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PurposeSome women undergoing stimulated cycles have elevated serum progesterone (P) on the day of ovulation trigger, but its effect on embryo quality is unclear. We analyze embryo quality among patients with high and low serum P undergoing preimplantation genetic testing for aneuploidy (PGT-A).MethodsThis retrospective study included 1597 patients divided into two groups by serum P values: < 1.5 ng/mL or ≥ 1.5 ng/mL. A gonadotrophin-releasing hormone (GnRH) antagonist protocol was established for each patient. Serum P levels were measured on the day of triggering. Propensity score matching and Poisson regression were done. Age, body mass index, and ovarian sensitivity index were also compared.ResultsElevated serum P was not significantly associated with euploid embryo rate or other embryo-quality variables evaluated in our study. Age was the only variable associated with euploidy rate (per MII oocyte, P < 0.001; per biopsied embryo, P = 0.008), embryo biopsy rate (P < 0.001), absolute number of euploid embryos (P = 0.008), and top-quality embryo rate (P = 0.008). Categorical variables decreased in value for every year of increased age in patients with high serum P.ConclusionsElevated serum P did not affect the number of euploid and good-quality embryos for transfer in GnRH antagonist intracytoplasmic sperm injection (ICSI) cycles. Contrary to the clear influence of premature P elevation on endometrial receptivity based on literature, our results may help to tip the balance towards the absence of a negative effect of P elevation on embryo competence. More studies are needed to fully understand the effect of P elevation on reproductive outcomes.

Despite efforts made to improve the in vitro embryo culture conditions used during assisted reproduction procedures, human embryos must adapt to different in vitro oxygen concentrations and the new metabolic milieu provided by the diverse culture media used for such protocols. It has been shown that the embryo culture environment can affect not only cellular metabolism, but also gene expression in different species of mammalian embryos. Therefore we wanted to compare the metabolic footprint left by human cleavage-stage embryos under two types of oxygen atmospheric culture conditions (6% and 20% O2). The spent culture media from 39 transferred and implanted embryos from a total of 22 patients undergoing egg donation treatment was analyzed; 23 embryos came from 13 patients in the 6% oxygen concentration group, and 16 embryos from 9 patients were used in the 20% oxygen concentration group. The multivariate statistics we used in our analysis showed that human cleavage-stage embryos grown under both types of oxygen concentration left a similar metabolic fingerprint. We failed to observe any change in the net depletion or release of relevant analytes, such as glucose and especially fatty acids, by human cleavage-stage embryos under either type of culture condition. Therefore it seems that low oxygen tension during embryo culture does not alter the global metabolism of human cleavage-stage embryos.

Poor ovarian response (POR) patients often face the risk of not having enough competent oocytes. Then, aspirating small follicles could serve as a strategy to increase their number. Many efforts have been addressed to associate follicular size with oocyte competence, but results are controversial. Therefore, our study aimed to evaluate oocyte maturation and developmental competence, along with a non-invasive oocyte-maturation-related miRNA signature in oocytes retrieved from both large and small follicles. A total of 178 follicles, from 31 POR patients, were aspirated and measured on the day of ovarian puncture. Follicular diameters, oocyte collection, oocyte maturation, fertilization, blastocysts, and good-quality blastocyst rates were recorded. Simultaneously, follicular fluids were collected to quantify their miRNA expression. The efficacy of oocyte retrieval along with oocyte maturation, fertilization, and blastulation rates tended to increase with follicular size, but few significant differences were found. Despite there being significantly more collected oocytes from follicles > 11.5 mm compared to follicles ≤ 11.5 mm (p < 0.05), oocytes from the latter were also mature, with no significant differences in the miRNA signature, but only those > 13.5 mm demonstrated developmental competence. In conclusion, 11.5 mm follicles can produce mature oocytes, but only those larger than 13.5 mm yielded transferable embryos.

PurposeTo investigate whether embryo rebiopsy increases the yield of in vitro fertilization (IVF) cycles.MethodsRetrospective study including 18,028 blastocysts submitted for trophectoderm biopsy and preimplantation genetic testing for aneuploidy (PGT-A) between January 2016 and December 2021 in a private IVF center. Out of the 517 embryos categorized as inconclusive, 400 survived intact to the warming procedure, re-expanded, and were suitable for rebiopsy. Of them, 71 rebiopsied blastocysts were transferred. Factors affecting the probability of obtaining an undiagnosed blastocyst and clinical outcomes from blastocysts biopsied once and twice were investigated.ResultsThe overall diagnostic rate was 97.1%, with 517 blastocysts receiving inconclusive reports. Several blastocyst and laboratory features, such as the day of the biopsy, the stage of development, and the biopsy methodology, were related to the risk of obtaining an inconclusive diagnosis after PGT-A. A successful diagnosis was obtained in 384 of the rebiopsied blastocysts, 238 of which were chromosomally transferable. A total of 71 rebiopsied blastocysts were transferred, resulting in 32 clinical pregnancies [(clinical pregnancy rate (CPR)=45.1%], 16 miscarriages [(miscarriage rate (MR)=41%], and, until September 2020, 12 live births [(live birth rate (LBR)=23.1%]. A significantly lower LBR and higher MR were obtained after transferring rebiopsied blastocysts compared to those biopsied once.ConclusionAlthough an extra round of biopsy and vitrification may cause a detrimental effect on embryo viability, re-analyzing the test-failure blastocysts contributes to increasing the number of euploid blastocysts available for transfer and the LBR.

PurposeDoes vitrification/warming affect the mitochondrial DNA (mtDNA) content and the gene expression profile of blastocysts?MethodsProspective cohort study in which 89 blastocysts were obtained from 50 patients between July 2017 and August 2018. mtDNA was measured in a total of 71 aneuploid blastocysts by means of real-time polymerase chain reaction (RT-PCR). Transcriptomic analysis was performed by RNA sequencing (RNA-seq) in an additional 8 aneuploid blastocysts cultured for 0 h after warming, and 10 aneuploid blastocysts cultured for 4–5 h after warming.ResultsA significant decrease in mtDNA content just during the first hour after the warming process in blastocysts was found (P < 0.05). However, mtDNA content experimented a significantly increased along the later culture hours achieving the original mtDNA levels before vitrification after 4–5 h of culture (P < 0.05). Gene expression analysis and functional enrichment analysis revealed that such recovery was accompanied by upregulation of pathways associated with embryo developmental capacity and uterine embryo development. Interestingly, the significant increase in mtDNA content observed in blastocysts just after warming also coincided with the differential expression of several cellular stress response-related pathways, such as apoptosis, DNA damage, humoral immune responses, and cancer.ConclusionTo our knowledge, this is the first study demonstrating in humans, a modulation in blastocysts mtDNA content in response to vitrification and warming. These results will be useful in understanding which pathways and mechanisms may be activated in human blastocysts following vitrification and warming before a transfer.

We conducted surveillance studies in Sinaloa, Mexico, to determine the circulation of tick-borne relapsing fever spirochetes. We collected argasid ticks from a home in the village of Camayeca and isolated spirochetes. Genomic analysis indicated that Borrelia turicatae infection is a threat to those living in resource-limited settings.

Natural Killer (NK) cells are promising candidates for targeting persistently infected CD4 + T cells in people with HIV-1 (PWH). However, chronicity of HIV-1 infection impairs NK cell functionality, requiring additional strategies to potentiate their cytotoxic activity. This study demonstrates that dendritic cells primed with nanoparticles containing Poly I:C (Nano-PIC-MDDC) enhance the natural cytotoxic function of NK cells from effective responder PWH. These NK cells exhibit increased proportions of NKG2C+ cell subsets capable of eliminating HIV-1 infected CD4 + T cells through the TRAIL receptor. In contrast, in non-responder PWH, elevated expression of the inhibitory receptor TIGIT is associated with reduced frequencies of NKG2C + NK cells and diminished TRAIL expression. TIGIT blockade restores cytotoxicity of NK cells from non-responder PWH against HIV-1-infected cells by upregulating TRAIL. Furthermore, combining Nano-PIC-MDDC-primed NK cells with anti-TIGIT immunotherapy in humanized NSG mice reduces the expansion of HIV-1 infected cells, preserves NKG2C + NK cell precursors and increases TRAIL expression in tissue. Collectively, these findings support the combined use of Nano-PIC-MDDC and TIGIT blockade as a promising immunotherapeutic strategy toward an HIV-1 cure. Synopsis New immunotherapies are needed to target persistent HIV-1 infected cells. Combined stimulation of Natural Killer (NK) cells with dendritic cells primed with nanoparticles loaded with TLR3 agonist Poly I:C (Nano-PIC-MDDC) and TIGIT blockade enhances their cytotoxic function against infected cells. Cytotoxic NK cell function is enhanced by treatment with Nano-PIC-MDDC in a subgroup of effective responder people with HIV (ER-PWH). NK from ER-PWH were characterized by higher proportions of adaptive NKG2C+ NK cells and by increased expression of the receptor TRAIL, required for killing of HIV infected cells. Low responder PWH were characterized by dysfunctional NKs with high expression of the immune checkpoint receptor TIGIT after culture with nano-PIC-MDDC, which could be functionally restored by TIGIT blockade. Efficacy of the combined Nano-PIC MDCCs and TIGIT blockade immunotherapy was confirmed in a pre-clinical humanized NSG-mouse model reducing spread of HIV-1-infected cells by enhanced adaptive NK cells in tissue. New immunotherapies are needed to target persistent HIV-1 infected cells. Combined stimulation of Natural Killer (NK) cells with dendritic cells primed with nanoparticles loaded with TLR3 agonist Poly I:C (Nano-PIC-MDDC) and TIGIT blockade enhances their cytotoxic function against infected cells.

The BICNOW clinical trial evaluated the effectiveness, safety, satisfaction, adherence to treatment, and retention in the system of a rapid initiation strategy with bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) in naïve HIV-infected individuals. It also assessed the burden of this infection on individuals and healthcare systems using various instruments, participant questionnaires, and pharmacoeconomic evaluations of this antiretroviral therapy (ART). This substudy focused on changes in the health-related quality of life (HRQoL) of participants and on the economic impact of this rapid initiation strategy. Patients were recruited for this phase IV, multicenter, open, single-branch clinical trial with 48-week follow-up between November 2020 and July 2022. HRQoL data were gathered using EQ-5D-3L and dichotomized HIV-SI questionnaires. In the cost-utility pharmacoeconomic analysis, data in the literature were used for comparators. The 208 participants had a mean age of 34 (27-44) years, 87·5% were male, 42·9% had completed higher education, and 67·1% were employed. The mean EQ-5D questionnaire score was significantly increased at 48 weeks versus baseline (0·940 ± 0·117 vs. 0·959 ± 0·083, p = 0·012), and the utility value in quality-adjusted life years (QALYs) was 0·877 ± 0·093. There was a significant improvement in the \"usual activities\" dimension (10·8 vs 4·1% p = 0·036). The Moses extreme reaction test showed a significant difference in all dimensions between participants in AIDS versus non-AIDS stage (p < 0·001). HIV-SI results revealed a significantly smaller percentage of participants with bothersome symptoms at 48 weeks (75·4 vs. 62·2%, p = 0·035). The pharmacoeconomic study indicated a value of €6,550·21/QALY gained with this ART. BIC/FTC/TAF is an appropriate rapid initiation strategy in naïve PLHIV that improves their quality of life. It is pharmacoeconomically feasible and offers superior long-term health outcomes in comparison to other approaches. (NCT06177574).

Blood oranges have high concentrations of bioactive compounds that are beneficial to health. In Europe, the cultivation of blood oranges is increasing due to their excellent nutritional properties. In Citrus crops, rootstocks play an important role in juice and can increase the content of bioactive compounds. The morphological, qualitative and nutritional parameters were analyzed in cultivars ‘Tarocco Ippolito’, ‘Tarocco Lempso’, ‘Tarocco Tapi’ and ‘Tarocco Fondaconuovo’ grafted onto Citrus macrophylla and Citrus reshni. ‘Tarocco Lempso’ grafted onto Citrus macrophylla obtained the highest values of weight (275.78 g), caliber (81.37 mm and 76.79 mm) and juice content (162.11 g). ‘Tarocco Tapi’ grafted onto Citrus reshni obtained the most interesting qualitative parameters (15.40 °Brix; 12.0 MI). ‘Tarocco Lempso’ grafted onto Citrus reshni obtained the most intense red juice (a* = 9.61). Overall, the highest concentrations of primary metabolites were in proline, aspartate, citric acid, and sucrose. The results showed that ‘Tarocco Ippolito’ juice grafted onto Citrus reshni had the highest levels of total hydroxycinnamic acids (263.33 mg L−1), total flavones (449.74 mg L−1) and total anthocyanins (650.42 mg L−1). To conclude, ‘Tarocco Lempso’ grafted onto Citrus macrophylla obtained the best values of agronomic parameters, and the cultivars grafted onto Citrus reshni obtained significantly higher concentrations in primary and secondary metabolites.