ATP5PO levels regulate enteric nervous system development in zebrafish, linking Hirschsprung disease to Down Syndrome.

Hirschsprung disease (HSCR) is a complex genetic disorder characterized by the absence of enteric nervous system (ENS) in the distal region of the intestine. Down Syndrome (DS) patients have a >50-fold higher risk of developing HSCR than the general population, suggesting that overexpression of human chromosome 21 (Hsa21) genes contribute to HSCR etiology. However, identification of responsible genes remains challenging. Here, we describe a genetic screening of potential candidate genes located on Hsa21, using the zebrafish. Candidate genes were located in the DS-HSCR susceptibility region, expressed in the human intestine, were known potential biomarkers for DS prenatal diagnosis, and were present in the zebrafish genome. With this approach, four genes were selected: RCAN1, ITSN1, ATP5PO and SUMO3. However, only overexpression of ATP5PO, coding for a component of the mitochondrial ATPase, led to significant reduction of ENS cells. Paradoxically, in vitro studies showed that overexpression of ATP5PO led to a reduction of ATP5PO protein levels. Impaired neuronal differentiation and reduced mitochondrial ATP production, were also detected in vitro, after overexpression of ATP5PO in a neuroblastoma cell line. Finally, epistasis was observed between ATP5PO and ret, the most important HSCR gene. Taken together, our results identify ATP5PO as the gene responsible for the increased risk of HSCR in DS patients in particular if RET variants are also present, and show that a balanced expression of ATP5PO is required for normal ENS development.

Comparison of neonatal outcomes of cesarean sections performed under primary or secondary general anesthesia: a retrospective study.

BACKGROUND: The conversion of neuraxial anesthesia (NA) to general anesthesia (GA) during a cesarean section (CS) may be associated with a higher risk of neonatal morbidity by adding the undesirable effects of both these anesthesia techniques. We aimed to compare the neonatal morbidity of non-elective CS performed after conversion from NA to GA (secondary GA) vs. that after GA from the outset (primary GA). METHODS: We performed a monocentric retrospective study at the Angers University Hospital (France). All non-elective CSs performed under GA between January 2015 and December 2019 were included. The CSs were classified using a three-color coding system (green for non-urgent delivery, orange for urgent CS, and red for very urgent CS). The primary neonatal outcome was a composite of umbilical artery pH <7.10 or 5-min Apgar score <7. The crude and adjusted odds ratios (OR) for the risk of neonatal morbidity associated with secondary GA were estimated. RESULTS: We included 247 patients, of whom 101 (41.3%) had a secondary GA and 146 (58.7%) had primary GA. In the secondary GA group, 86.1% (87/101) had epidural anesthesia and 13.9% (14/101) had spinal anesthesia. Multivariate analysis showed no difference in neonatal morbidity between the two groups (adjusted odds ratio 1.18, 95% CI 0.56 to 2.51). CONCLUSIONS: Our study found insufficient evidence to identify a difference in neonatal outcomes between secondary compared with primary GA for CS, regardless of the level of emergency. However, our study is underpowered and additional studies are needed to confirm these data.

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.

Pregnancy after chemoradiotherapy in childhood: Complications and recommendations - about one case.

The question of pregnancy prognosis after radio chemotherapy is unaddressed. We report here the case of three successive spontaneous pregnancies 17 years after the management of a thigh rhabdomyosarcoma treated by radiochemotherapy. In 2018 the patient aged 22 presented with a spontaneous miscarriage. In 2019, she obtained a new spontaneous pregnancy. At 21 W G, she presented with threatened late miscarriage and gave birth to a live girl who would die. Three months after delivery, she had spontaneous pregnancy. At 18 W G, emergency cervical cerclage was performed. At 35 W G the ultrasound found severe intrauterine growth retardation. Cesarean section was performed allowing the birth of a girl in good health status. Childbirth was complicated by 1L8 postpartum hemorrhage secondary to uterine atony, controlled after surgical revision. To conclude, pregnancy in a patient with a history of pelvic irradiation in childhood must be considered high-risk pregnancy and its management must be multidisciplinary.

Positive impact of simulation training of residents on the patients' psychological experience following pregnancy loss.

OBJECTIVE: Our study aimed to assess the impact of a simulation training program for residents for the disclosure of diagnosis on the psychological experience of couples following a first trimester pregnancy loss (PL). METHODS: We performed an uncontrolled prospective single center, before-after study, at the gynecological emergency department of Angers University Hospital in France, between May 2014 and April 2015. We included all patients who had a confirmed diagnosis of first trimester PL. A self-administering questionnaire (SAQ) that included the short version of the perinatal grief scale (PGS) and questions about the couples' personal experience was sent by mail 8 weeks after the diagnosis. Patients were included before and after simulation training of the residents on the communication of the diagnosis of PL, and scores were compared between the two groups (before and after training). RESULTS: Overall 72 patients fulfilled the inclusion criteria and responded to the SAQ, 45 before and 27 after simulation training. Overall, simulation training significantly lowered the overall PGS (39.4±4.9 vs 57.3±5.6, p=0.03), significantly improved the attitude of the resident when announcing the diagnosis (more considerate (74.1 % vs 48.9 %, p=0.04) and available (59.3 % vs 28.9 %, p=0.01)), and significantly improved the quality of the information given (less incomprehensible (22.2 % vs 46.7 %, p=0.04). Finally, significantly fewer patients reported needing an additional consultation for further information following training (33.3 % vs 73.3 %, p=0.01). CONCLUSION: Simulation training of residents for the disclosure of early pregnancy loss significantly improves the couples' personal experience and decreases the psychological morbidity associated with the communication.

First case of spontaneous rupture of the left ureter in immediate post-partum.

The rupture of the ureter during pregnancy is a rare complication and is most frequently observed in the right ureter. We report below the case of a rupture in the left ureter. A 36-year old woman gave birth vaginally to a 3010-g girl without operative vaginal delivery or episiotomy. The following day, the patient exhibited a sudden pain in the left side spreading to the left iliac fossa. An abdominopelvic CT scan was carried out and revealed a flow of contrast agent at the left ureteral lumbar level and a left urinoma. A ureteral stent was inserted on the left side under X-ray control. Six weeks after delivery the ureteral stent was removed. The Uro CT scan allowed us to confirm the total recovery of the left ureter. We have reported below the first case of left rupture treated in a conservative manner with positive and functional clinical progress.

Effect of the use of a video tutorial in addition to simulation in learning the maneuvers for shoulder dystocia.

The development of video tutorials is flourishing and may make it possible to maintain knowledge learned during instruction with simulation. The aim of this study was to assess the effect of adding a video tutorial to a lecture and simulation for learning the maneuvers and protocol for the management of shoulder dystocia. Student midwives and medical students attended a lecture class including instruction about maneuvers and a presentation of an algorithm for the management of shoulder dystocia. They were randomized into two groups. The video group was reminded every two weeks to watch a short tutorial. The control group was reminded to consult the slide show. At the end of two months, they were evaluated by graders. The practice, theory, and global scores of the students in the video group were significantly higher than those of the students in the control group (14.8 vs. 10.4; 5.6 vs. 3.4; and 9.3 vs. 7.0, P<0.001). The scores for the video group improved at the second simulation session, compared with the first (14.8 vs. 9.9; 5.6 vs. 2.9; and 9.3 vs. 7, P<0.001). The addition of a video tutorial improved learning compared to a standard lecture and simulation session alone.

The impact of manual rotation of the occiput posterior position on spontaneous vaginal delivery rate: study protocol for a randomized clinical trial (RMOS).

BACKGROUND: The frequency of posterior presentations (occiput of the fetus towards the sacrum of the mother) in labor is approximately 20% and, of this, 5% remain posterior until the end of labor. These posterior presentations are associated with higher rates of cesarean section and instrumental delivery. Manual rotation of a posterior position in order to rotate the fetus to an anterior position has been proposed in order to reduce the rate of instrumental fetal delivery. No randomized study has compared the efficacy of this procedure to expectant management. We therefore propose a monocentric, interventional, randomized, prospective study to show the superiority of vaginal delivery rates using the manual rotation of the posterior position at full dilation over expectant management. METHODS: Ultrasound imaging of the presentation will be performed at full dilation on all the singleton pregnancies for which a clinical suspicion of a posterior position was raised at more than 37 weeks' gestation (WG). In the event of an ultrasound confirming a posterior position, the patient will be randomized into an experimental group (manual rotation) or a control group (expectative management with no rotation). For a power of 90% and the hypothesis that vaginal deliveries will increase by 20%, (10% of patients lost to follow-up) 238 patients will need to be included in the study. The primary endpoint will be the rate of spontaneous vaginal deliveries (expected rate without rotation: 60%). The secondary endpoints will be the rate of fetal extractions (cesarean or instrumental) and the maternal and fetal morbidity and mortality rates. The intent-to-treat study will be conducted over 24 months. Recruitment started in February 2017. To achieve the primary objective, we will perform a test comparing the number of spontaneous vaginal deliveries in the two groups using Pearson's chi-squared test (provided that the conditions for using this test are satisfactory in terms of numbers). In the event that this test cannot be performed, we will use Fisher's exact test. DISCUSSION: Given that the efficacy of manual rotation has not been proven with a high level of evidence, the practice of this technique is not systematically recommended by scholarly societies and is, therefore, rarely performed by obstetric gynecologists. If our hypothesis regarding the superiority of manual rotation is confirmed, our study will help change delivery practices in cases of posterior fetal position. An increase in the rates of vaginal delivery will help decrease the short- and long-term rates of morbidity and mortality following cesarean section. Manual rotation is a simple and effective method with a success rate of almost 90%. Several preliminary studies have shown that manual rotation is associated with reduced rates for fetal extraction and maternal complications: Shaffer has shown that the cesarean section rate is lower in patients for whom a manual rotation is performed successfully (2%) with a 9% rate of cesarean sections when manual rotation is performed versus 41% when it is not performed. Le Ray has shown that manual rotation significantly reduces vaginal delivery rates via fetal extraction (23.2% vs 38.7%, p < 0.01). However, manual rotation is not systematically performed due to the absence of proof of its efficacy in retrospective studies and quasi-experimental before/after studies. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT03009435 . Registered on 30 December 2016.

Induction of nuclear factor-kappaB and its downstream genes by TNF-alpha and IL-1beta has a pro-apoptotic role in pancreatic beta cells.

AIMS/HYPOTHESIS: IL-1beta and TNF-alpha contribute to pancreatic beta cell death in type 1 diabetes. Both cytokines activate the transcription factor nuclear factor-kappaB (NF-kappaB), but recent observations suggest that NF-kappaB blockade prevents IL-1beta + IFN-gamma- but not TNF-alpha + IFN-gamma-induced beta cell apoptosis. The aim of the present study was to compare the effects of IL-1beta and TNF-alpha on cell death and the pattern of NF-kappaB activation and global gene expression in beta cells. METHODS: Cell viability was measured after exposure to IL-1beta or to TNF-alpha alone or in combination with IFN-gamma, and blockade of NF-kappaB activation or protein synthesis. INS-1E cells exposed to IL-1beta or TNF-alpha in time course experiments were used for IkappaB kinase (IKK) activation assay, detection of p65 NF-kappaB by immunocytochemistry, real-time RT-PCR and microarray analysis. RESULTS: Blocking NF-kappaB activation protected beta cells against IL-1beta + IFNgamma- or TNFalpha + IFNgamma-induced apoptosis. Blocking de novo protein synthesis did not increase TNF-alpha- or IL-1beta-induced beta cell death, in line with the observations that cytokines induced the expression of the anti-apoptotic genes A20, Iap-2 and Xiap to a similar extent. Microarray analysis of INS-1E cells treated with IL-1beta or TNF-alpha showed similar patterns of gene expression. IL-1beta, however, induced a higher rate of expression of NF-kappaB target genes putatively involved in beta cell dysfunction and death and a stronger activation of the IKK complex, leading to an earlier translocation of NF-kappaB to the nucleus. CONCLUSIONS/INTERPRETATION: NF-kappaB activation in beta cells has a pro-apoptotic role following exposure not only to IL-1beta but also to TNF-alpha. The more marked beta cell death induced by IL-1beta is explained at least in part by higher intensity NF-kappaB activation, leading to increased transcription of key target genes.