FET/IVF has spectacularly increased in the last years mainly thanks to the pursuit of an ovarian hyperstimulation syndrome free clinic and the development of preimplantation genetic testing (PGT). There is currently a big concern regarding the endometrial preparation for FET, especially in relation to serum P4 levels around the time of embryo transfer. Several studies have described impaired pregnancy outcomes in those patients with low P4 levels around the time of FET, considering 10 ng/ml as one of the most accepted reference values. To date, no prospective study has been designed to compare the reproductive outcomes between patients with adequate P4 the day previous to euploid FET and those with low, but restored P4 levels on the transfer day after iLPS through daily Psc started on the day previous to FET. STUDY DESIGN, SIZE, DURATION: A prospective observational study was conducted at a university-affiliated fertility centre between November 2018 and January 2020 in patients undergoing PGT for aneuploidies (PGT-A) IVF cycles and a subsequent FET under hormone replacement treatment (HRT). A total of 574 cycles (453 patients) were analysed: 348 cycles (leading to 342 euploid FET) with adequate P4 on the day previous to FET, and 226 cycles (leading to 220 euploid FET) under iLPS after low P4 on the previous day to FET, but restored P4 levels on the transfer day. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall we included 574 HRT FET cycles (453 patients). Standard HRT was used for endometrial preparation. P4 levels were measured the day previous to euploid FET. P4 > 10.6 ng/ml was considered as adequate and euploid FET was performed on the following day (FET Group 1). P4 < 10.6 ng/ml was considered as low, iLPS was added in the form of daily Psc injections, and a new P4 analysis was performed on the following day. FET was only performed on the same day when a restored P4 > 10.6 ng/ml was achieved (98.2% of cases) (FET Group 2). MAIN RESULTS AND THE ROLE OF CHANCE: Patient's demographics and cycle parameters were comparable between both euploid FET groups (FET Group 1 and FET Group 2) in terms of age, weight, oestradiol and P4 levels and number of embryos transferred. No statistically significant differences were found in terms of clinical pregnancy rate (56.4% vs 59.1%: rate difference (RD) -2.7%, 95% CI [-11.4; 6.0]), ongoing pregnancy rate (49.4% vs 53.6%: RD -4.2%, 95% CI [-13.1; 4.7]) or live birth rate (49.1% vs 52.3%: RD -3.2%, 95% CI [-12; 5.7]). No significant differences were also found according to miscarriage rate (12.4% vs 9.2%: RD 3.2%, 95% CI [-4.3; 10.7]). LIMITATIONS, REASONS FOR CAUTION: Only iLPS through daily Psc was evaluated. The time for Psc injection was not stated and no serum P4 determinations were performed once the pregnancy was achieved. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides information regarding an 'opportunity window' for improved ongoing pregnancy rates and miscarriage rates through a daily Psc injection in cases of inadequate P4 levels the day previous to FET (P4 < 10.6 ng/ml) and restored values the day of FET (P4 > 10.6 ng/ml). Only euploid FET under HRT were considered, avoiding one of the main reasons of miscarriage and implantation failure and overcoming confounding factors such as female age, embryo quality or ovarian stimulation protocols. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received. B.C. reports personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, IBSA and Gedeon Richter outside the submitted work. N.P. reports grants and personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, Theramex and Besins International and personal fees from IBSA and Gedeon Richter outside the submitted work. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NCT03740568.

Prevalence, types and possible factors influencing mosaicism in IVF blastocysts: results from a single setting.

RESEARCH QUESTION: Are intrinsic or extrinsic factors associated with embryo mosaicism prevalence in IVF cycles? DESIGN: Retrospective cohort study of preimplantation genetic testing for aneuploidy (PGT-A) cycles carried out at a university-affiliated IVF clinic between October 2017 and October 2019. Trophectoderm biopsies were analysed by next generation sequencing. Mosaicism prevalence, type of anomaly and the chromosomes involved were analysed. Intrinsic and extrinsic factors potentially inducing mosaicism were studied: maternal and paternal age, antral follicle count, cumulus-oocyte complexes retrieved, female body mass index, PGT-A indication, sperm concentration, total dosage of gonadotrophins, embryo quality and day of blastocyst formation, single-step commercial media used and biopsy operator. RESULTS: Overall prevalence of mosaicism in our PGT-A setting was 13.9%. In segmental mosaicism, larger chromosomes tended to be more affected, which was not observed in whole-chromosome mosaicism. Additionally, segmental mosaicism was mostly observed in monosomy (69.6%; P < 0.01) compared with whole-chromosome mosaicism (49.7% monosomies versus 50.3% trisomies; P = 0.83). Although a high inter-patient variability was observed, only paternal age showed a positive association with mosaicism (adjusted OR 1.26, 95% CI 1.02 to 1.54) among the analysed variables. CONCLUSIONS: Our results suggest remarkable differences in the mechanisms generating segmental and whole-chromosome mosaicism, indicating that they may deserve different consideration when studying them and when prioritizing them for transfer. Male factor seems to be associated with mosaicism and may be worthy of specific assessment in future studies.

Metabolomic diferences between COVID-19 and H1N1 influenza induced ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by lung inflammation and pulmonary edema. Coronavirus disease 2019 (COVID-19) is associated with ARDS in the more severe cases. This study aimed to compare the specificity of the metabolic alterations induced by COVID-19 or Influenza A pneumonia (IAP) in ARDS. METHODS: Eighteen patients with ARDS due to COVID-19 and twenty patients with ARDS due to IAP, admitted to the intensive care unit. ARDS was defined as in the American-European Consensus Conference. As compared with patients with COVID-19, patients with IAP were younger and received more often noradrenaline to maintain a mean arterial pressure > 65 mm Hg. Serum samples were analyzed by Nuclear Magnetic Resonance Spectroscopy. Multivariate Statistical Analyses were used to identify metabolic differences between groups. Metabolic pathway analysis was performed to identify the most relevant pathways involved in ARDS development. RESULTS: ARDS due to COVID-19 or to IAP induces a different regulation of amino acids metabolism, lipid metabolism, glycolysis, and anaplerotic metabolism. COVID-19 causes a significant energy supply deficit that induces supplementary energy-generating pathways. In contrast, IAP patients suffer more marked inflammatory and oxidative stress responses. The classificatory model discriminated against the cause of pneumonia with a success rate of 100%. CONCLUSIONS: Our findings support the concept that ARDS is associated with a characteristic metabolomic profile that may discriminate patients with ARDS of different etiologies, being a potential biomarker for the diagnosis, prognosis, and management of this condition.

Severe pain during hysterosalpingo-contrast sonography (HyCoSy): a systematic review and meta-analysis.

PURPOSE: To assess the frequency of severe pain perception during hysterosalpingo-contrast sonography (HyCoSy) in infertile women and to assess whether there are differences in the frequency of associated pain according to the contrast used. DESIGN: Systematic review and meta-analysis. PATIENTS: Women undergoing HyCoSy due to infertility. INTERVENTIONS: Searches were carried out in two databases (Pubmed and Web of Science). We included prospective or retrospective cohort observational studies that specified the type of contrast used during HyCoSy and reported data regarding the number of patients who perceived severe pain during the procedure and the scale used for pain perception score. MAIN OUTCOME MEASURES: Pooled frequency of severe pain perception during HyCoSy and the pooled frequency of severe pain perception based on the contrast used. RESULTS: Twenty-nine studies were included in this meta-analysis including a total of 7139 patients. In 10 studies, Saline solution with air was used as contrast EchoVist™ was used in ten studies, in five studies, SonoVue™ was used and in four studies, ExEm-Foam™ was used as contrast. Pooled estimated frequency of severe pain perception during HyCoSy was 6% (95% CI 4-9). No statistically significant differences have been described regarding frequency of severe pain perception in relation to the different contrasts used. CONCLUSIONS: HyCoSy is a tolerable outpatient procedure. We did not find any evidence that one specific contrast was better tolerated than any other was.

G2-S16 Polyanionic Carbosilane Dendrimer Can Reduce HIV-1 Reservoir Formation by Inhibiting Macrophage Cell to Cell Transmission.

Human immunodeficiency virus (HIV-1) is still a major problem, not only in developing countries but is also re-emerging in several developed countries, thus the development of new compounds able to inhibit the virus, either for prophylaxis or treatment, is still needed. Nanotechnology has provided the science community with several new tools for biomedical applications. G2-S16 is a polyanionic carbosilane dendrimer capable of inhibiting HIV-1 in vitro and in vivo by interacting directly with viral particles. One of the main barriers for HIV-1 eradication is the reservoirs created in primoinfection. These reservoirs, mainly in T cells, are untargetable by actual drugs or immune system. Thus, one approach is inhibiting HIV-1 from reaching these reservoir cells. In this context, macrophages play a main role as they can deliver viral particles to T cells establishing reservoirs. We showed that G2-S16 dendrimer is capable of inhibiting the infection from infected macrophages to healthy T CD4/CD8 lymphocytes by eliminating HIV-1 infectivity inside macrophages, so they are not able to carry infectious particles to other body locations, thus preventing the reservoirs from forming.

Cognitive impairment in patients with central nervous system tuberculosis.

INTRODUCTION: Tuberculosis (TB) in Mexico remains an important cause of morbidity and mortality; in the past 4 years, 110,681 cases of pulmonary tuberculosis and 1571 cases of tuberculous meningitis were reported. OBJECTIVE: To determine the neurocognitive sequelae, clinical presentation and neuroimaging alterations in patients with central nervous system tuberculosis. METHODS: A retrospective, analytical, and cross-sectional study was carried out from 2010 to 2019. Patients with central nervous system tuberculosis, with and without HIV/AIDS coinfection, were included. RESULTS: During the study period, 104 cases with a definitive or probable central nervous system tuberculosis diagnosis were included; 38% had HIV/AIDS coinfection, and 55%, various comorbidities (p = 0.0001); 49% had cognitive alterations, and 14% died. CONCLUSIONS: Although HIV/AIDS infection can contribute to cognitive decline in patients with tuberculous meningitis, no differences were observed between patients with and without HIV/AIDS. Cognitive sequelae showed improvement during follow-up with adequate management and therapeutic control of the patients.

INTRODUCCIÓN: La tuberculosis en México sigue siendo causa importante de morbimortalidad; en los últimos cuatro años, se reportaron 110 681 casos de tuberculosis pulmonar y 1571 casos de tuberculosis meníngea. OBJETIVO: Determinar las secuelas neurocognoscitivas, presentación clínica y alteraciones en los estudios de neuroimagen en pacientes con tuberculosis del sistema nervioso central. MÉTODOS: Se realizó un estudio retrospectivo, analítico y transversal de 2010 a 2019. Se incluyeron pacientes con tuberculosis del sistema nervioso central, con y sin coinfección por VIH/sida. RESULTADOS: Durante el periodo de estudio se incluyeron 104 casos con diagnóstico definitivo y probable de tuberculosis del sistema nervioso central; de acuerdo con los criterios de Marais, 38 % presentó coinfección por VIH/sida y 55 %, diversas comorbilidades (p = 0.0001); 49 % presentó alteraciones cognoscitivas y 14 % falleció. CONCLUSIONES: Aunque la infección por VIH/sida puede contribuir al deterioro cognitivo del paciente con tuberculosis meníngea, no se observaron diferencias entre pacientes con y sin VIH/sida. Las secuelas cognoscitivas mostraron mejoría en el seguimiento con el adecuado manejo y control terapéutico de los pacientes.