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In coastal zones, a major objective of groundwater management is often to determine sustainable pumping rates which avoid well salinization. Understanding how model and climate uncertainties affect optimal management solutions is essential for providing groundwater managers with information about salinization risk and is facilitated by the use of optimization under uncertainty (OUU) methods. However, guidelines are missing for the widespread implementation of OUU in real-world coastal aquifers and for the incorporation of climate uncertainty into OUU approaches. An ensemble-based OUU approach was developed considering parameter, observation and climate uncertainty and was implemented in a real-world island aquifer in the Magdalen Islands (Quebec, Canada). A sharp-interface seawater intrusion model was developed using MODFLOW-SWI2 and a prior parameter ensemble was generated containing multiple equally plausible realizations. Ensemble-based history matching was conducted using an iterative ensemble smoother which yielded a posterior parameter ensemble conveying both parameter and observation uncertainty. Sea level and recharge ensembles were generated for the year 2050 and were then used to generate a predictive parameter ensemble conveying parameter, observation and climate uncertainty. Multi-objective OUU was then conducted, aiming to both maximize pumping rates and minimize the probability of well salinization. As a result, the optimal trade-off between pumping and the probability of salinization was quantified considering parameter, historical observation and future climate uncertainty simultaneously. The multi-objective, ensemble-based OUU led to optimal pumping rates that were very different from a previous deterministic OUU and close to the current and projected water demand for risk-averse stances. Incorporating climate uncertainty into the OUU was also critical since it reduced the maximum allowable pumping rates for users with a risk-averse stance. The workflow used tools adapted to very high-dimensional, nonlinear models and optimization problems to facilitate its implementation in a wide range of real-world settings.

Deep monitoring wells with long screens crossing the transition zone between freshwater and saltwater are often used in coastal areas to characterize fresh groundwater resources and the depth of saline groundwater. However, past studies have demonstrated that long-screen wells can lead to biased observations of the transition zone, since vertical flow within the borehole can modify the shape and elevation of the transition zone in and around the borehole compared to undisturbed conditions without a well. Here, field observations and variable-density numerical flow simulations are used to evaluate, under natural flow conditions, how the installation of long-screen wells can provide time-varying biased observations of the freshwater-saltwater transition zone, and how various aquifer and well parameters affect the magnitude of these biases. Results show that long-screen wells can lead to a more dispersed interface, an upward displacement of the transition zone of between 5 and 10 m, and a salinity decrease in the saltwater portion of the well on the order of 10 to 15 g/L. The perturbations take up to 5 years to fully develop and stabilize. The degree of displacement depends on the screen diameter, screen length, aquifer anisotropy, and hydraulic conductivity, whereas the displacement is independent of the distance of the well from the coast. This analysis provides insight into which well and aquifer characteristics increase the risk of obtaining biased observations in long-screen wells, and provides orders of magnitude for these biases., (© 2025 The Author(s). Groundwater published by Wiley Periodicals LLC on behalf of National Ground Water Association.)

Positron emission tomography imaging using radiolabeled dolutegravir (DTG) is an interesting approach to understand the biodistribution of this antiretroviral drug at HIV-1 sanctuary sites. In the course of clinical translation, we depict herein an improved and pharmaceutically compliant radiosynthesis of [ 18 F]DTG from an original tin precursor. The radiosynthesis was achieved in two steps by copper-mediated radiofluorination, followed by enol ether deprotection using a kit-based AllInOne module. Ready-to-inject [ 18 F]DTG was obtained in 20 ± 5% ( n = 12) decay-corrected radiochemical yield within 90 min, representing a 4-fold increase compared to the previously published three-step radiosynthesis. Quality control was carried out with three consecutive [ 18 F]DTG productions according to the current European Pharmacopoeia guidelines, which include pH determination, identity and purity (chemical, radiochemical, and radionuclide) assessments, residual solvent quantification, dosage of lithium, copper, and tin traces, sterility and bacterial endotoxin tests. [ 18 F]DTG (∼2 GBq) was obtained with a molar activity of 59 ± 2 GBq/μmol at the time of injection and was suitable for human applications., Competing Interests: The authors declare the following competing financial interest(s): Thomas Bonasera is employed by GSK. Chris M. Parry is employed by ViiV Healthcare and has stock/shares in GSK., (© 2024 The Authors. Published by American Chemical Society.)

Background: Cardiovascular diseases (CVDs) are currently the leading cause of maternal death in Western countries. Although multidisciplinary cardio-obstetric teams are recommended to improve the management of pregnant women with CVD, data supporting this approach are scarce., Aims: To describe the characteristics and outcomes of pregnant patients with CVD managed within the cardio-obstetric programme of a tertiary centre., Methods: We included every pregnant patient with history of CVD managed by our cardio-obstetric team between June 2017 and December 2019, and collected all major cardiovascular events (death, heart failure, acute coronary syndromes, stroke, endocarditis and aortic dissection) that occurred during pregnancy, peripartum and the following year., Results: We included 209 consecutive pregnancies in 202 patients. CVDs were predominantly valvular heart diseases (37.8%), rhythm disorders (26.8%), and adult congenital heart diseases (22.5%). Altogether, 47.4% were classified modified World Health Organization (mWHO)>II, 66.5% had CARdiac disease in PREGnancy score (CARPREG II)≥2 and 80 pregnancies (38.3%) were delivered by caesarean section. Major cardiovascular events occurred in 16 pregnancies (7.7%, 95% confidence interval [CI] 4.5-12.2) during pregnancy and in three others (1.5%, 95% CI 0.3-4.1) during 1-year follow-up. Most events (63.1%) occurred in the 16.3% of patients with unknown CVD before pregnancy., Conclusions: The management of pregnant patients with CVD within a cardio-obstetric team seems encouraging as we found a relatively low rate of cardiovascular events compared to the high-risk profile of our population. However, most of the remaining events occurred in patients without cardiac monitoring before pregnancy., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Faced with the pandemic viral circulation of SARS-CoV-2, healthcare establishments have had to maintain an effective screening strategy in order to prevent nosocomial clusters. Automated antigenic tests appear to be a reliable and complementary alternative to RT-PCR (reverse transcriptase polymerase chain reaction) in order to optimize patient care in the emergency department. We report our experience of the deployment of the LumiraDx antigen tests on the LumiraDx platform, as well as the comparison of these tests' results with the RT-PCR results on a population of patients sampled in the emergency department.

Objectives: Aldosterone and renin determinations play an important role in the etiological diagnosis of secondary hypertension. The analytical performances of new aldosterone and renin immunoassays on the Lumipulse G600II ® system (Fujierbio) were investigated and compared with those of the iSYS ® system (IDS) on patients concerned by medical investigations in a context of suspected or proven Primary aldosteronism., Methods: By using the Lumipulse ® G Aldosterone and Renin assays we performed imprecision study, linearity and method comparison (n=107). Accuracy of this new renin assay was tested using the International Standard (WHO IS 68/356). We also assessed the equivalence of the different samples types (n=29)., Results: The imprecision evaluation showed all CVs <3% and <6% for Lumipulse ® G Aldosterone and Renin assays respectively. The linearity was excellent over the clinical range and the comparison with the iSYS ® assays (n=79) showed a strong correlation (R 2 =1) despite a slight tendency to underestimation (bias of -17.53 pg/mL or 48.56 pmol/L for aldosterone and -15.395 pg/mL for renin). Moreover, the contingency studies based on diagnostic criteria showed that Lumipulse ® G results lead to the same clinical diagnosis that iSYS ® results. A clear correlation was obtained between EDTA and heparin plasma as well as with the serum for all range of measures., Conclusions: The Lumipulse ® G Aldosterone and Renin assays present performances compatible with a routine use in medical laboratories. The precise quantification in the low range can be of interest in some clinical contexts especially standing/laying tests. However, the standardisation against the WHO International Standard Renin would be advisable., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Microglia, the innate immune cells of the brain, are essential for maintaining homeostasis by their ramified, highly motile processes and for orchestrating the immune response to pathological stimuli. They are implicated in several neurodegenerative diseases like Alzheimer's and Parkinson's disease. One commonality of these diseases is their strong correlation with aging as the highest risk factor and studying age-related alterations in microglia physiology and associated signaling mechanism is indispensable for a better understanding of age-related pathomechanisms. CD22 has been identified as a modifier of microglia phagocytosis in a recent study, but not much is known about the function of CD22 in microglia. Here we show that CD22 surface levels are upregulated in aged versus adult microglia. Furthermore, in the amyloid mouse model PS2APP, Aβ-containing microglia also exhibit increased CD22 signal. To assess the impact of CD22 blockage on microglia morphology and dynamics, we have established a protocol to image microglia process motility in acutely prepared brain slices from CX3CR1-GFP reporter mice. We observed a significant reduction of microglial ramification and surveillance capacity in brain slices from aged versus adult mice. The age-related decrease in surveillance can be restored by antibody-mediated CD22 blockage in aged mice, whereas surveillance in adult mice is not affected by CD22 inhibition. Moreover to complement the results obtained in mice, we show that human iPSC-derived macrophages exhibit an increased phagocytic capacity upon CD22 blockage. Downstream analysis of antibody-mediated CD22 inhibition revealed an influence on BMP and TGFβ associated gene networks. Our results demonstrate CD22 as a broad age-associated modulator of microglia functionality with potential implications for neurodegenerative disorders., Competing Interests: During the course of this study, all authors are or were full time employees or trainees at Roche and they may additionally hold Roche stock/stock options. The reviewer DE declared a shared affiliation with one of the authors VA to the handling editor at the time of the review., (Copyright © 2021 Aires, Coulon-Bainier, Pavlovic, Ebeling, Schmucki, Schweitzer, Kueng, Gutbier and Harde.)

A large body of preclinical research has shown that neuroimmunity plays a key role in the deleterious effects of alcohol (ethanol) to the brain. Translational imaging techniques are needed to monitor the efficacy of strategies to prevent or mitigate neuroinflammation and alleviate ethanol-induced neurotoxicity. Opioid receptor antagonists such as nalmefene are antagonists of the toll-like receptor 4, which may block the proinflammatory signaling cascade induced by ethanol at this specific target. Male adolescent rats received a validated protocol of ethanol injection (i.p, 3 g/kg daily for two consecutive days followed by two resting days) during 14 days. Positron emission tomography (PET) imaging with the translocator protein 18 kDa (TSPO) radioligand [ 18 F]DPA-714 was performed at day-15. Toxicity induced by repeated binge-like ethanol exposure (71% mortality) was drastically reduced by nalmefene pretreatment (0.4 mg/kg, 14% mortality). No mortality was observed in animals that received vehicle (control) or nalmefene alone. Compared with control animals (n = 10), a significant 2.8-fold to 4.6-fold increase in the volume of distribution (V T ) of [ 18 F]DPA-714 was observed among brain regions in animals exposed to ethanol only (n = 9). Pretreatment with nalmefene significantly alleviated the neuroimmune response to ethanol exposure in all brain regions (1.2-fold to 2.5-fold increase in V T ; n = 5). Nalmefene alone (n = 6) did not impact [ 18 F]DPA-714 V T compared with the control group. Nalmefene may protect against the neuroinflammatory response and overall toxicity associated with binge drinking. [ 18 F]DPA-714 PET imaging can be used to noninvasively address the neuroimmune impact of ethanol exposure and its modulation by pharmacological strategies in vivo, with translational perspectives., (© 2020 Society for the Study of Addiction.)

Background: Today, many agricultural products claiming a link to their origin and typicity receive a warm welcome on the market. Nevertheless, the notion of typicity is blurred for consumers and needs to be objectified for communication purposes. This study aims at formalizing a methodology for studying typicity of terroirs, with PDO wines as an example, using a participatory approach with professionals of the wine sector from terroirs, using focus group and tasting. The vision of typicity of terroirs by professionals outside of these terroirs has been studied by a free word association task., Results: This study allowed a clear distinguishing of the typicity of the studied terroirs. Professionals from terroirs identified the global conceptual typicity of their terroirs using various factors, mainly soil, geography and grape variety, whereas professionals outside terroirs expressed their visions of terroirs by reputation or sensory characteristics of wines. Tasting results showed a discrimination of wines based on their typicity and highlighted descriptors involved in sensory perceptual typicity for each studied terroir., Conclusions: Professionals from terroirs share a common vision of their typicity and identify more typicity factors than professionals outside terroirs. Sensory typicity has been highlighted for five of the six terroirs studied, according to the various descriptors. The study of two populations, from and outside terroirs, shows the gap between the typicities identified by professionals from terroirs and those perceived by professionals outside terroirs. © 2020 Society of Chemical Industry., (© 2020 Society of Chemical Industry.)

Introduction: Glyburide is an approved anti-diabetes drug binding to the sulfonylurea receptors-1 (SUR-1) and substrate of solute carrier (SLC) transporters, which can be isotopically radiolabelled with carbon-11 for PET imaging. The aim of this work is to present an original and reproducible automated radiosynthesis of [ 11 C]glyburide and a full European Pharmacopeia 9.7 compliant quality control to use [ 11 C]glyburide in PET imaging clinical trials., Methods: Different conditions were explored to afford non-radioactive glyburide by one or two-step methylation. These experiments were monitored by UPLC-MS. The optimized process was applied to the automated radiosynthesis of [ 11 C]glyburide using a TRACERlab® FX C Pro. A complete quality control according to Pharmacopeia guidelines was realized., Results: One-step methylation revealed regioselectivity issues as methylation occurred preferentially on the sulfonylurea moiety. Two-step approach by methylation followed by reaction with cyclohexyl isocyanate afforded glyburide without formation of methylated side products. Ready-to-inject [ 11 C]glyburide was obtained in 5% non-decay corrected radiochemical yield and 110 ± 20 GBq/μmol molar activity within 40 min (n = 8). [ 11 C]Glyburide quality control was compliant with the Pharmacopeia requirements., Conclusions: We have described a highly reproducible and automated two-step radiosynthesis of [ 11 C]glyburide which was qualified as a radiopharmaceutical for human injection. This whole manufacturing process is currently being used to conduct a clinical trial to elucidate the hepatic transport of drugs., Advances in Knowledge: Compared to previously reported radiosynthesis of [ 11 C]glyburide, this work provides an original and reproducible approach which can be transferred to any PET centre interested in using this radiotracer for preclinical or clinical imaging., Implication for Patient Care: This work provides a method to manufacture [ 11 C]glyburide for human PET imaging. This radiopharmaceutical could be used to elucidate the role of transporters in drug exposure of different organs or to monitor brain recovery after central nervous system (CNS) injuries., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To determine the ophthalmological and extra-ophthalmological clinical characteristics and visual prognosis of patients with sarcoid uveitis in different ethnic groups., Methods: We retrospectively analysed the data from patients with sarcoid uveitis seen at two departments of Ophthalmology between December 2003 and December 2017. Patients presented biopsy-proven sarcoidosis and/or presumed sarcoid uveitis based on the following criteria: compatible thoracic imaging, associated with elevated angiotensin-conversion enzyme (ACE) and/or lymphocytic alveolitis on bronchoalveolar lavage fluid analysis (> 15% lymphocytes and CD4/CD8 > 3.5). Ophthalmological and general characteristics, as well as visual and global prognoses, were compared in three pre-defined ethnic groups: White Europeans, North Africans and Afro-Caribbeans., Results: A total of 194 patients were included: 145 with biopsy-proven and 49 with presumed sarcoid uveitis. Overall, 68% were White Europeans while 20.6% were North Africans and 11.3% were Afro-Caribbeans. Sixty-nine per cent were women and the median age at presentation was 52.1 years. Median ages at first ocular manifestation of the disease in Afro-Caribbeans and North Africans were respectively 34.3 and 43.1 years, while it was 57.8 years in White Europeans (p < 0.001). Ocular involvement was bilateral in 77.8% (n = 151) of the cases and nearly half of the patients had panuveitis (48.5%). Anterior uveitis was more frequent in Afro-Caribbeans (59.1%; p < 0.0001), while White Europeans presented more frequently with intermediate uveitis. There was a significantly higher frequency of systemic involvement of sarcoidosis in North Africans while White Europeans showed a higher frequency of isolated ocular involvement at onset and during follow-up. Afro-Caribbeans, who had a complete visual recovery in 72.7% of the cases, had a better visual prognosis than other ethnic groups (p = 0.025)., Conclusion: In this large European series of sarcoid uveitis, we observed ethnicity-related differences regarding uveitis clinical presentation and visual outcome. Although good overall, the visual prognosis seems to be better in Afro-Caribbeans than in other ethnic groups.

Esophageal atresia (EA) is prenatally diagnosed in less than one third of the cases and is usually only suspected. Recently, magnetic resonance imaging (MRI) with dynamic sequence and biochemistry of the amniotic fluid have been proposed to enhance prenatal diagnosis of EA. We report the case of a triple negative screening (ultrasound, MRI with dynamic sequence and biochemistry of the amniotic fluid) with a postnatal diagnosis of EA type III with a small defect. Even using second line tests, prenatal diagnosis of EA remains a challenge., (Copyright © 2018. Published by Elsevier Masson SAS.)

Background: Almost 20% of parvovirus B19 foetal infections require intrauterine transfusions. In addition, myocardial dysfunction has been observed in severe parvovirus B19 infections. One objective of an intrauterine exchange transfusion (IUET) is to avoid an overload during the transfusion. Our aim was to study the obstetrical and neonatal outcomes in cases of IUETs performed for foetal parvovirus infections and to compare our survival rate to those studies in which simple in utero transfusions were chosen., Study Design and Methods: This was a retrospective monocentre study of all patients followed up for parvovirus B19 infections in which IUETs were performed. An IUET was indicated when foetal hydrops was observed and/or when severe foetal anaemia was diagnosed though an elevation in the middle cerebral artery peak systolic velocity. The characteristics of each pregnancy and the neonatal outcomes were studied until hospital discharge., Results: Thirty-five IUETs were performed in 26 foetuses. The median gestational age of the first IUET was 22.6 weeks. Only one foetal bradycardia incidence was recorded during the procedure. Three medical pregnancy terminations were observed in our series, secondary to severe cerebral anomalies confirmed in the magnetic resonance imaging. Five in utero deaths occurred, in which 2 of the foetuses underwent multiple IUETs. All the neonates had normal haemoglobin levels at birth, and none were transferred to the neonatal intensive care unit. The overall survival rate was 70%., Conclusion: IUETs exhibit a survival rate similar to that of simple intrauterine transfusions in foetal parvovirus infection cases., (© 2018 AABB.)

Purpose: To investigate choriocapillaris (CC) blood flow in unaffected fellow eyes of patients with central serous chorioretinopathy (CSC) using quantitative optical coherence tomography angiography (OCTA) analysis., Design: Case-control study., Methods: Patients with acute, recurrent, or persistent CSC, along with healthy sex- and age-matched subjects, were included. Objective assessment of CC blood flow was performed using OCTA measurements. Total area of flow signal voids was quantified at baseline, 3 months, and 6 months. Active serous retinal detachment (SRD) was considered as a potential source of false-positive flow impairment; affected eyes were therefore excluded at onset and during follow-up, if this finding was unresolved at the time of measurement., Results: Sixty patients with CSC and 60 control subjects were included in this study. The total average flow signal void area was significantly higher in the unaffected eyes of CSC patients at baseline (2.70 ± 0.53 mm 2 vs 2.23 ± 0.43 mm 2 , P < .001). At 3 months, the total average flow signal void area was greater in the affected eyes of CSC patients with resolved SRD compared with unaffected eyes (3.25 ± 0.77 mm 2 vs 2.67 ± 0.68 mm 2 , P < .001). This total average flow signal void area was larger in unaffected eyes at baseline in recurrent/persistent cases of CSC compared to acute forms (3.74 ± 0.66 mm 2 vs 2.93 ± 0.69 mm 2 , P = .01)., Conclusions: Vascular abnormalities in CSC involve CC hypoperfusion, suggestive of a primary choroidopathy including ischemic processes. These microvascular flow deficits may constitute one of a number of underlying subclinical changes preceding CSC and other pachychoroid spectrum disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The effects of acute alcohol exposure to the central nervous system are hypothesized to involve the innate immune system. The neuroimmune response to an initial and acute alcohol exposure was investigated using translocator protein 18 kDa (TSPO) PET imaging, a non-invasive marker of glial activation, in adolescent baboons. Three different alcohol-naive adolescent baboons (3-4 years old, 9 to 14 kg) underwent 18 F-DPA-714 PET experiments before, during and 7-12 months after this initial alcohol exposure (0.7-1.0 g/l). The brain distribution of 18 F-DPA-714 (V T ; in ml/cm 3 ) was estimated in several brain regions using the Logan plot analysis and the metabolite-corrected arterial input function. Compared with alcohol-naive animals (V Tbrain  = 3.7 ± 0.7 ml/cm 3 ), the regional V T s of 18 F-DPA-714 were significantly increased during alcohol exposure (V Tbrain  = 7.2 ± 0.4 ml/cm 3 ; p < 0.001). Regional V T s estimated several months after alcohol exposure (V Tbrain  = 5.7 ± 1.4 ml/cm 3 ) were lower (p < 0.001) than those measured during alcohol exposure, but remained significantly higher (p < 0.001) than in alcohol-naive animals. The acute and long-term effects of ethanol exposure were observed globally across all brain regions. Acute alcohol exposure increased the binding of 18 F-DPA-714 to the brain in a non-human primate model of alcohol exposure that reflects the 'binge drinking' situation in adolescent individuals. The effect persisted for several months, suggesting a 'priming' of glial cell function after initial alcohol exposure., (© 2017 Society for the Study of Addiction.)

Introduction: Intrauterine transfusion (IUT) has changed fetal anemia prognosis. However, long-term neurodevelopmental outcome is altered in 5% of children. Our objective was to study the contribution of fetal MRI to diagnosis brain lesions in case of fetal anemia., Material and Methods: Retrospective monocentric descriptive study from 2005 to 2016, including all patients followed for fetal anemia requiring IUT. The indications for MRI were: hydrops fetalis and / or hemoglobin <5 g / dL and / or more than 3 IUTs and / or acute severe anemia and / or ultrasound abnormality. Fetal and neonatal outcome and pediatric neurological monitoring were studied., Results: 89 patients were followed for fetal anemia with IUT and 28 (29.1%) had fetal MRI, 12 of which were abnormal. Two out of twelve had abnormal ultrasound. Seven out of twelve had poor neurological prognosis: 2 medical terminations of pregnancy were performed; 2 children had severe developmental delay and 3 children had schooling difficulties. Five out of twelve children had favorable neurological prognosis., Conclusion: MRI of the fetal brain makes it possible to better detect brain lesions than ultrasound does in the management of severe fetal anemia and seems particularly appropriate in cases of acute anemia., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Elacridar (GF120918) is a highly potent inhibitor of both P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), the main efflux transporters expressed at the blood-brain barrier (BBB). Elacridar shows very low aqueous solubility, which complicates its formulation for i.v. administration. An intravenous infusion protocol would be preferred to achieve high and controlled plasma concentrations of elacridar in large animals, including nonhuman primates. Formulation of elacridar for i.v. infusion was achieved using a co-solvent strategy, resulting in an aqueous dispersion with a final concentration of 5 g L -1 elacridar with tetrahydrofuran (5% w/v) in aqueous D-glucose solution (2.5%, w/v). Particle size (mean = 2.8 ± 0.9 μm) remained stable for 150 min. The preparation was i.v. administered as a continuous infusion (12 mg kg -1  h -1 for 90 min) to three baboons. Arterial and venous plasma pharmacokinetics (PK) of elacridar were monitored using a newly developed and validated HPLC-UV method. Elacridar concentration increased rapidly to reach a plateau at 9.5 μg mL -1 within 20 min after the start of infusion. Elacridar PK in venous plasma did not differ from arterial plasma facing the BBB, indicating the absence of an arteriovenous concentration gradient. Intravenous infusion of elacridar allows for controlled exposure of the BBB and offers a useful tool to assess the impact of ABCB1/ABCG2 on drug disposition to the brain in nonhuman primates, a relevant animal model for the study of transporter function at the BBB.

Background: The antibody primarily responsible for fetal anemia may influence treatment and prognosis. The primary objective was to compare ante- and postnatal management and the outcomes of maternal red blood cell (RBC) alloimmunizations according to the antibody involved. The secondary objective was to compare anti-D alloimmunizations according to associated number of antibodies., Study Design and Methods: A single-center study from 1999 to 2015 including maternal RBC alloimmunizations requiring intrauterine transfusion (IUT) was conducted. Patients were classified according to the antibody involved: anti-D, other Rh (anti-c and anti-E), and anti-K1. Obstetric data, IUT characteristics, and neonatal outcome were compared. A specific study on the anti-D, when isolated or associated, was then conducted., Results: There were 106 pregnancies included, with 77.4% having anti-D, 9.4% having another anti-Rh (Rh group), and 13.2% having anti-K1. No significant difference between the anti-D and Rh groups was found for management and prognosis. The hemoglobin level in the first IUT was higher in the anti-D group than in the Kell group (6.8 vs. 4.7 g/dL, p = 0.008). Newborns in the anti-D group had significantly higher bilirubin levels and phototherapy duration than those in the Kell group. The mean estimated daily decrease in hemoglobin and that between the first two IUTs were lower with an isolated anti-D, compared with anti-D associated with two antibodies (p = 0.04)., Conclusion: Anti-K1 alloimmunizations seem to cause more severe fetal anemia than anti-D alloimmunizations. Moreover, a decrease in hemoglobin appears to be more rapid when anti-D is associated with other antibodies., (© 2018 AABB.)

The main cause of fetal anemia is maternal red blood cell alloimmunization (AI). The search of maternal antibodies by indirect antiglobulin test allows screening for AI during pregnancy. In case of AI, fetal genotyping (for Rh-D, Rh-c, Rh-E and Kell), quantification (for anti-rhesus antibodies) and antibody titration, as well as ultrasound monitoring, are performed. This surveillance aims at screening for severe anemia before hydrops fetalis occurs. Management of severe anemia is based on intrauterine transfusion (IUT) or labor induction depending on gestational age. After intrauterine transfusion, follow-up will focus on detecting recurrence of anemia and detecting fetal brain injury. With IUT, survival of fetuses with alloimmunization is greater than 90% but 4.8% of children with at least one IUT have neurodevelopmental impairment., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

We demonstrate editing of post-mitotic neurons in the adult mouse brain following injection of Cas9 ribonucleoprotein (RNP) complexes in the hippocampus, striatum and cortex. Engineered variants of Cas9 with multiple SV40 nuclear localization sequences enabled a tenfold increase in the efficiency of neuronal editing in vivo. These advances indicate the potential of genome editing in the brain to correct or inactivate the underlying genetic causes of neurological diseases.

Background: To best predict the recurrence of fetal anemia after intrauterine transfusion (IUT), the measurement of middle cerebral artery peak systolic velocity (PSV) and the estimation of hemoglobin (Hb) daily decrease are compared., Study Design and Methods: A retrospective study including 38 patients who had at least two IUTs in a context of red blood cell alloimmunization was conducted. PSV values before first, second, and third IUTs were collected and expected Hb level was calculated according to various Hb daily decrease formulas as proposed in the literature., Results: Comparison of PSV receiver operating characteristic curves with the various Hb levels did not find any significant difference between first and second IUTs. On the other hand, we found a significant difference between the second and third IUTs, with better prediction of fetal anemia through Hb decrease calculation, whatever the formula. Between the second and third IUTs, no formula was significantly better than the others., Conclusion: The timing of a second transfusion can be difficult to determine with certainty, but PSV can give an accurate assessment of when to resample the fetus with probably a higher recommended threshold for the diagnosis of fetal anemia. Subsequent to a second transfusion, the intertransfusion interval should be based on estimated Hb decrease rather than PSV thresholds, whatever the chosen formula proposed in the literature. Larger numbers are needed to definitely make this recommendation and it will be interesting to evaluate correlation between different antibodies., (© 2017 AABB.)

Half of acute aortic dissection in women under the age of 40 occurs during pregnancy or peripartum period. Marfan syndrome is the most common syndromic presentation of ascending aortic aneurysm, but other syndromes such as vascular Ehlers-Danlos syndrome, Loeys-Dietz syndrome and Turner syndrome also have ascending aortic aneurysms and the associated cardiovascular risk of aortic dissection and rupture. Management of aortic root aneurysm has been established in recent recommendations, even if levels of evidence are weak. Pregnancy and postpartum period should be followed very closely and determined to be at high risk. Guidelines suggest that women with aortopathy should be counseled against the risk of pregnancy and about the heritable nature of the disease prior to pregnancy., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Biofilm formation is a complex, ordered process. In the opportunistic pathogen Pseudomonas aeruginosa, Psl and Pel exopolysaccharides and extracellular DNA (eDNA) serve as structural components of the biofilm matrix. Despite intensive study, Pel's chemical structure and spatial localization within mature biofilms remain unknown. Using specialized carbohydrate chemical analyses, we unexpectedly found that Pel is a positively charged exopolysaccharide composed of partially acetylated 1→4 glycosidic linkages of N-acetylgalactosamine and N-acetylglucosamine. Guided by the knowledge of Pel's sugar composition, we developed a tool for the direct visualization of Pel in biofilms by combining Pel-specific Wisteria floribunda lectin staining with confocal microscopy. The results indicate that Pel cross-links eDNA in the biofilm stalk via ionic interactions. Our data demonstrate that the cationic charge of Pel is distinct from that of other known P. aeruginosa exopolysaccharides and is instrumental in its ability to interact with other key biofilm matrix components.

Objective: Doppler measurement of peak velocity of systolic blood flow in the middle cerebral artery (PVS-MCA) can safely replace invasive testing in the diagnosis of fetal anemia in Rh-alloimmunized pregnancies and PSV-MCA is now the reference technique. However, no study has evaluated its impact in antenatal care and in survival rate. Our objective was to evaluate the impact of the measurement of PVS-MCA in antenatal management and neonatal outcome in maternal red cell alloimmunization requiring in utero transfusion (IUT)., Study Design: Retrospective study between January 1999 and January 2013. We excluded all cases of hydrops without follow-up before first IUT. From 1999 to 2006, an IUT was indicated on the optical index at 450 nm (Period 1) and was then replaced by the use of PVS-MCA (Period 2)., Results: 77 patients were included, 39 in Period 1 (104 IUT) and 38 in Period 2 (89 IUT). 5 cases of hydrops fetalis (12.8%) were diagnosed during the follow up in Period 1 and none during Period 2. The average number of IUT, the delays between 2 IUT and between last IUET and birth were comparable. The total rate of complication per IUT during the first period was 9.6% vs 1.1% during the second one (p=0.01). The overall survival rate in our population was 34/39 (86.8%) during Period 1 vs 38/38 (100%) during Period 2., Conclusion: PSV-ACM allowed an improved monitoring with fewer occurrences of hydrops. Conversely, it did not modify antenatal management and timing of delivery., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Prenatal diagnosis of esophageal atresia (EA) remains a challenge. Our objective was to evaluate the combination of sonography, magnetic resonance imaging (MRI), and amniotic fluid biochemical markers in prenatal diagnosis of EA., Study Design: A retrospective study of all cases with prenatal suspicion of EA from January 2008 to May 2013 in our regional reference center was carried out. Patients were included if all the three tests were performed. For each test, sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) were evaluated. Each test was compared using Fisher's exact test., Results: Fifteen patients were referred at a median gestational age of 28(+5)  weeks (24-36) for suspicion of EA on the basis of small or non-visualized fetal stomach bubble and/or polyhydramnios. Se, Sp, PPV, and NPV for sonographic pouch sign/MRI/biochemical amniotic fluid were respectively 40/100/100/45.5%, 80/100/100/71.4%, and 90/60/81.8/75%. MRI was the best predictive test (p = 0.007)., Conclusion: In case of ultrasound prenatal suspicion of EA (with or without visualization of the pouch sign), an MRI at 30-32 weeks using fast imaging employing steady-state acquisition should be proposed. Biochemical amniotic fluid may be helpful and should be evaluated in a larger study., (© 2014 John Wiley & Sons, Ltd.)

Objective: To assess the efficacy of moxibustion (heating of the acupuncture needle with an igniting charcoal moxa stick) with acupuncture for version of breech presentations after 33 4/7 weeks of gestation to reduce their rate at 37 weeks of gestation and at delivery., Methods: This was a randomized placebo-controlled single-blind trial including 328 pregnant women recruited in a university hospital center between 33 4/7 and 35 4/7 weeks of gestation. Moxibustion with acupuncture or inactivated laser (placebo) treatment was applied to point BL 67 for six sessions. The principal endpoint was the percentage of fetuses in breech presentation at 37 2/7 weeks of gestation., Results: The study included 328 women randomized into two groups: moxibustion with acupuncture (n=164) or placebo (n=164). The percentage of fetuses in breech presentation at 37 2/7 weeks of gestation was not significantly different in both groups (72.0 in the moxibustion with acupuncture group compared with 63.4% in the placebo group, relative risk 1.13, 95% confidence interval 0.98-1.32, P=.10)., Conclusion: Treatment by moxibustion with acupuncture was not effective in correcting breech presentation in the third trimester of pregnancy., Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01487590.

Congenital diaphragmatic hernia (CDH) has an incidence of around 1/3,000 births. The pathogenesis of this developmental anomaly remains largely unknown and the description of small chromosomal imbalances in cases of CDH is of major interest for the identification of candidate genes. We report on a tandem 4q31.23 triplication encompassing the EDNRA gene identified by array-CGH in a male presenting an isolated left postero-lateral CDH. This copy number variation was inherited from the asymptomatic father, carrier of a size-identical duplication. We demonstrate that EDNRA mRNA is over-expressed in the proband in blood tissue. Consistent with the expression of EDNRA in the developing diaphragm and the observation that the endothelin system is up-regulated in human and animal models of CDH, we conclude that the EDNRA triplication may be the cause of CDH in our patient., (© 2013 Wiley Periodicals, Inc.)

A new cyanido-bridged Re(IV)-Mn(III) heterometallic 1D system, [Mn(III)(5-Me-saltmen)](2)[Re(IV)Cl(4)(CN)(2)]·3CH(3)CN (1), was designed and structurally characterized. Interchain interactions stabilize a canted antiferromagnetic ordered state below 6.2 K that does not prevent slow relaxation of the magnetization reminiscent of the single-chain magnet properties of the individual chains.

Unlabelled: Aim Peripartum cardiomyopathy (PPCM) is a rare cause of dilated cardiomyopathy responsible for heart failure toward the end of pregnancy, which can lead to chronic heart failure in 50% of cases. In this short report, we assessed the benefit of cardiac resynchronization in patients with PPCM and chronic systolic dysfunction despite optimal medical treatment., Methods and Results: For the last 10 years, we managed eight patients diagnosed with PPCM. Two of them presented severe systolic dysfunction, and medical treatment resulted in limited improvement from 10% to 25% and from 25% to 28% despite optimal treatment for 9 and 6 years, respectively. These two patients were porposed to receive an implantatable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT). Six months after ICD-CRT treatment, we observed a significant improvement in systolic function from 25% to 45% and 28% to 50%, respectively, and positive remodelling with reduction of left ventricular end-diastolic volume from 216 to 144 mL and from 354 to 105 mL, which represent a 34% and a 70% reduction, respectively., Conclusions: Physicians in charge of patients with PPCM should offer the opportunity of CRT for patients whose cardiac function has not significantly improved under standard medical treatment.

Despite increasing concerns of direct pathogenicity and/or their role as hosts for other microorganisms there are currently no standard methods for the inactivation of amoebae that belong to the genus Acanthamoeba. Methods used to grow amoebae and produce cysts for these tests may be important as they can dramatically modify cyst susceptibility. We compared resistance of cysts produced from trophozoites grown in peptone-yeast extract-glucose broth or by feeding on HEp-2 cells and then encysted in Neff's medium. We observed that trophozoites grown using HEp-2 cells as a nutrient source produce cysts that are significantly more resistant to SDS and to most biocides tested, including heat. Increased resistance is likely due to a higher proportion of mature cysts presenting thicker cell walls as demonstrated using transmission electron microscopy. This was confirmed by calcofluor white staining demonstrating higher cellulose content in cysts produced from trophozoites grown using HEp-2 cells as a feeding source. These results demonstrate that not only methods used to produce cysts from trophozoites are critical, but that methods used to grow trophozoites before encystment should also be chosen carefully. This should be taken into account for the development of protocols to evaluate biocides and antimicrobials against amoebal cysts., (© 2012 The Author(s) Journal of Eukaryotic Microbiology © 2012 International Society of Protistologists.)

The term 'Chlamydia-like organisms' encompasses obligate intracellular bacterial species phylogenetically close to Chlamydiaceae. Most are associated with free-living amoebae, and several could be responsible for respiratory tract infections and abortion in human and animals. Despite increasing concern about their pathogenic role, the prevalence, biodiversity and ecology of Chlamydia-related bacteria still remain largely unknown. In this study, six members of the Chlamydiales were tested, including Parachlamydia acanthamoebae (two different strains), Protochlamydia naegleriophila, Waddlia chondrophila, Criblamydia sequanensis and Chlamydia trachomatis as a reference. Intracellular growth was tested in 11 different Acanthamoeba strains, demonstrating significant differences in host susceptibilities to infection depending on strains investigated. Survival of host-free bacteria in suspension or dried onto surfaces was also explored, demonstrating that Chlamydia-like organisms present better survival capacity than C. trachomatis. Longer survival times were observed for bacteria suspended in rich culture medium, with survivors being detected after 10 weeks incubation. We also tested susceptibility of host-free Chlamydia-like organisms to several disinfection treatments. Each chemical biocide tested reduced viability of host-free Chlamydia by more than 4 logs. Conversely, all Chlamydia-like organisms tested resisted exposure at 55 °C for 10 min, while C. trachomatis was completely inactivated., (© 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

Introduction: LBT-999, (E)-N-(4-fluorobut-2-enyl)-2β-carbomethoxy-3β-(4'-tolyl)nortropane, has been developed for PET imaging of the dopamine transporter. [(18)F]LBT-999 PET studies in baboons showed a lower brain uptake than [(11)C]LBT-999 and a high bone uptake, suggesting the presence of interfering metabolites. Therefore, in vitro and in vivo metabolism of these radiotracers was investigated., Methods: Rat and human liver microsomal incubations, baboon plasma and rat brain extracts were analyzed by radio-HPLC and LC-MS-MS., Results: In vitro experiments demonstrated the formation by P450s of five polar metabolites. The main routes of LBT-999 metabolism proposed were N-dealkylation, tolyl-hydroxylation and dealkylation plus tolyl-hydroxylation. In vivo in baboons, [(18)F]LBT-999 was rapidly converted into a [(18)F]hydroxylated metabolite likely oxidized in plasma into a [(18)F]carboxylic acid and into unlabeled N-dealkyl-LBT-999. The latter was detected in baboon plasma and in rat brain by LC-MS-MS. The time course of unchanged [(18)F]LBT-999 decreased rapidly in plasma and was higher than that of [(11)C]LBT-999 due to the formation of unlabeled N-dealkyl-LBT-999. In rats, striatum-to-cerebellum ratios of [(18)F]LBT-999, [(18)F]hydroxylated and [(18)F]acidic metabolite were 20, 4.2 and 1.65, respectively, suggesting a possible accumulation of the hydroxylated compound in the striatum., Conclusion: P450s catalyzed the formation of dealkylated and hydroxylated metabolites of LBT-999. In baboons, an extensive metabolism of [(18)F]LBT-999, with formation of unlabeled N-dealkyl-LBT-999, [(18)F]fluorobutenaldehyde (or its oxidation product) and [(18)F]hydroxy-LBT-999 able to penetrate the brain, prevented an easy and accurate estimation of the input function of the radiotracer. CYP3A4 being the main P450 involved in the metabolism of LBT-999, a similar pathway may occur in humans and confound PET quantification., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Imaging of TSPO 18 kDa with PET is more and more considered as a relevant biomarker of inflammation in numerous diseases. Development of new radiotracers for TSPO 18 kDa has seen acceleration in the last years and the challenge today is to make available large amounts of such a radiotracer in compliance with GMP standards for application in humans. We present in this technical note automated productions of [(18)F]DPA-714, [(18)F]PBR111 and [(18)F]FEDAA1106, three promising radiotracers for TSPO 18 kDa imaging, using a TRACERlab FX-FN synthesizer. This note also includes the quality control data of the validation batches for the manufacturing qualification of clinical production of [(18)F]DPA-714., (Copyright © 2011 Elsevier Ltd. All rights reserved.)