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Research question What is the intra- and inter-centre reliability in embryo grading performed according to the Istanbul Consensus across several IVF clinics? Design Forty Day 3 embryos and 40 blastocysts were photographed on three focal planes. Senior and junior embryologists from 65 clinics were invited to grade them according to the Istanbul Consensus (Study Phase I). All participants then attended interactive training where a panel of experts graded the same embryos (Study Phase II). Finally, a second set of pictures was sent to both embryologists and experts for a blinded evaluation (Study Phase III). Intra-centre reliability was reported for Study Phase I as Cohen's kappa between senior and junior embryologists; inter-centre reliability was instead calculated between senior/junior embryologists and experts in Study Phase I versus III to outline improvements after training (i.e. upgrade of Cohen's kappa category according to Landis and Koch). Results Thirty-six embryologists from 18 centres participated (28% participation rate). The intra-centre reliability was (i) substantial (0.63) for blastomere symmetry (range –0.02 to 1.0), (ii) substantial (0.72) for fragmentation (range 0.29–1.0), (iii) substantial (0.66) for blastocyst expansion (range 0.19–1.0), (iv) moderate (0.59) for inner cell mass quality (range 0.07–0.92), (v) moderate (0.56) for trophectoderm quality (range 0.01–0.97). The inter-centre reliability showed an overall improvement from Study Phase I to III, from fair (0.21–0.4) to moderate (0.41–0.6) for all parameters under analysis, except for blastomere fragmentation among senior embryologists, which was already moderate before training. Conclusions Intra-centre reliability was generally moderate/substantial, while inter-centre reliability was just fair. The interactive training improved it to moderate, hence this workflow was deemed helpful. The establishment of external quality assessment services (e.g. UK NEQAS) and the avant-garde of artificial intelligence might further improve the reliability of this key practice for embryo selection.

Introduction: In Italy, the transport of cryopreserved biological material is controlled by several Decrees (Legislative Decree No. 191/2007 and No. 16/2010 and Health Ministry's Decree of October 10, 2012). Given the nature of their applications, the transport of reproductive cells has peculiar quality and safety requirements that must be applied universally, minimizing the chance of error. To standardize the cross-border shipping procedure to meet the quality, traceability, and safety criteria for cells and tissues, it is appropriate to establish a unified process using the same tools, forms, and communication channels. Methods: A working group has been created by SIERR. This "FOCUS Group" was constituted by representatives from Italian-assisted reproductive technology centers and sperm banks who worked together to define joint procedural steps and create specific forms to support the movement of cryopreserved samples. Results: The FOCUS Group identified the critical steps in the communication procedures between Italian centers and created the related forms: patient authorization, request from the recipient center, critical checks carried out by both sending and recipient centers, start of samples transfer, collection, transport and taking responsibility of the biological material, acknowledgment of samples arrival, and acknowledgement of any adverse event that occurred. Discussion: Indications on shipping between tissue institutions and legal responsibilities are important points and a working protocol with shared transport forms has been defined. Standard Operating Procedures are necessary in light of the increasingly widespread movement of biological samples between the various countries, and represent a valid means of support for the patients who could have a higher awareness of safety and traceability during each stage of gamete transport.

A realistic picture of our world shows that it is heavily polluted everywhere. Coastal regions and oceans are polluted by farm fertilizer, manure runoff, sewage and industrial discharges, and large isles of waste plastic are floating around, impacting sea life. Terrestrial ecosystems are contaminated by heavy metals and organic chemicals that can be taken up by and accumulate in crop plants, and water tables are heavily contaminated by untreated industrial discharges. As deadly particulates can drift far, poor air quality has become a significant global problem and one that is not exclusive to major industrialized cities. The consequences are a dramatic impairment of our ecosystem and biodiversity and increases in degenerative or man-made diseases. In this respect, it has been demonstrated that environmental pollution impairs fertility in all mammalian species. The worst consequences are observed for females since the number of germ cells present in the ovary is fixed during fetal life, and the cells are not renewable. This means that any pollutant affecting hormonal homeostasis and/or the reproductive apparatus inevitably harms reproductive performance. This decline will have important social and economic consequences that can no longer be overlooked.

Background: folliculogenesis is a strictly regulated process that may be affected by endocrine disrupting chemicals (EDCs) through sometimes not so clear molecular mechanisms. Methods: we conducted a multicentric observational study involving six fertility centers across Italy, prospectively recruiting 122 women attending a fertility treatment. Recruited women had age ≤42 years, and normal ovarian reserve. Blood and follicular fluid samples were taken for EDCs measurement using liquid chromatography tandem mass spectrometry and each woman completed an epidemiological questionnaire. Results: The main EDCs found were monobutyl phthalate (MBP) (median blood: 8.96 ng/mL, follicular fluid 6.43 ng/mL), monoethylhexyl phthalate (MEHP) (median blood: 9.16 ng/mL, follicular fluid 7.68 ng/mL) and bisphenol A (BPA) (median blood: 1.89 ng/mL, follicular fluid 1.86 ng/mL). We found that serum MBP concentration was significantly associated with the considered area (p < 0.001, adj. mean: 7.61 ng/mL, 14.40 ng/mL, 13.56 ng/mL; Area 1: Milan–Turin, Area 2: Rome–Naples; Area 3: Catania–Bari, respectively) but negatively with home plastic food packaging (p = 0.004). Follicular MBP was associated with irregular cycles (p = 0.019). No association was detected between EDCs and eating habits and other clinical and epidemiological features. Conclusions: This study represents the first Italian biomonitoring of plastic EDCs in follicular fluid, laying the basis for future prospective evaluation on oocyte quality before assisted reproduction techniques (ART).

We describe successful controlled ovarian stimulation (COS) and the first known IVF pregnancy in a trisomy X carrier with associated hypogonadotropic hypogonadism (HH) linked to a chromosome 4 double mutation in the allele of the Gonadotropins Releasing Hormone receptor (GnRHr) gene. Previous administration of low dose of gonadotropins, as recommended in patients with HH, led to poor follicular recruitment. Since trisomy X is a risk factor for diminished ovarian reserve (DOR) and premature ovarian insufficiency (POI), higher doses of gonadotropins led to better ovarian response. The report readknowledges the importance of a correct genetic evaluation in a competent laboratory as a reliable base for treatment planning in this kind of patients.

Carbon monoxide acute intoxication is a common cause of accidental poisoning in industrialized countries and sometimes it produces a real mass casualty incident. The incident described here occurred in a church in the province of Verona, when a group of people was exposed to carbon monoxide due to a heating system malfunction. Fifty-seven people went to the Emergency Department. The mean carboxyhemoglobin (COHb) level was 10.1±5.7% (range: 3-25%). The clinicians, after medical examination, decided to move 37 patients to hyperbaric chambers for hyperbaric oxygen (HBO) therapy. This is the first case report that highlights and analyses the logistic difficulties of managing a mass carbon monoxide poisoning in different health care settings, with a high influx of patients in an Emergency Department and a complex liaison between emergency services. This article shows how it is possible to manage a complex situation with good outcome. (Disaster Med Public Health Preparedness. 2017;11:251–255)

In human IVF, cryopreservation of oocytes has become an alternative to embryo storage. It has also shown enormous potential for oocyte donation, fertility preservation and animal biotechnology. Mouse oocytes have represented the elective model to develop oocyte cryopreservation in the human and over several decades their use has made possible the development of theoretical and empirical approaches. Progress in vitrification has overshadowed slow freezing to such an extent that it has been suggested that vitrification could soon become the exclusive cryopreservation choice in human IVF. However, recent studies have clearly indicated that human embryo slow freezing, a practice considered well established for decades, can be significantly improved by a simple empirical approach. Alternatively, recent and more advanced theoretical models can predict oocyte responses to the diverse factors characterizing an entire slow-freezing procedure, offering a global method for the improvement of current protocols. This gives credit to the notion that oocyte slow freezing still has considerable margins for improvement. In human IVF, cryopreservation of oocytes has become an alternative to embryo storage. It has also shown enormous potential for oocyte donation, fertility preservation and animal biotechnology. Mouse oocytes have represented the elective model to develop oocyte cryopreservation in the human and over several decades their use has made possible the development of theoretical and empirical approaches. Progress in vitrification has overshadowed slow freezing to such an extent that it has been suggested that vitrification could soon become the exclusive cryopreservation choice in human IVF. However, recent studies have clearly indicated that human embryo slow freezing, a practice considered well established for decades, can be significantly improved by a simple empirical approach. Alternatively, recent and more advanced theoretical models can predict oocyte responses to the diverse factors characterizing an entire slow freezing procedure, offering a global method for the improvement of current protocols. This gives credit to the notion that oocyte slow freezing still has considerable margins of improvement.

Polycystic ovary syndrome (PCOS) is often characterized by chronic oligo- or anovulation (usually manifested as oligo- or amenorrhea), and hyperandrogenism. In addition, 30-40% of PCOS women have impaired glucose tolerance, and a defect in the insulin signaling pathway (inositol-containing phosphoglycan mediators) seems to be implicated in the pathogenesis of insulin resistance. PCOS patients are subfertile as a consequence of such ovulatory disorders and often need drugs, such as clomiphene citrate or follicle-stimulating hormone, for ovulation induction, which increases the risk of multiple pregnancy and ovarian hyperstimulation syndrome. We hypothesized that the administration of an isoform of inositol (myo-inositol), belonging to the vitamin B complex, would improve the insulin-receptor activity, restoring normal ovulatory function.Twenty-five PCOS women of childbearing age with oligo- or amenorrhea were enrolled in the study. Ovulatory disorder due to PCOS was apparently the only cause of infertility; no tubal defect or deficiency of male semen parameters was found. Myo-inositol combined with folic acid (Inofolic) 2 g twice a day was administered continuously. During an observation period of 6 months, ovulatory activity was monitored with ultrasound scan and hormonal profile, and the numbers of spontaneous menstrual cycles and eventually pregnancies were assessed.Twenty-two out of the 25 (88%) patients restored at least one spontaneous menstrual cycle during treatment, of whom 18 (72%) maintained normal ovulatory activity during the follow-up period. A total of 10 singleton pregnancies (40% of patients) were obtained. Nine clinical pregnancies were assessed with fetal heart beat at ultrasound scan. Two pregnancies evolved in spontaneous abortion.Myo-inositol is a simple and safe treatment that is capable of restoring spontaneous ovarian activity and consequently fertility in most patients with PCOS. This therapy did not cause multiple pregnancy.

Background Rare copy number variations (CNVs) are today recognized as an important cause of various neurodevelopmental disorders, including mental retardation and epilepsy. In some cases, a second CNV may contribute to a more severe clinical presentation. Results Here we describe a patient with epilepsy, mental retardation, developmental disorders, and dysmorphic features, who inherited a deletion of 16p13.11 and a triplication of 19p13.3 from his father and mother, respectively. The mother presented mild mental retardation and language delay too. Conclusions We discuss the phenotypic consequences of the two CNVs and suggest that their synergistic effect is likely responsible for the complicated clinical features observed in our patient.

Women with polycystic ovary syndrome (PCOS) typically have abnormal gonadotropin secretion and, in 30% of cases, mild and transient hyperprolactinemia. Elevated prolactin (PRL) is found in the late follicular and luteal phases of natural as well as stimulated cycles. Increased levels of both PRL and luteinizing hormone (LH) conceivably reflect a reduced dopamine inhibitory effect. To clarify the influence of dopaminergic control in PCOS, the investigators retrospectively examined the effects of cabergoline, a potent dopamine agonist that inhibits PRL secretion, on the ovarian response to stimulation with recombinant follicle-stimulating hormone (FSH). Enrolled in the study were 44 couples in which the women were diagnosed as having PCOS, in part because of anovulatory infertility and/or oligomenorrhea or amenorrhea. Eighteen women (group A) whose mean serum PRL was 32. 8 ng/ml received 0.25 mg of cabergoline (Dostinex) per week before and during ovarian stimulation. The remaining 26 women (group B), with a mean PRL of 31.3 ng/ml, received no treatment for hyperprolactinemia. For ovarian stimulation investigators used Triptorelin, a gonadotropin-releasing hormone agonist; FSH in an individualized dose; and human chorionic gonadotropin (hCG). The two groups were similar demographically and clinically. The total of 107 ovulatory-stimulated cycles available for study represented approximately 2 ½ per participant. Cabergoline reduced the mean serum prolactin to 12.5 ng/ml at the time stimulation began. Women not given cabergoline received significantly less recombinant FSH per cycle and were stimulated for a shorter time before hCG was given. Their peak serum estradiol levels were significantly higher than in group A women. Serum progesterone levels on the day of hCG treatment did not differ significantly in the two groups. Ultrasonography showed that hyperprolactinemic women developed significantly more follicles of all sizes on the day hCG was given than did those given cabergoline. Mild ovarian hyperstimulation syndrome (OHSS) developed in 6.2% of group B women and 2.4% of those in group A; all these cycles were canceled. There were 8 pregnancies in group A, 3 of them multiple, and 11 in group B, 5 of them multiple; the differences were not significant. These findings agree with the existence of a dopaminergic component in the regulation of LH release in women with PCOS. Pretreatment with the dopamine agonist cabergoline seems to reduce the ovarian response to recombinant FSH without altering the pregnancy rate or the risk of multiple pregnancy. This might be a helpful means of limiting the risk of OHSS.

In view of the frequent absence of symptoms related to pancreatic lesions, screening tests for VHL should always include assessment of the pancreas and, considering the frequency of polycystic manifestations, VHL should always be borne in mind in the differential diagnosis of multiple pancreatic cysts, especially when occurring in young patients and in the absence of a positive history of pancreatic disease. Von Hippel-Lindau disease (VHL) is a hereditary disease transmitted with an autosomal dominant character and characterized by hemangioblastomas of the central nervous system and retina, renal tumors and cysts, and pheochromocytoma. Pancreatic manifestations of VHL are reported in the literature with incidences ranging from 16 to 29% of cases and consist mainly in cystadenomas of the serous type and in multiple cystic lesions, often with complete replacement of the gland. We report five cases of VHL with a polycystic pancreas as the main or only manifestation, all devoid of symptoms related to involvement of the pancreas, who were referred to our Pancreatic Surgery center with diagnoses of multiple pancreatic pseudocysts of undefined origin.

Background. The aim of this study was to evaluate hysteroscopy routinely performed prior to in vitro fertilization-embryo transfer (IVF-ET).Methods. We analyzed in a prospective study 300 patients who underwent hysteroscopy before the first IVF-ET cycle. We analyzed then in a retrospective manner 300 patients who did not perform hysteroscopy.Results. One-hundred-and-eighty (60%) hysteroscopies were normal but 120 (40%) revealed an unsuspected intrauterine abnormality. We did not find statistically significant differences between patients with normal or abnormal hysteroscopy in any characteristic. We found a statistically significant difference in pregnancy rate between women who performed hysteroscopy before IVF-ET cycle and in women who did not perform it.Conclusions. Hysteroscopy, as a routine examination, should be performed before the first IVF-ET cycle in all patients.

In human IVF, cryopreservation of oocytes has become an alternative to embryo storage. It has also shown enormous potential for oocyte donation, fertility preservation and animal biotechnology. Mouse oocytes have represented the elective model to develop oocyte cryopreservation in the human and over several decades their use has made possible the development of theoretical and empirical approaches. Progress in vitrification has overshadowed slow freezing to such an extent that it has been suggested that vitrification could soon become the exclusive cryopreservation choice in human IVF. However, recent studies have clearly indicated that human embryo slow freezing, a practice considered well established for decades, can be significantly improved by a simple empirical approach. Alternatively, recent and more advanced theoretical models can predict oocyte responses to the diverse factors characterizing an entire slow-freezing procedure, offering a global method for the improvement of current protocols. This gives credit to the notion that oocyte slow freezing still has considerable margins for improvement. In human IVF, cryopreservation of oocytes has become an alternative to embryo storage. It has also shown enormous potential for oocyte donation, fertility preservation and animal biotechnology. Mouse oocytes have represented the elective model to develop oocyte cryopreservation in the human and over several decades their use has made possible the development of theoretical and empirical approaches. Progress in vitrification has overshadowed slow freezing to such an extent that it has been suggested that vitrification could soon become the exclusive cryopreservation choice in human IVF. However, recent studies have clearly indicated that human embryo slow freezing, a practice considered well established for decades, can be significantly improved by a simple empirical approach. Alternatively, recent and more advanced theoretical models can predict oocyte responses to the diverse factors characterizing an entire slow freezing procedure, offering a global method for the improvement of current protocols. This gives credit to the notion that oocyte slow freezing still has considerable margins of improvement.

Objective: To determine the effects of myo-inositol on oocyte quality in polycystic ovary syndrome (PCOS) patients undergoing intracytoplasmic sperm injection (ICSI) cycles. Design: A prospective, controlled, randomized trial. Setting: Assisted reproduction centers. Patient(s): Sixty infertile PCO patients undergoing ovulation induction for ICSI. Intervention(s): All participants underwent standard long protocol. Starting on the day of GnRH administration, 30 participants received myo-inositol combined with folic acid (Inofolic) 2 g twice a day and 30 control women received folic acid alone, administrated continuously. Main Outcome Measure(s): Primary end points were number of morphologically mature oocytes retrieved, embryo quality, and pregnancy and implantation rates. Secondary end points were total number of days of FSH stimulation, total dose of gonadotropin administered, E2 level on the day of hCG administration, fertilization rate per number of retrieved oocytes, embryo cleavage rate, live birth and miscarriage rates, cancellation rate, and incidence of moderate or severe ovarian hyperstimulation syndrome. Result(s): Total r-FSH units (1,958 � 695 vs. 2,383 � 578) and number of days of stimulation (11.4 � 0.9 vs. 12.4 � 1.4) were significantly reduced in the myo-inositol group. Furthermore, peak E2 levels (2,232 � 510 vs. 2,713 � 595pg/mL)athCGadministrationweresignificantlylowerinpatientsreceivingmyo-inositol.Themeannumberof oocytes retrieved did not differ in the two groups, whereas in the group cotreated with myo-inositol the mean number of germinal vesicles and degenerated oocytes was significantly reduced (1.0 � 0.9 vs. 1.6 � 1.0), with a trend for increased percentage of oocytes in metaphase II (0.82 � 0.11% vs. 0.75 � 0.15%). Conclusion(s): These data show that in patients with PCOS, treatment with myo-inositol and folic acid, but not folic acid alone, reduces germinal vesicles and degenerated oocytes at ovum pick-up without compromising total number of retrieved oocytes. This approach, reducing E2 levels at hGC administration, could be adopted to decrease therisk of hyperstimulationin such patients. (Fertil Steril� 2009;91:1750‐4. � 2009byAmerican Society for Reproductive Medicine.)