Implicit bias in diagnosing mosaicism amongst preimplantation genetic testing providers: results from a multicenter study of 36 395 blastocysts.

STUDY QUESTION: Does the diagnosis of mosaicism affect ploidy rates across different providers offering preimplantation genetic testing for aneuploidies (PGT-A)? SUMMARY ANSWER: Our analysis of 36 395 blastocyst biopsies across eight genetic testing laboratories revealed that euploidy rates were significantly higher in providers reporting low rates of mosaicism. WHAT IS KNOWN ALREADY: Diagnoses consistent with chromosomal mosaicism have emerged as a third category of possible embryo ploidy outcomes following PGT-A. However, in the era of mosaicism, embryo selection has become increasingly complex. Biological, technical, analytical, and clinical complexities in interpreting such results have led to substantial variability in mosaicism rates across PGT-A providers and clinics. Critically, it remains unknown whether these differences impact the number of euploid embryos available for transfer. Ultimately, this may significantly affect clinical outcomes, with important implications for PGT-A patients. STUDY DESIGN, SIZE, DURATION: In this international, multicenter cohort study, we reviewed 36 395 consecutive PGT-A results, obtained from 10 035 patients across 11 867 treatment cycles, conducted between October 2015 and October 2021. A total of 17 IVF centers, across eight PGT-A providers, five countries and three continents participated in the study. All blastocysts were tested using trophectoderm biopsy and next-generation sequencing. Both autologous and donation cycles were assessed. Cycles using preimplantation genetic testing for structural rearrangements were excluded from the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: The PGT-A providers were randomly categorized (A to H). Providers B, C, D, E, F, G, and H all reported mosaicism, whereas Provider A reported embryos as either euploid or aneuploid. Ploidy rates were analyzed using multilevel mixed linear regression. Analyses were adjusted for maternal age, paternal age, oocyte source, number of embryos biopsied, day of biopsy, and PGT-A provider, as appropriate. We compared associations between genetic testing providers and PGT-A outcomes, including the number of chromosomally normal (euploid) embryos determined to be suitable for transfer. MAIN RESULTS AND THE ROLE OF CHANCE: The mean maternal age (±SD) across all providers was 36.2 (±5.2). Our findings reveal a strong association between PGT-A provider and the diagnosis of euploidy and mosaicism. Amongst the seven providers that reported mosaicism, the rates varied from 3.1% to 25.0%. After adjusting for confounders, we observed a significant difference in the likelihood of diagnosing mosaicism across providers (P < 0.001), ranging from 6.5% (95% CI: 5.2-7.4%) for Provider B to 35.6% (95% CI: 32.6-38.7%) for Provider E. Notably, adjusted euploidy rates were highest for providers that reported the lowest rates of mosaicism (Provider B: euploidy, 55.7% (95% CI: 54.1-57.4%), mosaicism, 6.5% (95% CI: 5.2-7.4%); Provider H: euploidy, 44.5% (95% CI: 43.6-45.4%), mosaicism, 9.9% (95% CI: 9.2-10.6%)); and Provider D: euploidy, 43.8% (95% CI: 39.2-48.4%), mosaicism, 11.0% (95% CI: 7.5-14.5%)). Moreover, the overall chance of having at least one euploid blastocyst available for transfer was significantly higher when mosaicism was not reported, when we compared Provider A to all other providers (OR = 1.30, 95% CI: 1.13-1.50). Differences in diagnosing and interpreting mosaic results across PGT-A laboratories raise further concerns regarding the accuracy and relevance of mosaicism predictions. While we confirmed equivalent clinical outcomes following the transfer of mosaic and euploid blastocysts, we found that a significant proportion of mosaic embryos are not used for IVF treatment. LIMITATIONS, REASONS FOR CAUTION: Due to the retrospective nature of the study, associations can be ascertained, however, causality cannot be established. Certain parameters such as blastocyst grade were not available in the dataset. Furthermore, certain platform-related and clinic-specific factors may not be readily quantifiable or explicitly captured in our dataset. As such, a full elucidation of all potential confounders accounting for variability may not be possible. WIDER IMPLICATIONS OF THE FINDINGS: Our findings highlight the strong need for standardization and quality assurance in the industry. The decision not to transfer mosaic embryos may ultimately reduce the chance of success of a PGT-A cycle by limiting the pool of available embryos. Until we can be certain that mosaic diagnoses accurately reflect biological variability, reporting mosaicism warrants utmost caution. A prudent approach is imperative, as it may determine the difference between success or failure for some patients. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Torres Quevedo Grant, awarded to M.P. (PTQ2019-010494) by the Spanish State Research Agency, Ministry of Science and Innovation, Spain. M.P., L.B., A.R.L., A.L.R.d.C.L., N.P.P., M.P., D.S., F.A., A.P., B.M., L.D., F.V.M., D.S., M.R., E.P.d.l.B., A.R., and R.V. have no competing interests to declare. B.L., R.M., and J.A.O. are full time employees of IB Biotech, the genetics company of the Instituto Bernabeu group, which performs preimplantation genetic testing. M.G. is a full time employee of Novagen, the genetics company of Cegyr, which performs preimplantation genetic testing. TRIAL REGISTRATION NUMBER: N/A.

Occurrence and limited zoonotic potential of Cryptosporidium spp., Giardia duodenalis, and Balantioides coli infections in free-ranging and farmed wild ungulates in Spain.

Little information is currently available on the occurrence and molecular diversity of the enteric protozoan parasites Cryptosporidium spp., Giardia duodenalis, and Balantioides coli in wild ungulates and the role of these host species as potential sources of environmental contamination and consequent human infections. The presence of these three pathogens was investigated in eight wild ungulate species present in Spain (genera Ammotragus, Capra, Capreolus, Cervus, Dama, Ovis, Rupicapra, and Sus) by molecular methods. Faecal samples were retrospectively collected from free-ranging (n = 1058) and farmed (n = 324) wild ungulates from the five Spanish bioregions. Overall infection rates were 3.0% (42/1382; 95% CI: 2.1-3.9%) for Cryptosporidium spp., 5.4% (74/1382; 95% CI: 4.2-6.5%) for G. duodenalis, and 0.7% (9/1382; 95% CI: 0.3-1.2%) for B. coli. Cryptosporidium infection was detected in roe deer (7.5%), wild boar (7.0%) and red deer (1.5%), and G. duodenalis in southern chamois (12.9%), mouflon (10.0%), Iberian wild goat (9.0%), roe deer (7.5%), wild boar (5.6%), fallow deer (5.2%) and red deer (3.8%). Balantioides coli was only detected in wild boar (2.5%, 9/359). Sequence analyses revealed the presence of six distinct Cryptosporidium species: C. ryanae in red deer, roe deer, and wild boar; C. parvum in red deer and wild boar; C. ubiquitum in roe deer; C. scrofarum in wild boar; C. canis in roe deer; and C. suis in red deer. Zoonotic assemblages A and B were detected in wild boar and red deer, respectively. Ungulate-adapted assemblage E was identified in mouflon, red deer, and southern chamois. Attempts to genotype samples positive for B. coli failed. Sporadic infections by canine- or swine-adapted species may be indicative of potential cross-species transmission, although spurious infections cannot be ruled out. Molecular evidence gathered is consistent with parasite mild infections and limited environmental contamination with (oo)cysts. Free-ranging wild ungulate species would not presumably play a significant role as source of human infections by these pathogens. Wild ruminants do not seem to be susceptible hosts for B. coli.

Vitrification does not affect birth weight: lessons from the oocyte donation model.

RESEARCH QUESTION: Is embryo cryopreservation a cause of high birth weight and large for gestational age (LGA) in singletons resulting from vitrified-warmed embryo transfer? DESIGN: Retrospective cohort study evaluating 670 oocyte recipients who underwent fresh (367 cycles) or vitrified-warmed embryo transfer (303 cycles) at Instituto Bernabeu between July 2017 and March 2019. All single blastocyst transfers carried out in an artificial cycle that resulted in a singleton live birth were included. RESULTS: Maternal age (42.21 ± 4.45; 42.79 ± 3.83; P = 0.519), body mass index (23.34 ± 3.69; 23.80 ± 3.78; P = 0.075), gestational age (38.96 ± 1.97; 38.77 ± 2.15; P = 0.207), maternal smoking (10.8%; 13.0%; P = 0.475), gestational diabetes (4.9%; 4.3% P = 0.854), preeclampsia (2.7%; 5.6%; P = 0.074), hypertensive disorders (3.3%; 2.3%; P = 0.494), maternal parity (multiparous 18.5%; 14.5%; P = 0.177) and liveborn gender (female 44.5%; 48.8%; P = 0.276) were not significantly different between fresh or vitrified-warmed groups. Endometrial thickness was significantly higher in the fresh versus vitrified-warmed group (8.83 ± 1.73 versus 8.57 ± 1.59; P = 0.035, respectively). Oocyte donor height was similar between the fresh versus vitrified-warmed group (163.22 ± 5.88 versus 164.27 ± 6.66 cm; P = 0.057, respectively). Mean birth weight was not significantly different (3239.21 ± 550.43; 3224.56 ± 570.83; adjusted P = 0.058). No differences were observed in macrosomia (7.1%; 6.3%; adjusted OR 0.857, 95% CI 0.314 to 2.340, P = 0.764), LGA (6.0%; 6.7%; adjusted OR 0.450, 95% CI 0.176 to 1.149, P = 0.095), pre-term birth (10.9%; 9.0% adjusted P = 0.997), very pre-term birth (0.8%; 1.3%; adjusted P = 1.000), extremely pre-term birth (0%; 1.0%; adjusted P = 0.998); underweight (10.0%; 7.0%; adjusted P = 0.050); very low weight (0.6; 1.1%; adjusted P = 1.000) and small for gestational age (1.9%; 0.7%; adjusted P = 0.974) between fresh or vitrified-warmed groups. CONCLUSION: This study eliminates potential confounders that might influence fetal growth and demonstrates that embryo vitrification and warming procedures do not affect birth weight.

Titanium - castor oil based polyurethane composite foams for bone tissue engineering.

Polyurethanes (PU) foams with titanium particles (Ti) were prepared with castor oil (CO) and isophorone diisocyanate (IPDI) as polymeric matrix, and 1, 3 and 5 wt.% of Ti. Composites were physicochemically and mechanically characterized and their biocompatibility assessed using human dental pulp stem cells (HDPSC). PU synthesis was confirmed by FTIR, but the presence of Ti was detected by RAMAN, X-ray diffraction (peak at 2θ = 40.2°) and by EDX-mapping. Materials showed three decomposition temperatures between 300 °C and 500 °C and their decomposition were not catalyzed by Ti particles. Compressive modulus (164-846 kPa), compressive strength (12.9-116.7 kPa) and density (128-240 kg/m3) tend to increase with Ti concentration but porosity was reduced (87% to 80%). Composites' foams were fully degraded in acid and oxidative media while remained stable in distilled water. HDPSC viability on all composites was higher than 80% up to 14 days while proliferation dropped up to 60% at 21 days. Overall, these results suggest that these foams can be used as scaffolds for bone tissue regeneration.

Análisis de las posibles interfases producidas en la fijación de postes de fibra de vidrio a la estructura dentaria / Analysis of the possible interfaces produced in the fixation of glass fiber posts to the tooth structure

En este trabajo se analizó el comportamiento de las posibles interfases producidas por algunos medios de fijación en la cementación de postes de fibra de vidrio. Para ello recurrimos a dos experimentos: Visualización microscópica de las posibles interfases y el análisis de la penetración de un colorante en la interfase del complejo dentina/ medio de fijación ­ poste de fibra de vidrio. Se conformaron tres grupos de diez unidades experimentales para cada experimento respectivamente. Los materiales con los que se trabajó presentan algún tipo de adhesión a la estructura dentaria. Ellos son el Cemento de Ionómero vítreo convencional, Cemento de resina con adhesivo dentinario y Cemento resinoso autoacondicionante. Con esta investigación se espera poder determinar cuál es el medio de fijación que posibilite la menor interfase en el complejo dentina-medio de fijación- poste de fibra de vidrio (AU)

In this work the behavior of the possible interfaces produced by some fixation media in the cementation of fiberglass poles was analyzed. To do this we used two experiments: Microscopic visualization of the possible interfaces and the analysis of the penetration of a dye in the interface of the dentin complex / fixation medium - glass fiber post. Three groups of ten experimental units were formed for each experiment, respectively. The materials with which they were worked present some type of adhesion to the dental structure. They are conventional Vitreous Ionomer Cement, Resin Cement with Dentin Adhesive and Self-Adhesion Resin Cement. With this research it is expected to be able to determine which is the fixation medium that allows the smallest interface in the dentine complex-fixation medium-fiber glass post (AU)

Bone regeneration in mandibular fractures after the application of autologous mesenchymal stem cells, a randomized clinical trial.

BACKGROUND/AIM: Facial injury in adults can commonly result in fractures of the mandible. Autologous mesenchymal stem cells (AMSCs) transplantation is proposed as an alternative to conventional graft treatment to improve bone regeneration. The aim was to evaluate the effectiveness of AMSCs application in mandibular fractures to reduce regeneration time and increase bone quality. MATERIALS AND METHODS: This study was a single-blind controlled clinical trial conducted in patients with mandibular angle fractures. Patients were divided into two groups: study group fracture reduction plus application of AMSCs and control group only fracture reduction. AMSCs were obtained from adipose tissue 24 h before the procedure. Intensity and density were evaluated in normal bone and fractured bone at 4 and 12 weeks after surgery using panoramic radiography and computed tomography. RESULTS: A total of 20 patients, 10 in each group, were included. The study group had a mean age of 31.2 ± 6.3 years, and the control group mean age was 29.7 ± 7.2 years. All patients were male. Bone quality measured in grey levels at week 4 was 108.82 ± 3.4 vs 93.92 ± 2.6 (P = 0.000) using panoramic radiography and 123 ± 4.53 vs 99.72 ± 5.72 (P = 0.000) using computed tomography. At week 12, the measurements were 153.53 ± 1.83 vs 101.81 ± 4.83 (P = 0.000) using panoramic radiography and 165.4 ± 4.2 vs 112.9 ± 2.0 (P = 0.000) using tomography in the study and control groups, respectively. CONCLUSION: Similar ossification values were obtained after 4 weeks when the use of AMSCs was compared to simple fracture reduction. However, after 12 weeks, the AMSCs group had a 36.48% higher ossification rate.

Androgen receptor CAG repeat length is associated with ovarian reserve but not with ovarian response.

The human androgen receptor (AR) gene contains a highly polymorphic CAG repeat sequence within exon 1. In-vitro studies have shown a relationship between CAG repeats in the AR gene and its transactivation potential. This variation in length may play a role in anovulatory infertility. The objective of this study was to investigate whether CAG polymorphism of the AR gene has a predictive value for ovarian reserve, response and cycle outcome in an egg donor programme. CAG length of the AR gene was determined in 147 oocyte donors. All donors underwent ovarian stimulation with a gonadotrophin-releasing hormone antagonist protocol (n = 355). No differences were reported in days of stimulation, gonadotrophin doses, and number of oocytes retrieved. Clinical outcomes were not affected by the CAG repeat length of the AR gene; the primary end-point, antral follicle count, was significantly affected (P < 0.05). In conclusion, in a population of fertile egg donors AR gene CAG polymorphism does not affect ovarian response to gonadotrophins. Antral follicle count was associated with the CAG polymorphism genotype. This suggests that genetic factors may increase susceptibility to poor ovarian reserve, and that AR gene genotype could play a role in the natural ovarian ageing process.

Effect of surgically removing subcutaneous fat by abdominoplasty on leptin concentrations and insulin sensitivity.

The aim of this study was to identify the effect of surgically removing subcutaneous fat by abdominoplasty on leptin concentrations and insulin sensitivity. An open clinical trial with a noninterventional parallel group was carried out in 12 obese women. After randomization, 6 volunteers were selected for abdominoplasty, and the other 6 women were considered as the noninterventional group. A metabolic profile, including leptin concentrations, and insulin tolerance test to assess insulin sensitivity were performed on all volunteers before intervention or nonintervention and 40-50 days afterward. A significant reduction in body mass index (30.7 +/- 0.9 versus 29.6 +/- 0.7 kg/m; P = 0.02) and in leptin concentrations (41.3 +/- 10.6 versus 32.0 +/- 10.2 ng/mL; P = 0.02) was observed after abdominoplasty. Insulin sensitivity did not change after intervention. In conclusion, surgically removing subcutaneous fat by abdominoplasty decreased leptin concentrations, with no change in insulin sensitivity.

Frecuencia de hemorragia intracraneana en niños hemofílicos / Intracranial hemmorrhage frequency in patients hemophilic

La hemorragia intracraneana es la principal causa de muerte entre los pacientes hemofílicos. Por esta razón se revisaron 75 expedientes clínicos de pacientes menores de 16 años con el diagnóstico de hemofilia. Se encontraron seis niños con hemorragia intracraneana (HIC). El tiempo de inicio de la sintomatología fue de 12 h hasta cuatro días con una media de 39 h. Los signos y síntomas encontrados fueron: cefalea, vómito, crisis convulsiva, hematoma en el sitio del traumatismo, hemiperesia corporal izquierda, nistagmus, náusea. Se dio tratamiento substitutivo en todos los niños. Cuatro presentaron secuelas neurológicas. La frecuencia de HIC se estimó en 8 por ciento de los hemofílicos. Se concluye que para prevenir la muerte y minimizar las secuelas, una terapia de reemplazo adecuada, ésta debe ser instituida tan pronto como se sospecha el sangrado o inmediatamente después del traumatismo craneoencefálico