An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Postpartum hemorrhage resulting from uterine atony after vaginal delivery: factors associated with severity.: Factors associated with postpartum hemorrhage severity

International audienceOBJECTIVE: To identify factors associated with severity of postpartum hemorrhage among characteristics of women and their delivery, the components of initial postpartum hemorrhage management, and the organizational characteristics of maternity units. METHODS: This population-based cohort study included women with postpartum hemorrhage due to uterine atony after vaginal delivery in 106 French hospitals between December 2004 and November 2006 (N=4,550). Severe postpartum hemorrhage was defined by a peripartum change in hemoglobin of 4 g/dL or more. A multivariable logistic model was used to identify factors independently associated with postpartum hemorrhage severity. RESULTS: Severe postpartum hemorrhage occurred in 952 women (20.9%). In women with postpartum hemorrhage, factors independently associated with severity were: primiparity; previous postpartum hemorrhage; previous cesarean delivery; cervical ripening; prolonged labor; and episiotomy; and delay in initial care for postpartum hemorrhage. Also associated with severity was 1) administration of oxytocin more than 10 minutes after postpartum hemorrhage diagnosis: 10-20 minutes after, proportion with severe postpartum hemorrhage 24.6% compared with 20.5%, adjusted OR 1.38, 95% CI 1.03-1.85; more than 20 minutes after, 31.8% compared with 20.5%, adjusted OR 1.86, CI 1.45-2.38; 2) manual examination of the uterine cavity more than 20 minutes after (proportion with severe postpartum hemorrhage 28.2% versus 20.7%, adjusted OR 1.83, 95% CI 1.42-2.35); 3) call for additional assistance more than 10 minutes after (proportion with severe postpartum hemorrhage 29.8% versus 24.8%, adjusted OR 1.61, 95% CI 1.23-2.12 for an obstetrician, and 35.1% compared with 29.9%, adjusted OR 1.51, 95% CI 1.14-2.00 for an anesthesiologist); 4) and delivery in a public non-university hospital. Epidural analgesia was found to be a protective factor against severe blood loss in women with postpartum hemorrhage. CONCLUSION: Aspects of labor, delivery, and their management; delay in initial care; and place of delivery are independent risk factors for severe blood loss in women with postpartum hemorrhage caused by atony

Modelling the response of a double-barred sandy beach system to time-varying wave angles

Sandy beaches typically have one or more shore-parallel bars with superimposed smaller-scale three-dimensional (3D) bars. Knowledge of their morphodynamic behaviour under more realistic wave conditions is limited. This study investigates the response of beaches with two shore-parallel bars to sinusoidally time-varying angles of incidence, using a non-linear morphodynamic model. Different periods and amplitudes of this sinusoidal variation are considered, as well as different time-mean wave angles. For time-invariant and normally incident waves, results show that alongshore rhythmic 3D bars form in the domains of inner and outer shore-parallel bars. The 3D bars in the inner domain are coupled at half the outer-bars wavelength. This phase coupling breaks up when the wave angle varies in time. Initially, regular 3D bars form in the inner domain (free behaviour), which become irregular when 3D bars develop in the outer domain (forced behaviour). The heights of the 3D bars oscillate with time, reaching maximum values when the forcing period is comparable to the system adjustment time scale (∼ 10–20 days). For a time-varying wave angle around an oblique mean, alongshore migrating 3D bars emerge in both inner and outer domains. In contrast, for an oblique (constant) wave angle, 3D bars only form in the inner domain and they hardly migrate alongshore. For any forcing period, the dominant response period of the oscillating bar heights is at half the forcing period when waves are (on average) normally incident, and it equals the forcing period when waves are on average obliquely incident. Compared with time-invariant angles, heights of inner and outer 3D bars are (on average) smaller and larger, respectively, when the angle varies with time, particularly for forcing periods in the order of the system adjustment time scale. Increasing the amplitude of the time-varying wave angle weakens bar growth. Explanations of these results are also provided

OmegaROP-2 prospective study: Expression of placental fatty acid receptors in preterm newborns with retinopathy of prematurity

Abstract Background Incomplete vascularization of the retina in preterm infants carries a risk of retinopathy of prematurity (ROP). Progress in neonatal resuscitation in developing countries has led to the survival of an increasing number of premature infants, resulting in an increased rate of ROP and consequently in visual disability. Strategies to reduce ROP involve optimizing oxygen saturation, nutrition, and normalizing factors such as insulin-like growth factor 1 and n-3 long-chain polyunsaturated fatty acids (LC-PUFA). Our previous study, OmegaROP, showed that there is an accumulation or retention of docosahexaenoic acid (DHA) in mothers of infants developing ROP, suggesting abnormalities in the LC-PUFA placental transfer via fatty acid transporting proteins. The present study aims to better understand the LC-PUFA transport dysfunction in the fetoplacental unit during pregnancy and to find a novel target for the prevention of ROP development. Methods The study protocol is designed to evaluate the correlation between the expression level of placental fatty acid receptors and ROP occurrence. This ongoing study will include 100 patients: patients giving birth before 29 weeks of gestational age (GA) and patients with full-term pregnancies. Recruitment is planned for over 46 months. Maternal and cord blood samples as well as placental tissue samples will be taken following delivery. ROP screening will be performed using wide-field camera imaging according to the International Classification of ROP consensus statement. Discussion The results of this study will have a tangible impact on public health. Indeed, if we show a correlation between the expression level of placental omega-3 receptors and the occurrence of ROP, it would be an essential step in discovering novel pathophysiological mechanisms involved in this retinopathy. Trial registration: 2020-A03253-3

A clinical and histopathological study of malformations observed in fetuses infected by the Zika virus

Background: The recent outbreak of Zika virus (ZIKV) infection and the associated increased prevalence of microcephaly in Brazil underline the impact of viral infections on embryo fetal development. The aim of the present study is to provide a detailed clinical and histopathological study of the fetal disruption caused by the ZIKV, with a special focus on the associated neuropathological findings. Methods: A detailed feto-placental examination, as well as neuropathological and neurobiological studies were performed on three fetuses collected after pregnancy termination between 22 and 25 weeks of gestation (WG), because brain malformations associated with a maternal and fetal ZIKV infection was diagnosed. Results: In all three cases, the maternal infection occurred during the first trimester of pregnancy. A small head was observed on the ultrasound examination of the second trimester of pregnancy and led to the diagnosis of ZIKV fetopathy and pregnancy termination. The fetal histopathological examination was unremarkable on the viscera but showed on the testis an interstitial lymphocytic infiltrate. The placenta contained a Hofbauer cells hyperplasia with signs of inflammation. Neuropathological findings included a meningoencephalitis and an ex vacuo hydrocephalus. Immunohistochemical studies showed the presence of T lymphocytic and histiocytic meningitis associated with an abundant cerebral astroglial and macrophagic reaction. In situ hybridization demonstrated, abundant ZIKV particles within the cerebral parenchyma mainly in the ventricular/subventricular zone and in the cortical plate. In addition massive cells death and endoplasmic reticulum damage were present. Conclusion: The present study reports on the clinical and histopathological findings observed in three fetuses infected by the ZIKV. It emphasizes the severity of brain damages and the minimal visceral and placental changes observed upon ZIKV infection. This confirms the selective neurotropism of ZIKV. Finally, it allows us to describe the cascade of multifactorial developmental defects leading to microcephaly. © 2018 International Society of Neuropatholog

Study protocol of OmegaROP-2 prospective study: expression of placental fatty acid receptors in preterm newborns with retinopathy of prematurity

Correspondence to: [email protected] audienceBackground Incomplete vascularization of the retina in preterm infants carries a risk of retinopathy of prematurity (ROP). Progress in neonatal resuscitation in developing countries has led to the survival of an increasing number of premature infants, resulting in an increased rate of ROP and consequently in visual disability. Strategies to reduce ROP involve optimizing oxygen saturation, nutrition, and normalizing factors such as insulin-like growth factor 1 and n-3 long-chain polyunsaturated fatty acids (LC-PUFA). Our previous study, OmegaROP, showed that there is an accumulation or retention of docosahexaenoic acid (DHA) in mothers of infants developing ROP, suggesting abnormalities in the LC-PUFA placental transfer via fatty acid transporting proteins. The present study aims to better understand the LC-PUFA transport dysfunction in the fetoplacental unit during pregnancy and to find a novel target for the prevention of ROP development. Methods The study protocol is designed to evaluate the correlation between the expression level of placental fatty acid receptors and ROP occurrence. This ongoing study will include 100 mother-infant dyads: mother-infant dyads born before 29 weeks of gestational age (GA) and mother-infant dyads with full-term pregnancies. Recruitment is planned over a period of 46 months. Maternal and cord blood samples as well as placental tissue samples will be taken following delivery. ROP screening will be performed using wide-field camera imaging according to the International Classification of ROP consensus statement. Discussion The results of this study will have a tangible impact on public health. Indeed, if we show a correlation between the expression level of placental omega-3 receptors and the occurrence of ROP, it would be an essential step in discovering novel pathophysiological mechanisms involved in this retinopathy. Trial registration NCT04819893

A snapshot of the Covid-19 pandemic among pregnant women in France

International audienc

Maintenance darunavir/ritonavir monotherapy to prevent perinatal HIV transmission, ANRS-MIE 168 MONOGEST study

International audienceObjectives: Because NRTIs can have fetal toxicities, we evaluated a perinatal NRTI-sparing strategy to prevent perinatal HIV transmission. Our primary objective was to determine the proportion maintaining a viral load (VL) of 50 copies/mL. Neonates received nevirapine prophylaxis for 14 days.Results: Of 89 patients switching to darunavir/ritonavir monotherapy, 4 miscarried before 22 weeks' gestation, 2 changed treatment for elevated liver enzymes without virological failure, and 83 were evaluable for the main outcome. Six had virological failure confirmed on a repeat sample (median VL=193 copies/mL; range 78-644), including two before switching to monotherapy. In these six cases, ART was intensified with tenofovir disoproxil fumarate/emtricitabine. The success rate was 75/83, 90.4% (95% CI, 81.9%-95.7%) considering two patients with VL missing at delivery as failures, and 77/83, 92.8% (95% CI, 84.9%-97.3%) when considering them as successes since both had undetectable VL on darunavir/ritonavir throughout pregnancy. In ITT, the last available VL before delivery was <50 copies/mL in all of the patients. There was no case of perinatal HIV transmission.Conclusions: Darunavir/ritonavir maintenance monotherapy required intensification in nearly 10% of cases. This limits its widespread use, thus other regimens should be evaluated in order to limit exposure to antiretrovirals, particularly NRTIs, during pregnancy