Ovarian tissue cryopreservation for fertility preservation before hematopoietic stem cell transplantation in patients with sickle cell disease: safety, ovarian function follow-up, and results of ovarian tissue transplantation.

PURPOSE: To describe the experience of performing ovarian tissue cryopreservation (OTC) before hematopoietic stem cell transplantation (HSCT), among girls/women with severe sickle cell disease (SCD)(SS or S/ß0-thalassemia) who are, besides the usual surgical risk, at risk of SCD-related complications during the fertility preservation procedure for improving their counseling and management. METHODS: This retrospective study included 75 patients (girls/women) with SCD who have had OTC before myeloablative conditioning regimen (MAC) for HSCT. Characteristics of patients and data on OTC, ovarian status follow-up, and results of ovarian tissue transplantation (OTT) were collected in medical records. RESULTS: At OTC, the median (IQR 25-75; range) age of the patients was 9.6 (6.9-14.1; 3.6-28.3) years, 56/75 were prepubertal, and no SCD or surgery-related complications occurred. The median follow-up post-HSCT was > 9 years. At the last follow-up, among prepubertal patients at HSCT, 26/56 were ≥ 15 years old and presented with a premature ovarian insufficiency (POI), except 2, including the patient who had received an OTT to induce puberty. Eight were 13-15 years old and presented for POI. The remaining 22 patients were under 13. Among the 19 patients who were menarche at HSCT, 2 died 6 months post-HSCT and we do not have ovarian function follow-up for the other 2 patients. All the remaining patients (n = 15) had POI. Five patients had OTT. All had a return of ovarian function. One patient gave birth to a healthy baby. CONCLUSION: OTC is a safe fertility preservation technique and could be offered before MAC independent of the patient's age.

Factors associated with the collection of isolated immature oocytes during ovarian tissue cryopreservation.

PURPOSE: To identify patient characteristics associated with successful isolated immature oocyte retrieval (IsO) during ovarian tissue cryopreservation (OTC) and to determine whether they are predictive of the collection of larger numbers of oocytes. METHODS: We retrospectively analyzed all patients undergoing OTC with IsO for fertility preservation over three years of activity at a university hospital. Univariate and multivariate analyses were used to identify the patients with the highest and lowest chances of oocyte recovery, and those with the largest numbers of oocytes. We also analyzed the correlation of IsO with the number of ovarian fragments collected and histological parameters. RESULTS: We analyzed 257 consecutive patients undergoing these procedures, at a median age of 17.1 years [0.3-38.3 years]. Isolated oocytes were obtained from 47.1% of patients, and IsO was more likely in patients with ovulatory cycles (63.0% vs. 38.6%; P≤ .001), without chemotherapy before OTC (61.4% vs. 33.1; P< .001) and with non-malignant diseases other than Turner syndrome (77.5%). Oocyte collection failure rates were highest in patients with Turner syndrome (OR 25.0, 95% CI 3.99-157.0; P< .001) or undergoing chemotherapy with alkylating agents before OTC (OR 37.6, 95% CI 8.36-168.8; P< .001). Prepubescent status (P= .043) and large numbers of ovarian fragments (P< .001) were associated with the retrieval of larger numbers of oocytes. Oocyte recovery was correlated with the presence of follicles in the medulla, but not with follicular density. CONCLUSION: The chances of IsO differ between patients. Identifying patients with the highest chances of success facilitates appropriate resource allocation.

[The lessons of the Ebola epidemic for a more effective preparedness face to health crises]. / Les enseignements de l'épidémie d'Ebola pour une meilleure préparation aux urgences.

Although uncommon, public health crises cause considerable human suffering and death and have major political, economic and social impacts. For many years, countries have made considerable efforts to prepare for emergencies. The Ebola epidemic in West Africa, as well as recent events and emerging public health threats force countries to strengthen, adapt or implement their Emergency Preparedness Plans. Emergency Preparedness is a difficult process. Some authors would even say that it is an impossible mission. What do we mean by preparedness ? How can preparedness be evaluated ? What measures must be taken following the Ebola crisis ? Preparedness is one of the Emergency Management phases and is essential to meet the challenges of future crises. Preparedness still constitutes a major challenge for countries and the international community. Based on missions conducted in West Africa and on a review of the literature, the authors review the concepts of emergency preparedness. In particular, they present standards and tools to assess emergency preparedness, using the example of Ebola preparedness assessment in West Africa.

Application of a new approach methodology (NAM)-based strategy for genotoxicity assessment of data-poor compounds.

The conventional battery for genotoxicity testing is not well suited to assessing the large number of chemicals needing evaluation. Traditional in vitro tests lack throughput, provide little mechanistic information, and have poor specificity in predicting in vivo genotoxicity. New Approach Methodologies (NAMs) aim to accelerate the pace of hazard assessment and reduce reliance on in vivo tests that are time-consuming and resource-intensive. As such, high-throughput transcriptomic and flow cytometry-based assays have been developed for modernized in vitro genotoxicity assessment. This includes: the TGx-DDI transcriptomic biomarker (i.e., 64-gene expression signature to identify DNA damage-inducing (DDI) substances), the MicroFlow® assay (i.e., a flow cytometry-based micronucleus (MN) test), and the MultiFlow® assay (i.e., a multiplexed flow cytometry-based reporter assay that yields mode of action (MoA) information). The objective of this study was to investigate the utility of the TGx-DDI transcriptomic biomarker, multiplexed with the MicroFlow® and MultiFlow® assays, as an integrated NAM-based testing strategy for screening data-poor compounds prioritized by Health Canada's New Substances Assessment and Control Bureau. Human lymphoblastoid TK6 cells were exposed to 3 control and 10 data-poor substances, using a 6-point concentration range. Gene expression profiling was conducted using the targeted TempO-Seq™ assay, and the TGx-DDI classifier was applied to the dataset. Classifications were compared with those based on the MicroFlow® and MultiFlow® assays. Benchmark Concentration (BMC) modeling was used for potency ranking. The results of the integrated hazard calls indicate that five of the data-poor compounds were genotoxic in vitro, causing DNA damage via a clastogenic MoA, and one via a pan-genotoxic MoA. Two compounds were likely irrelevant positives in the MN test; two are considered possibly genotoxic causing DNA damage via an ambiguous MoA. BMC modeling revealed nearly identical potency rankings for each assay. This ranking was maintained when all endpoint BMCs were converted into a single score using the Toxicological Prioritization (ToxPi) approach. Overall, this study contributes to the establishment of a modernized approach for effective genotoxicity assessment and chemical prioritization for further regulatory scrutiny. We conclude that the integration of TGx-DDI, MicroFlow®, and MultiFlow® endpoints is an effective NAM-based strategy for genotoxicity assessment of data-poor compounds.

Impact of a multipronged education strategy on antibiotic prescribing in Quebec, Canada.

BACKGROUND: Antibiotic overuse and resistance have become a major threat in the last 2 decades. Many programs tried to optimize antibiotic consumption in the inpatient setting, but the outpatient environment that represents the bulk of antibiotic use has been challenging. Following a significant rise of Clostridium difficile infections, all the health care stakeholders in the province of Quebec, Canada initiated a global education program targeting physicians and pharmacists. METHODS: A bundle approach was used; 11 user-friendly guidelines were produced by a group of experts and sent to all physicians and pharmacists in Quebec in January 2005. Downloadable versions of guidelines were posted on a dedicated Web site. They were promoted by professional organizations, universities, and experts during educational events, and there was strong acceptance by the pharmaceutical industry with a willingness to follow the recommendations in their marketing. The Intercontinental Medical Statistics (IMS) database was used to analyze and compare Quebec's total outpatient prescriptions per 1000 inhabitants with those in the other Canadian provinces for 2 time periods: preintervention (January 2003 to December 2004), and postintervention (February 2005 to December 2007). RESULTS: In 2004, antibiotic consumption per capita was 23.3% higher in Canada generally than in Quebec. After the guidelines dissemination, the gap between Quebec and the other Canadian provinces increased by 4.1 prescriptions/1000 inhabitants (P = .0002), and the trend persisted 36 months later. Antibiotic costs fell $134.5/1000 inhabitants in Quebec compared with the rest of Canada (P = .054). CONCLUSIONS: The implementation of guidelines significantly reduced antibiotic prescriptions in Quebec compared with the rest of the country, and there was a strong trend toward significant cost reduction.

The fetal safety of hydrocortisone-pramoxine (Proctofoam-HC) for the treatment of hemorrhoids in late pregnancy.

OBJECTIVE: Fetal safety has never been studied for any drug used in the treatment of hemorrhoids. Proctofoam-HC is a combination of a corticosteroid and a local anaesthetic that is proven effective for the treatment of hemorrhoids. The objective of this study was to assess prospectively the fetal safety of third trimester exposure to Proctofoam-HC. METHODS: In a multicentre study, 204 [corrected] women exposed to Proctofoam-HC in the third trimester and a similar number of control pregnant women were followed up postnatally. RESULTS: When compared to controls exposure to Proctofoam-HC was not associated with any adverse fetal effects on birth weight, gestational age, rates of prematurity, or pre- or postnatal complications. CONCLUSION: Proctofoam-HC is safe to use in the treatment of hemorrhoids in late pregnancy.

Laparoscopic ovarian tissue harvesting and orthotopic ovarian cortex grafting for fertility preservation: less is more.

OBJECTIVE: To describe our surgical techniques for laparoscopic ovarian tissue harvesting and orthotopic ovarian cortex grafting (LOOCG). DESIGN: This video article uses surgical cases to demonstrate the detailed surgical techniques. Institutional Review Board approval was not required for this video presentation. SETTING: University hospital. PATIENT(S): Patients presenting with indication for fertility preservation by means of ovarian tissue harvesting and orthotopic ovarian cortex grafting (in case of setting up a high risk of gonadotoxicity treatment or patients presenting with a pathology with risk of premature ovarian failure). INTERVENTION(S): Ovarian tissue harvesting: The entire ovary is harvested by placing an EndoGIA stapler to ensure the control of infundibulopelvic ligament and then, after reloading, the section of the mesovarium. LOOCG one-step procedure: A large and superficial incision of the peritoneum is performed to create a peritoneal pocket. The fragments of ovarian cortex are secured with the use of nonresorbable surgical wire (Prolene 5.0) and introduced into the peritoneal pocket. The peritoneum is not closed after placing the graft. MAIN OUTCOME MEASURE(S): Value and feasibility of LOOCG. Restoration of endocrine function and fertility results. RESULT(S): Thirty-four patients were included from November 2011 to October 2017. LOOCG restored ovarian endocrine activity in 88.2% of cases. Ten patients had become pregnant (29.4%), and the same number gave birth to at least one child. CONCLUSION(S): Our surgical approach is simple, safe, and reproducible and seems to be as effective as previously described techniques. It deserves to be proposed to patients eligible for ovarian cortex grafting.

Training program-induced skeletal muscle adaptations in two men with myotonic dystrophy type 1.

OBJECTIVE: The purpose of this side product of another unpublished research project, was to address the effects of a training program on skeletal muscle adaptations of people with myotonic dystrophy type 1 (DM1), under a multifaceted perspective. The objective of this study was to look at training induced muscular adaptations by evaluating changes in muscle strength, myofiber cross-sectional area (CSA), proportion of myofiber types and with indirect markers of muscle growth [proportion of centrally nucleated fibers (CNF) and density of neutrophils and macrophages]. Two men with DM1 underwent a 12-week strength/endurance training program (18 sessions). Two muscle biopsies were obtained pre- and post-training program. RESULTS: Muscular adaptations occurred only in Patient 1, who attended 72% of the training sessions compared to 39% for Patient 2. These adaptations included increase in the CSA of type I and II myofibers and changes in their proportion. No changes were observed in the percentage of CNF, infiltration of neutrophils and macrophages and muscle strength. These results illustrate the capacity of skeletal muscle cells to undergo adaptations linked to muscle growth in DM1 patients. Also, these adaptations seem to be dependent on the attendance. Trial registration Clinicaltrials.gov NCT04001920 retrospectively registered on June 26th, 2019.

The impact of Infection Prevention and control (IPC) bundle implementationon IPC compliance during the Ebola virus outbreak in Mbandaka/Democratic Republic of the Congo: a before and after design.

OBJECTIVES: To assess the impact of refresher training of healthcare workers (HCWs) in infection prevention and control (IPC), ensuring consistent adequate supplies and availability of IPC kits and carrying out weekly monitoring of IPC performance in healthcare facilities (HCFs) DESIGN: This was a before and after comparison study SETTINGS: This study was conducted from June to July 2018 during an Ebola virus disease (EVD) outbreak in Equateur Province in the Democratic Republic of the Congo (DRC). PARTICIPANTS: 48 HCFs INTERVENTIONS: HCWs capacity building in basic IPC, IPC kit donation and IPC mentoring. PRIMARY OUTCOME MEASURES: IPC score RESULTS: 48 HCFs were evaluated and 878 HCWs were trained, of whom 437 were women and 441 were men. The mean IPC score at baseline was modestly higher in hospitals (8%) compared with medical centres (4%) and health centres (4%), respectively. The mean IPC score at follow-up significantly increased to 50% in hospitals, 39% in medical centres and 36% in health centres (p value<0.001). The aggregate mean IPC score at baseline for all HCFs, combined was 4.41% and at follow-up it was 39.51% with a mean difference of 35.08% (p-value<0.001). CONCLUSIONS: Implementation of HCW capacity building in IPC, IPC kit donation to HCF and mentoring in IPC improved IPC compliance during the ninth EVD outbreak in the DRC.

Comparison and analysis of three different methods to evaluate vertical jump height.

The purpose of this study was to compare three methods to assess vertical jump height, to determine their limitations and to propose solutions to mitigate their effects. The chosen methods were the contact mat, the optical system and the Sargent jump. The testing environment was designed such that all three systems simultaneously measured the vertical jump height. A total of 41 kinesiology students (18 women, 23 men, mean age 23·2 ± 4·5 years) participated in this study. Data show that the contact mat and the optical system essentially provide similar results (P = 0·912) and that the correlation coefficient between the two systems was 0·972 (r(2)  = 0·944). However, it was found that the Sargent jump has a tendency to overestimate the height, providing a measurement that is significantly different from the other two methods as the jumps are higher than 30·64 cm (P = 0·044). Through the design of the experiment, several sources of errors were identified and mathematically modelled. These sources include optical sensor placement, flat-footed landing and hip/knee bend. Whenever possible, the errors were quantified and solutions were proposed.

[Fertility and cancer]. / Fertilité et cancer.

Information about chemo and/or radiotherapy gonadotoxicity and about fertility preservation is essential. Sperm cryopreservation has to be systematically offered before gonadotoxic treatments. Efficiency of ovarian function preservation with GnRH agonists is still debated. A controlled ovarian stimulation is necessary before oocyte or embryo cryopreservation. It is only feasible if the treatment is not urgent and if the tumor is not hormone-sensitive. If the treatment is highly gonadotoxic, an ovarian tissue cryopreservation may be appropriate. It is the only fertility preservation technique feasible for prepubertal girls. It is now possible to preserve the fertility of prepubertal boys by cryopreservation of testicular tissue. It is essential to send patients and/or their parents to a specialized fertility preservation center.

Phenotyping and genetic studies of 357 consecutive patients presenting with premature ovarian failure.

OBJECTIVE: Premature ovarian failure (POF) encompasses a heterogeneous spectrum of conditions, with phenotypic variability among patients. The etiology of POF remains unknown in most cases. We performed a global phenotyping of POF women with the aim of better orienting attempts at an etiological diagnosis. DESIGN AND METHODS: We performed a mixed retrospective and prospective study of clinical, biological, histological, morphological, and genetic data relating to 357 consecutive POF patients between 1997 and 2008. The study was conducted at a reproductive endocrinology referral center. RESULTS: Seventy-six percent of the patients presented with normal puberty and secondary amenorrhea. Family history was present in 14% of the patients, clinical and/or biological autoimmunity in 14.3%. Fifty-six women had a fluctuating form of POF. The presence of follicles was suggested at ultrasonography in 50% of the patients, and observed in 29% at histology; the negative predictive value of the presence of follicles at ultrasonography was 77%. Bone mineral density alterations were found in 58% of the women. Eight patients had X chromosomal abnormalities other than Turner's syndrome, eight other patients evidenced FMR1 pre-mutation. Two other patients had autoimmune polyendocrine syndrome type 2 and 1. CONCLUSION: A genetic cause of POF was identified in 25 patients, i.e. 7% of the whole cohort. POF etiology remains most often undiscovered. Novel strategies of POF phenotyping are in such content mandatory to improve the rate of POF patients for whom etiology is identified.

Impact of infertility drugs after treatment of borderline ovarian tumors: results of a retrospective multicenter study.

OBJECTIVE: To evaluate safety and fertility outcome after the use of infertility drugs in patients who were treated conservatively for a borderline ovarian tumor (BOT). DESIGN: A retrospective multicenter study. SETTING: Centers participating in the French National Register on In Vitro Fertilization registry. PATIENT(S): Thirty patients who were treated for BOT who underwent ovarian induction (OI). INTERVENTION(S): Ovarian induction was performed in 25 patients for infertility after conservative surgery and before surgery for recurrent disease in 5 patients with a single ovary (emergency cases). MAIN OUTCOMES MEASURE(S): Fertility and recurrences rates. RESULT(S): The mean number of cycles of OI per patient was 2.6 (range, 1-10 cycles). The median follow-up time after treatment of the BOT was 93 months (range, 26-276 months). After a median follow-up time of 42 months after OI, 4 recurrences were observed (initial management was simple cystectomy in 3 of them). All recurrences were borderline tumors on a remaining ovary that had been treated by surgery alone. All patients are currently disease-free. Thirteen pregnancies were observed (10 pregnancies (40%) in the group of 25 patients who were treated for infertility). CONCLUSION(S): These results suggest that infertility drugs could be used safely in patients who experience infertility after conservative management of an early-stage BOT.