Assessment of operator performance during oocyte retrievals: residents' learning curve and continuous monitoring of senior physicians.

BACKGROUND: The learning curve cumulative summation test (LC CUSUM test) allows to define an individualized learning curve and determine the moment when clinical proficiency is attained. After acquisition of the skills, the cumulative summation test (CUSUM test) allows to monitor the maintenance of the required level over time. The LC CUSUM test has been frequently used in the field of Obstetrics and Gynecology (Ob/Gyn) for several procedures, but only once for OR. METHODS: We performed a retrospective study at Angers university hospital between May 2017 and September 2018. Seven Ob/Gyn residents and 5 senior physicians were included, and all OR performed during that time (n = 690) were analyzed. The performance index assessed was the oocyte retrieval rate (ORR), defined as the ratio of oocytes retrieved to follicles aspirated. We used the LC CUSUM test to analyze the learning curves of residents, and the CUSUM test to monitor the performance of senior physicians. An ORR ≥50% in 60% of retrievals was defined as the threshold for clinical proficiency. RESULTS: Six hundred seventy-four oocyte retrieval (OR) were included: 315 were performed by residents, 220 by senior physicians, and 139 by both residents and physicians (mixed retrievals). Four residents (57%) reached the threshold after aspirating 82, 67, 53 and 46 ovaries, respectively. The mean number of ovaries aspirated in order to reach clinical proficiency was 62, and the mean number of weeks needed was 21. The duration of the learning period varied between 26 and 80 days. Two senior physicians (40%) remained proficient across the duration of the study, while two physicians (40%) had one statistically "suboptimal" OR, and one physician (20%) had two suboptimal retrievals. CONCLUSION: There is a large variability in the duration of the learning period and the number of procedures needed for a resident to master OR. Senior physicians maintain an adequate performance.

Surgical treatment of septate uterus in cases of primary infertility and before assisted reproductive technologies.

Septate uterus is the most common congenital uterine malformation in women with infertility. Several criteria are available for the definition of septate uteri, such as the one proposed by the European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynecological Endoscopy (ESGE) (ESHRE/ESGE), or by the American Society for Reproductive Medicine (ASRM), with notable differences between the two. Recently, a simplified classification was proposed by the Congenital Uterine Malformations Experts (CUME), where a septum is defined as an internal indentation depth≥10mm. To date, there is no consensus on the management of women with a septate uterus and infertility. We have performed an extensive literature appraisal and reviewed all the available international guidelines in order to propose a management strategy for infertile patients with a uterine septum. Hysteroscopic septum incision seems to improve natural conception rates in the year following surgery. Moreover, it improves in vitro fertilization (IVF) outcomes when performed before the embryo transfer, by improving embryo implantation rates. On the other hand, for patients with an arcuate uterus (indentation<1.5cm according to the ASRM guidelines) and infertility, it seems that assisted reproductive technologies are the most appropriate first line treatment. However, in cases of recurrent implantation failure or recurrent pregnancy loss following IVF, hysteroscopic section could be proposed. Overall, we recommend hysteroscopic septum incision for patients with primary infertility, and for patients undergoing assisted reproductive technologies.

[In vitro fertilization versus conversion to intrauterine insemination in patients with poor response to controlled ovarian hyperstimulation]. / Réponse insuffisante à la stimulation en vue de FIV : maintenir la ponction ou choisir l' insémination ?

In women undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF), a poor ovarian response, defined as three of fewer mature follicles, can lead to cancellation of the cycle. However, in women with at least one patent tube and normal semen parameters, conversion to intrauterine insemination (IUI) is considered an option, offering reasonable pregnancy rates at a lower cost and without the complications associated with oocyte retrieval. Studies have shown that in cycles with only one mature follicle, IVF should be canceled. However, in cycles with 2 or 3 mature follicles, patients have the choice between IVF and conversion to IUI. Some studies have shown that IVF is superior to IUI in such cases, whereas other reports failed to find any difference. Most of these studies are retrospective and limited by the presence of several biases and low numbers of cycles, and to this date, there is no consensus on the best approach. We have thus designed a multicenter, randomized non-inferiority study, comparing live birth rates following conversion to IUI or IVF in patients with 2 or 3 mature follicles in COH cycles. Nine hundred and forty patients will be randomized on trigger day to either IVF or conversion to IUI. Our study will also include a medico-economic analysis.

[Alzheimer's disease and pharmacists in contact with the public]. / La maladie d'Alzheimer et les pharmaciens en contact avec le public.

All healthcare professionals are concerned by Alzheimer's disease, which in France will affect, in just a few years, over one million persons, mainly women. Pharmacists have shown particular interest, irrespective of their sector of activity. Here, we wanted to better define the role of colleagues who are constantly in contact with the public, i.e. in France in drug dispensaries and biology laboratories. Within the framework of the French pharmacy committee for health and social education, Cespharm, the Ethics and Communications working group of the 2008-2012 Alzheimer Disease Committee headed by Professor Joël Menard proposed a project worksheet which can be used by French pharmacists in their action to help Alzheimer patients and their caregivers. This project, prepared by Fabienne Blanchet, the Cespharm director and Christine Curty, mission head, was approved by the Menard commission and is inscribed in the National Alzheimer Plan 2008-2012 presented by this commission in November 2007. Here, our objective is to motivate pharmacists to participate in a structured initial and continuing training program proposed by specialists from the School of Pharmacy and other organizations duly approved by the High Committee for Continuing Education in Pharmacy. In keeping with the general operative procedures of Cespharm, information tools should be developed for colleagues and the public. Available interventions, in terms of prevention, diagnosis and treatment should be updated permanently and transmitted to professionals. Information which can be delivered to patients, and most importantly to their caregivers, concerning local assistance programs should be collected and transmitted to the local professionals. The role of the pharmacist can be summarized with four verbs: listen, reassure, orient, support. It is important to identify all available means enabling a confidential relationship with the persons needing help. Of particular interest are the relationship guides which have been developed to help allied professionals adapt their approach to the patient without evoking the diagnosis, which belongs to the medical physician. Finally, we emphasize the importance of the creation of multidisciplinary local networks where healthcare professionals, medicosocial workers, local public authorities, and patient groups and associations can unite their efforts to develop personalized assistance for patients and caregivers. We also mention the evaluation of the actions undertaken, their funding, and the remuneration of colleagues who devote time to these actions. Pharmacists have a special role to play in the assistance for persons suffering from Alzhiemer's disease and other neurodegenerative diseases. More than four million persons visit drug dispensaries or biology laboratories every day in France. These persons often confide in our colleagues, sharing their worries and problems related not only to their medical condition, but also to their psychological and social environment. We should provide our colleagues with the necessary means to fulfill their mission of assistance to patients and families suffering from a poorly understood disease. We encourage pharmacists to participate in the major public health action initiated by the President of the Republic and well defined in the Alzheimer Plan 2008-2012.

[Blood screening of glucose and lipid disorders as coronary atherosclerosis risks factors in French adolescents 16 to 19-20 years old]. / Dépistage des anomalies sanguines glucidolipidiques à risque coronarien, de 16 à 19-20 ans. A propos d'une enquête menée chez 599 jeunes volontaires.

A screening of fasting blood glucose and lipids disorders, presumely linked to premature atherosclerosis namely affecting Coronary arteries, has been performed among 599 adolescents of both sexes with the goal of establishing the actual prevalence of these disorders in French population recruited through different areas of the country. All of them were between ages of 16 and 19-20 years old, and invited to give, in total gratuity, their blood samples to private and accreditable laboratories close to their living habitation. After 262 exclusions due to either previous screening not signaled before or present use of contraceptive pill in girls, only 202 boys and 135 girls remained eligible for such a prevalence study. Using plasma enzymatic dosages of CT, HDL C, (calculated) LDLC, TG, and blood glucose, cut off points for each of these parameters, were analysed as well as calculated international index of CT/HDLC and CT minus HDLC. But the first one index was shown the best tool for the final estimation of the frequency of lipid disorders, which requires primary prevention. Indeed, despite of a rather high frequency of overlaps of CT and LDLC respectively found at 16.3 and 22.5% for boys, and 27.3 and 27.5% for girls, the still higher increase of frequency of HDL C at 31% for boys and 28.1% for girls has shown a very significant compensation of these previous increases. In such a way as the authentic prevalence of atherogenic lipid disorders is found reduced in boys to 8.4% and in girls to 7.4% for CT/HDLC>/=4.5 ratio, and to 5.4% in boys and 5.2% in girls for CT less HDLC. A Familial Dominant Hypercholesterolemia was discovered only two times in two girls 16 years old. Other abnormal lipid profiles were rather those of Mixed H., type IV, chiefly mild Hypercholesterolemia, and some rare cases of HypoHDLemia. The only greater linked cardiovascular risk factor was direct parental C.V. heredity, round 30% among lipid disorders. Obesity remained rare, as well as Metabolic Syndrome in the present recruitment. Contraceptive pill increases significantly all lipid parameters and atherogenic index: chiefly CT minus HDLC which reaches almost the double of frequency (15%) versus that of girls without pill. But 53% of boys with proatherogenic lipid disorders are smokers, while only 10% of these dyslipidemic girls smoke.

[Recent data on prion diseases]. / Données récentes sur les maladies à prions.

The transmissible spongiform encephalopathies (TSEs) or "prions diseases", provokes some controversies about their origins and possible transmission from animals to humans. Important advances were obtained recently on the genetical TSEs with the genotypic diagnosis methods based on the discovery of numerous mutations and inclusions in the PRNP gene coding for prion protein. The possible connection between the bovine spongiform encephalopathy (BSE) and the newvariant of Creutzfeldt-Jakob disease (nv-CJD) ask numerous questions in terms of public health. Lastly, the important problem of biological diagnosis of "prions diseases" presents interesting advances that must be continued and supported by the public health authorities.

[Hommage to M.L. Girard: gestation and birth of biochemistry in hospitals]. / Hommage a M.L. Girard: gestation et naissance de la biochimie hospitaliere.

Prof Claude Dreux pays hommage to Prof Maurice-Louis Girard and relates the gestation and the birth of biochemistry in hospitals. He successively evokes Hippocrates, Galen, Paracelsius, Robert Boyle, Nicolas Vauquelin, J.J. Von Scherer, J.F. Zeller, G.H. Esbach, Apollinaire Bouchardat, Georges Deniges, Paul Yvon, Ambard, Loiseleur, Leon Grimbert, Paul Fleury, Jean-Emile Courtois and last but not the least Maurice-Louis Girard.

A "septide-sensitive" receptor is not involved in tachykinin-mediated secretory and inositol phosphate responses in rat parotid gland: are several transduction pathways involved after the stimulation of the NK1 receptor?

In the rat parotid gland, the neuropeptide substance P (SP), as well as SP(4-11), and septide elicited inositol phosphate production (EC50 values 0.44, 2, and 20 nM, respectively). No additivity of the maximal response to the three agonists was observed. SP, SP(4-11), and septide also stimulated protein secretion; for SP, two EC50 were determined (0.5 and 160 nM), whereas a single one could be determined for SP(4-11) and septide (EC50 values 15 and 20 nM, respectively). The selective tachykinin NK1 receptor antagonist RP67580 acted as a competitive inhibitor of both SP- and SP(4-11)-induced inositol phosphate production. Its effect on septide-induced inositol phosphate production was noncompetitive. RP67580 is apparently as potent at antagonizing septide, SP, or SP(4-11) (in all cases KB = 3 nM). These results show that in parotid gland, only NK1 receptors are activated by SP, SP(4-11), and septide. We also showed that the protein secretion stimulated by SP was inhibited competitively by RP67580, whereas the effect of RP67580 was noncompetitive on protein secretion when SP(4-11) or septide was used. Our data indicate that in rat parotid gland, the existence of a specific "septide-sensitive" receptor can be ruled out and that only the NK1 receptor is present and mediates cellular responses. Taken together, these results show that in this tissue the NK1 receptor would present at least two different binding sites that could be coupled to different transduction pathways and that would regulate protein secretion.

Beta-adrenergic-induced calcium efflux in rat parotid gland. Is mitochondrial Na+/Ca2+ exchange involved?

The effects of diltiazem were examined on 45Ca efflux in rat parotid glands. First, we showed that mitochondrial Na+/Ca2+ exchange occurs in rat parotid glands and that diltiazem inhibited the mitochondrial Na(+)-dependent calcium efflux. We also confirmed that in rat parotid gland, diltiazem did not modify calcium movements at plasma membrane level. Secondly, we tested the effects of diltiazem on pieces of parotid glands. Diltiazem alone induced 45Ca efflux from parotid lobules. When the effect of diltiazem was tested on isoproterenol-induced 45Ca efflux, the effects of the two drugs were less than additive. By comparison, diltiazem did not modify carbachol induced 45Ca efflux. Diltiazem was able to induce calcium efflux from an intracellular calcium pool, which is not the IP3 sensitive one. These data support the previous hypothesis that isoproterenol and carbachol do not mobilize the same calcium pool. Although we did not precisely determine the calcium pool sensitive to beta-adrenergic stimulation, we cannot rule out the hypothesis that mitochondria would be that store.

Phosphoinositide synthesis in desensitized rat pancreatic acinar cells.

To help understand the possible role of phosphoinositide turnover in the desensitization process, the availability of phosphatidylinositol 4,5-bisphosphate was investigated in normal and desensitized pancreatic acinar cells treated with carbamylcholine (Cch), caerulein (Cae), and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). In control acini, incorporation of [myo-3H]inositol into total phosphoinositides was maximal at 120 min, was Cch and Cae dose dependent, and was insensitive to TPA. Cch stimulation increased the proportion of [myo-3H]inositol incorporated into phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], whereas Cae specifically channeled [myo-3H]inositol incorporation into phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. In the desensitized cells, preexposure to Cch and Cae, but not to TPA, increased the subsequent basal rate of [myo-3H]inositol incorporation into total phosphoinositol (PI) by 66 and 50% above control values. There were no subsequent responses to increasing concentrations of Cch, Cae, and TPA during a second incubation. Desensitization of the pancreatic secretory responses to Cch, Cae, and TPA does not seem to result from a decrease either in total PI or in specific PtdIns(4,5)P2 synthesis, which is needed for inositol trisphosphate and diacylglycerol production.

Simultaneous determination of all-trans and 13-cis retinoic acids and their 4-oxo metabolites by adsorption liquid chromatography after solid-phase extraction.

All-trans retinoic acid (all-trans RA), the active metabolite of vitamin A, has been demonstrated to be an efficient alternative to chemotherapy in the treatment of acute promyelocytic leukemia (APL), the AML3 subtype of the FAB cytological classification. Complete remission is obtained by inducing terminal granulocytic differentiation of the leukemic cells. To study all-trans RA pharmacokinetics in patients with APL, a rapid, precise and selective high-performance liquid chromatographic (HPLC) assay was developed. This method is easy and shows good repeatability (C.V. = 8.41-12.44%), reproducibility (C.V. = 9.19-14.73%), accuracy (C.V. = 3.5-11%) and sensitivity with a detection limit of 5 pmol/ml. The analysis is performed using normal-phase HPLC in an isocratic mode with UV detection after solid-phase extraction on octadecyl (C18) columns. The mobile phase is hexane-dichloromethane-dioxane (78:18:4, v/v) containing 1% acetic acid.

[Molecular genetics of familial and sporadic forms of human prion diseases]. / Génétique moléculaire des formes familiales et sporadiques des maladies à prions humaines.

Prion diseases, also known as transmissible subacute spongiform encephalopathies (TSSE), are rare neurodegenerative disorders of both humans and animals. Their biochemical hallmark is an accumulation in the brain of an abnormal form of the host-encoded prion protein (PrP). This pathological accumulation could result from a protein conformational change under the influence of unknown factors. The normal function of PrP is unknown. The abnormal form is thought to induce neurodegeneration when experimentally or accidentally introduced in recipient hosts. Such a possibility would explain the transmissible character of these diseases illustrated in humans by iatrogenic contamination. Considerable attention has been focused on the host PrP gene and its relation with the genetic susceptibility of humans and animals. Mutations in PRNP, the gene which encodes PrP in humans, are present in 17% of the patients and might be causative. In patients without any PRNP mutation, a coding polymorphism (129 Met/Val) defines a predisposing factor. Important progress in the molecular genetics of TSSE in both humans and animals have been performed for few years and point out that the development of different forms of these diseases, experimental, iatrogenic or spontaneous, are strongly dependent on the primary structure of the host PrP.

The impact of clinical biochemistry on university education in France.

In France, clinical biochemistry, similar to other disciplines of laboratory medicine, is taught in both the regular medical and pharmacy curricula, but medical teaching is oriented more towards the interpretation of laboratory findings than test performance. At present, there is no compulsory program of lifelong continuing education, but it is planned to introduce such an obligation in the near future. The practice of laboratory medicine is regulated strictly by the national Health Administration. Clinical laboratories are multidisciplinary, covering simultaneously clinical biochemistry, microbiology, parasitology, hematology and immunology. The only officially recognized laboratory profession is that of 'Director of a Laboratory for Medical Analysis'. The practice of this profession is only open to physicians and pharmacists, provided they graduated in 'Medical Biology' after 4 years of specialized training through a particular type of residency called the 'internat'. The 'interns' are selected by competitive examination. After completing their curriculum, specialized physicians or pharmacists can without further examination or certification either enter a career in a hospital, a university, or both, or direct or co-direct a private laboratory. In this scheme, clinical biochemistry exists as a separate academic discipline, but barely as a distinct profession.

[Parotid gland in rats, a model for the study of regulated exocrine secretion]. / La glande parotide de rat, un modèle pour l'étude de la sécrétion exocrine régulée.

In rat parotid glands protein secretion studied in vitro is weakly stimulated by carbachol (which induces Phospholipase C activation) and strongly by isoprenaline (which activates the adenylate cyclase system). We show in this work that the simultaneous activation of the two types of receptors induces a potentiation of protein secretion. This is not due to an enhanced IP3 or cAMP accumulation nor any modification on calcium movements. Potentiation of protein secretion is also mimicked by analogues of second messengers suggesting that this phenomenon is a post-receptor event which takes place at a distal step from messenger production. Furthermore we also showed that the activation of beta-adrenergic receptor led to two parallel events: cAMP accumulation and calcium movements. These two events were required to obtain maximal secretion. We also show that cholinergic induced secretion is also the result of a synergism between calcium and protein kinase C activation. At a physiological level, the synergism between two different transduction pathways must play an important role. This surely allows the cells to give maximal response, without any desensitization phenomena.