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This comparative non-interventional study using data from the French National Health Database (Système National des Données de Santé) investigated real-world (cumulative) live birth outcomes following ovarian stimulation, leading to oocyte pickup with either originator recombinant human follicle-stimulating hormone (r-hFSH) products (alfa or beta), r-hFSH alfa biosimilars, or urinaries including mainly HP-hMG (menotropins), and marginally u-hFSH-HP (urofollitropin). Using data from 245,534 stimulations (153,600 women), biosimilars resulted in a 19% lower live birth (adjusted odds ratio (OR) 0.81, 95% confidence interval (CI) 0.76-0.86) and a 14% lower cumulative live birth (adjusted hazard ratio (HR) 0.86, 95% CI 0.82-0.89); and urinaries resulted in a 7% lower live birth (adjusted OR 0.93, 95% CI 0.90-0.96) and an 11% lower cumulative live birth (adjusted HR 0.89, 95% CI 0.87-0.91) versus originator r-hFSH alfa. Results were consistent across strata (age and ART strategy), sensitivity analysis using propensity score matching, and with r-hFSH alfa and beta as the reference group.

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The Outcome study examines the fate of 4083 patients beginning IVF in 41 IVF centres, between January 2010 and December 2013. Cumulative live birth rate per patient (CLBR), the best reflection of IVF efficacy, is rarely presented in publications as it requires long-term follow-up, including all successive cycles, and pregnancies outcome. Analysis of international publications shows an average CLBR of 41.6 % and a drop-out rate of 49.5 %, both greatly varying by country and IVF centres. Because of the frequency with which patients change centre (8%), the Outcome study distinguishes patients with a past history of IVF in another centre (CLBR=47.2 %) and patients undergoing their first true cycle (CLBR=56.4 %). Survival techniques by Competing Risk, intended to take account of drop-out and lost to follow-up, assessed the overall CLBR as being 65.4 %. Differences in performance between centres are considerable for both CLBR (32-64%) and Performance Index, taking account of the number of cycles required to achieve a pregnancy (2-5). Multiple variance logistic regression analysis shows that the indicators influencing performance are age, parity, number of oocytes, smoking habit and overweight. These indicators are independent each other and are influencing performance in a high significant way. After adjusting for these indicators, the differences between centres are reduced but remain large and very significant. No centre appears to have specific expertise in the management of patients with adverse indicators. The Outcome study therefore confirms that the large differences in performance between centres are not explained by a difference in the treated population.

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OBJECTIVES: The main objective of this study was to describe the ovulation rate in patients with polycystic ovary syndrome, treated with ovulation induction/intra-uterine insemination and follitropin alfa by gonadotrophins at a second attempt. METHODS: An observational, national and multicentre study was carried out: 51 French physicians (endocrinologists, gynaecologists) participated. Eligible patients were followed according to the usual clinical practices. The primary endpoint was the number of ovulations (spontaneous or triggered). Quality of life evaluation (by FertiQoL), compliance, and patient satisfaction were secondary endpoints. RESULTS: A total of 202 patients (mean age: 29.9 years; mean infertility: 2.9 years) were included: 78.4% met the Rotterdam definition. The ovulation rate was 93.3% (95% confidence interval [89.8; 96.8]%). At 12 weeks of gestation, 38 patients had an ongoing pregnancy. A difference of 10 points of the mean total FertiQoL score was observed between the two attempts. No patient reported missing injection. More than 9 in 10 patients said they were satisfied to very satisfied with the use of the pen injector for administration of follitropin alfa. Eight patients (4.0%) had hyperstimulation leading to cycle cancellation, and two patients (1.1%) reported ovarian hyperstimulation syndrome. CONCLUSIONS: At the second cycle of follitropin alfa stimulation, a high rate of ovulations, satisfactory compliance and tolerance profile associated with a change in quality of life were reported.

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OBJECTIVE: The present study was conducted in order to describe the variations and circadian rhythm of biochemical markers of bone remodelling at baseline and after weight gain in patients with anorexia nervosa (AN). SUBJECTS: We studied 9 women (mean age 21 years, range: 16-30) with established AN who remained amenorrhoeic during the study and with a low body mass index (BMI) after refeeding and 6 female controls (mean age 20 years, range, 18-24 and BMI: 20.6 +/- 1.1 kg/m2). Refeeding was not associated with any other intervention or treatment, especially oestrogen replacement or hormonal contraception. Serum levels of oestradiol remained below 70 pmol/l before and after refeeding. MEASUREMENTS: During the study, PTH and 25-hydroxyvitamin D measurements were performed. Markers of bone formation: serum intact osteocalcin (iBGP) and serum intact BGP + fragments (iBGP+F) and markers of bone resorption: urine C-teloptide of type I collagen (uCTX) and serum C-telopeptide ofvtype 1 collagen (s-CTX) were measured. RESULTS: At baseline, PTH and 25 OH-vitamin D concentrations were within the normal range in AN patients and no significant variation was observed after refeeding. Bone formation markers were found to be significantly different at baseline between AN patients and controls. After refeeding, iBGP and iBGP+F levels increased by 172% and 154%, respectively, to values no different from controls. Intact BGP and iBGP+F exhibited a significant circadian variation in controls (P < 0.05 and P < 0.002, respectively), whereas we did not find any such circadian rhythm in AN patients. After refeeding no significant circadian variation was observed; however, iGBP+F tended to peak in early morning and exhibited a nadir in the afternoon. At baseline, sCTX was 2-fold higher in AN patients than in controls. After weight gain sCTX decreased significantly and reached control values. Refeeding induced a non-significant 40% decrease in uCTX. We found positive correlations between uCTX and the 24-h mean value of sCTX levels (r2 = 0.93, P < 0.0001) and between uCTX and the mean value of sCTX peak levels at 0800 h (r2 = 0.65, P < 0.0003). Serum CTX exhibited a significant circadian variation in controls (P < 0.001) with a peak at 0800 h and a nadir at 1600 h with a 60% decrease between peak and nadir values. We found that anorexia nervosa suppressed the sCTX circadian variation which was restored by refeeding. We found a significant non-linear relationship between BMI and sCTX/iBGP ratio in AN (r2 = 0.6, P < 0.0001), thus illustrating the influence of nutritional status on bone remodelling. CONCLUSIONS: In this study we found that weight gain, related to refeeding only, reversed the anorexia nervosa-induced uncoupling of bone remodelling and restored circadian variation of a bone resorption marker.

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Invasive candidiasis infections remain a major complication in I.C.U. patients. Numerous attempts have been made to evaluate potential prophylactic methods. Various agents have been tested. Gastrointestinal tract constitutes one of the major reservoirs for Candida species. One major problem is the difficulty in establishing an accurate, early, diagnosis of invasive fungal infection. A prospective randomized, controlled blind study was performed to assess the ability of oral Amphotericin B to prevent candidiasis in selected I.C.U. patients. Fifty one patients with serious infection and antibiotherapy were randomized to receive either oral Amphotericin B (2 g/day) or placebo, and observed until discharge. All patients were screened weekly for sites culture positive, sero-conversion and oesophagitis. Invasive candidiasis developed in 45% of patients receiving Amphotericin B compared with 41% receiving placebo. C. Albicans persists in the surveillance cultures. However a significant reduction of the colonization by the yeasts and a significant reduction of oesophagitis was demonstrated among the Amphotericin B group. No benefit was found in the total number of hospital days. Digestive decontamination can be successfully managed by Amphotericin B in I.C.U. patients but failed to prevent invasive candidiasis.

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Whole cell preparations derived from collagenase-treated rat liver were cocultivated overnight with stationary (non-shaking) cultures of L5178Y/TK+/- cells in the presence of 8 different chemicals selected as representative aromatic amine, polycyclic hydrocarbon, or nitrosamine procarcinogens. When tested in the presence of hepatocytes, 2-aminoanthracene, 2-aminofluorene, N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosodipropylamine, 3-methylcholanthrene, and benzo[a]pyrene all produced substantial dose-dependent increases in trifluorothymidine-resistant variants compared to solvent controls after 20 h total exposure time. Only N-nitrosodipropylamine (DPrN) and N-nitrosodiethylamine (DEN) produced any dose-related mutagenic activity in similar experiments where hepatocytes were omitted; however, the response for the DPrN was quite variable at high doses in the absence of hepatocytes and the mutagenic response for the DEN was consistently enhanced at all dose levels by the presence of hepatocytes. Benzanthracene was not active in the presence of whole hepatocytes, even when tested with cells from a rat pretreated 24 h earlier with 20 mg/kg benzanthracene. Excepting benzanthracene, these data suggest that rat hepatocytes can be used to active 3 types of procarcinogens to mutagens in the L5178Y/TK gene mutation assay.

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Eight procarcinogens including three nitrosamines, three polycyclic hydrocarbons, and two aromatic amines were tested for mutagenic potential at the thymidine kinase (TK) locus in L5178Y mouse lymphoma cells co-cultivated with viable hamster hepatocytes. All eight chemicals produced substantial mutagenic activity as indicated by increased trifluorothymidine resistance in L5178Y cells treated in the presence of hepatocytes. Mutagenic responses to benzo[alpha]pyrene, 3-methylcholanthrene, N-nitrosodiethylamine, and N-nitrosodipropylamine first increased, then plateaued within the range of mutagen concentrations tested, while consistent dose-dependent increases in mutant frequencies were observed following 2-aminoanthracene, 2-aminofluorene, or N-nitrosodimethylamine treatments. The relatively flat portions of the mutant frequency curves for benzo[alpha]pyrene and 3-methylcholanthrene coincided with maximum chemical solubility as obvious from visible or microscopically detectable precipitate. These hamster cells readily facilitated the metabolism of 1,2-benzanthracene to a detectable mutagen and were especially competent in the activation of the two aromatic amines. Thus, cultured hamster hepatocytes can activate a variety of chemical carcinogens including polycyclic hydrocarbons to mutagens in a whole cell-mediated in vitro assay using L5178Y/TK+/- cells as the target organism.

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Both sodium ascorbate and ascorbic acid were tested at millimolar concentrations in the mouse lymphoma L5178Y TK+/- cell for chemically-induced cytotoxicity and the induction of gene mutations at the thymidine kinase locus as detected by increased trifluorothymidine-resistance. Neither chemical caused any dose-related increases in trifluorothymidine resistance, even at toxic levels. Increased hydrogen ion concentration was not itself a contributing factor to ascorbic acid toxicity. Ascorbate toxicity was due to products formed in vitro in the absence of cells via chemical reactions with medium components. The formation or persistence of these toxic substances could be prevented by co-incubation with catalase prior to the addition of L5178Y cells. These results suggest that ascorbic acid would not be a mammalian cell mutagen normal physiological conditions.

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Direct treatment of L5178Y mouse lymphoma TK+/- cells with N-acetyl-2-aminofluorene (AAF) from two commercial sources produced small, but reproducible increases in mutant frequency over background in the absence of exogenous microsomal enzymes. Unlike most direct-acting mutagens which typically produce regular, dose-dependent increases in mutant frequency; AAF treatment caused very slight dose-related increases or a saturation phenomenon which could be overcome by increased exposure time. Direct mutagenicity following prolonged (24h) exposure was confirmed when a third highly purified (99.9%) AAF sample was tested. Microsomal enzyme analyses of disrupted L5178Y cell preparations revealed negligible benzo[a]pyrene hydroxylase but measurable AAF-N-hydroxylase activity. These data demonstrate that L5178Y mouse lymphoma cells are capable of limited metabolism of AAF to an active mutagen.

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L5178Y/TK +/- cells treated with methyl methanesulfonate (MMS) were allowed to recover for 0,48,96,144, or 240 hours, and were then plated in soft-agar medium containing trifluorothymidine (TFT). Dose-dependent and consistent increases in the frequency of TFTR cells were observed after each of the 48-240-hour expression periods through the counting of predominantly large, mutant colonies. Size distributions of soft-agar colonies from either MMS-treated or control cells were bimodal in the presence, and unimodal in the absence, of TFT. An increase of small, presumptive TFTR colonies with either increasing MMS concentration or decreasing recovery time was probably a manifestation of chemical toxicity, for a similar increase in small-colony number was observed in the absence of TFT when cells were cloned immediately after MMS treatment, when no induced mutants were yet detectable. Recloning experiments with 22 small-colony-derived cell lines revealed that, with one exception, small-colony morphology was not a heritable trait. While all large- and some small-colony-derived stocks from MMS-treated cells were of the phenotypically stable TK-/- type; spontaneous small TFTR colonies generally were not, their occurrence being directly correlated with serum concentration. No aneuploidy was evident in MMS-treated cell lines several generations after isolation as small TFTR colonies. These results suggest that delayed MMS cytotoxicity in TK +/- cells can temporarily produce increased physiological resistance to TFT in some cells, giving rise to secondary populations of small-colony TFTR variants.

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The L5178Y Mouse Lymphoma TK assay was studied extensively to determine if this mammalian cell assay for gene mutations at the thymidine kinase (TK) locus could provide valid, interpretable determinations of mutagenic potential, and whether this information is of value in the safety evaluation of chemicals. We first determined that test-derived TFTR mutants were phenotypically stable, possessing little or no thymidine kinase activity as measured by labeled thymidine uptake, but demonstrating 100% cross resistance to bromodeoxyuridine. Common solvent vehicles such as acetone, dimethylsulfoxide and ethanol were shown to produce little cytotoxicity and no mutagenic activity when present at 1% levels. Out of a total of 10 noncarcinogens tested, all were negative when results were analyzed by a 2-sample loge t test on control and treated mutant count means. Of the 13 putative animal carcinogens tested, 10 were positive, 2 were negative (auramine O and sodium phenobarbital), and 1 showed sporadic activity (hydrazine sulfate) in the TK assay on the basis of test-derived t statistics. 2 compounds, 1,2-epoxybutane and ICR 191, which have been described as Ames positive non-carcinogens, were also positive in the TK assay. Although this sampling of a total of 29 compounds is insufficient for precise estimations of expected false-positive or false-negative frequencies, these data indicate the TK assay can be expected to detect a majority of carcinogens as mutagens including some missed by more established point-mutation assays.

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7 inorganic metal salts including magnesium chloride, cadmium chloride, nickel chloride, zinc chloride, cobalt(II) chloride, lead acetate, sodium arsenate, and the platinum coordination complex, trans-platinum(II) diaminedichloride, were tested for the potential to induce trifluorothymidine-resistant (TFTRes) mutants in L5178Y/TK+/- mouse lymphoma cell by directly exposing cells to varied doses of each compound for 3 h. Of these 8 chemicals, cadmium chloride, nickel chloride, and trans-platinum(II) diaminedichloride consistently produced dose-related increases in the absolute number of TFTRes mutants as well as increases in mutation frequencies at compound concentrations permitting greater than 20% survival. Trans-platinum(II) diaminedichloride was a particularly effective mutagen, comparable to the direct-acting mutagen, methyl methanesulfonate. 15 representative TFTRes mutant cell clones derived from cultures originally treated with either the cadmium, or nickel, or platinum compounds were first grown out for 7 days in nonselective medium, then verified as phenotypically stable TK-/- mutants by demonstrated cross-resistance to 5-bromodeoxyuridine and 100% sensitivity to the folate antagonist methotrexate in THMG medium. These results demonstrate that the soluble salts of 2 metals reported to be human carcinogens and 1 noble metal complex known to bind DNA are all mammalian cell mutagens as well.

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We have systematically evaluated the mouse lymphoma TK+/- leads to TK-/- mutagenesis assay to determine if this somatic-cell test system would be a useful addition to the routine screening battery already used in our laboratory for the detection of chemical mutagens. During these investigations we observed that, with certain modifications of the basic assay, mutagenicity data could be obtained in as little as 9 days once the relative cytotoxic properties of the test substance were known. By improving the culturing conditions, we were able to reduce the serum requirements by as much as 50--75% without appreciably altering either cell viability or the recovery of chemically-induced mutants. Phenotypic stability of test-derived trifluorothymidine resistant (TFTR) mutants was confirmed by demonstrating cross-resistance to bromodeoxyuridine and concomitant sensitivity to methotrexate (THMG) in TFTR cells grown for 20 generations under non-selective conditions. While reduced growth rates resulting from temporary cell-division delay in treated cells is probably not a contributing factor to the observed mutation frequencies, only TFTR colonies which formed large distinct colonies in the presence of trifluorothymidine were clearly phenotypically stable mutants when spontaneous mutants were isolated and verified. When a non-mutagen, a weak mutagen, and a well-established mutagen were compared at equitoxic doses under these modified conditions, clear quantitative differences were seen in the respective mutation frequencies induced by these 3 types of agents. With these technical modifications, we feel this assay is both reliable and amenable to the screening of diverse chemical compounds for point-mutational activity in a mammalian cell.

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