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Preterm infants are deficient in long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), a fatty acid (FA) associated with an increase in bronchopulmonary dysplasia (BPD). In two previous randomized control trials, DHA supplementation did not reduce the risk of BPD. We examined the breast milk FA profile, collected 14 days after birth, of mothers who delivered before 29 weeks of gestation and who were supplemented with DHA-rich algae oil or a placebo within 72 h after birth as part of the MOBYDIck trial. Milk FA were analyzed by gas chromatography. The total amount of FA (mg/mL) was similar in both groups but the supplementation increased DHA (expressed as % of total FA, mean ± SD, treatment vs placebo, 0.95 ± 0.44% vs 0.34 ± 0.20%; P

Context Fetal overgrowth “programs” an elevated risk of obesity and type 2 diabetes in adulthood. Plausibly, adipokines may be involved in programming metabolic health. Objective This work aimed to evaluate whether large-for-gestational-age (LGA), an indicator of fetal overgrowth, is associated with altered circulating leptin and adiponectin levels in infancy, and assess the determinants. Methods In the Canadian 3D birth cohort, we studied 70 LGA (birth weight > 90th percentile) and 140 optimal-for-gestational-age (OGA, 25th-75th percentiles) infants matched by maternal ethnicity, smoking, and gestational age at delivery. The primary outcomes were fasting leptin, and total and high-molecular-weight (HMW) adiponectin concentrations at age 2 years. Results LGA infants had higher body mass index (BMI) than OGA infants. However, there were no significant differences in leptin, and total and HMW adiponectin concentrations. Leptin concentrations were positively associated with female sex, weight (z score) gain 0 to 24 months, current BMI, and the sum of triceps and subscapular skinfold thickness, and negatively associated with maternal age and White ethnicity. Female sex was associated with lower total and HMW adiponectin concentrations. Weight (z score) gain 0 to 24 months and current BMI were positively correlated with total and HMW adiponectin concentrations in LGA infants only. Conclusion This study is the first to demonstrate that LGA does not matter for circulating leptin and adiponectin concentrations in infancy, and there may be LGA-specific positive associations between weight gain or current BMI and adiponectin concentrations in infancy, suggesting dysfunction in establishing the adiposity-adiponectin negative feedback loop in LGA individuals.

Objectives Even though SARS Cov2 outbreak management has been well-described, scant information is available in military settings. We aimed to describe a SARS Cov2 outbreak and its management on the Dixmude, a French landing helicopter dock. Patients and methods We performed an observational retrospective and monocentric study in a ship. Role 1 was reinforced by additional roles 1 and 2. Our analysis included all infected crew personnel. We described demographic data, outbreak course, and biological samples including Covid-19 diagnosis. All infected patients were monitored for 10 days. Results Between February 16th 2021 and March 12th 2021, 54 patients (10% of the entire crew) were included. No patient had previously been vaccinated against SARS Cov2. The global mission was maintained. The crew members were healthy, male, and young (median age 28 years) with no medical history. Ranks of every status were concerned. Covid-19 disease was mainly diagnosed by real-time reverse-transcriptase polymerase chain reaction (rt-PCR). Thirty-two patients (59%) were symptomatic, four (8%) were presymptomatic and 18 (33%) remained asymptomatic. Conclusions The present work describes specific SARS Cov2 outbreak management in an austere military environment. Early individual and global measures were set and implemented on board.

Introduction The maintenance of military surgeons’ operative skills is challenging. Different and specific training strategies have been implemented in this context; however, little has been evaluated with regard to their effectiveness. Cancer surgery is a part of military surgeons’ activities in their home hospitals. This study aimed to assess the role of oncological surgery in the improvement of military surgeons’ operative skills. Methods Between January and June 2019, the surgical activities of the departments of visceral, ear, nose, and throat, urological, and thoracic surgery were retrospectively reviewed and assessed in terms of the operative time (OT). All surgeons working at the Sainte Anne Military Teaching Hospital were sent a survey to rate on a 5-point scale the current surgical practices on their usefulness in improving surgical skills required for treating war injuries during deployment (primary endpoint) and to compare on a 10-point visual analog scale the influence of cancer surgery and specific training on surgical fluency (secondary endpoint). Results Over the study period, 2,571 hours of OT was analyzed. Oncological surgery represented 52.5% of the surgical activity and almost 1,350 hours of cumulative OT. Considering the primary endpoint, the mean rating allocated to cancer surgery was 4.53 ± 0.84, which was not statistically different than that allocated to trauma surgery (4.42 ± 1.02, P = 0.98) but higher than other surgery (2.47 ± 1.00, P Conclusion This study demonstrates the usefulness of cancer surgery in improving the operative skills of military surgeons.

The use of norepinephrine (NE) during uncontrolled haemorrhagic shock (HS) has mostly been investigated in experimental studies. Clinical data including norepinephrine dose and its impact on fluid resuscitation and organ function are scarce. We hypothesized that there is great variability in NE use and that high doses of NE could lead to increased organ dysfunction as measured by the sequential organ failure assessment (SOFA).We included patients with HS (systolic blood pressure90 mmHg in severely injured patients) who required haemostasis surgery and a transfusion of more than 4 packed red blood cells (PRBC) in the first 6 h of admission and the used of norepinephrine infusion to maintain the blood pressure goal, between admission and the end of haemostasis surgery in a prospective trauma database. A ROC curve determined that, using Youden's criterion, a dose of NE ≥ 0.6 µg/kg/min was the optimal threshold associated with intrahospital mortality. Patients were compared according to this threshold in a propensity score (PS) model. In a generalized linear mixed model, we searched for independent factors associated with a SOFA ≥ 9 at 24 h RESULTS: A total of 89 patients were analysed. Fluid infusion rate ranged from 1.43 to 57.9 mL/kg/h and norepinephrine infusion rate from 0.1 to 2.8 µg/kg/min. The HDNE group received significantly less fluid than the LDNE group. This dose is associated with a higher SOFA score at 24h: 9 (7-10) vs. 7 (6-9) (p = 0.003). Factors independently associated with a SOFA score ≥ 9 at 24 h were maximal norepinephrine rate ≥ 0.6 µg/kg/min (OR 6.69, 95% CI 1.82 - 25.54; p = 0.004), non-blood resuscitation volume9 mL/kg/h (OR 3.98, 95% CI 1.14 - 13.95; p = 0.031) and lactate at admission ≥ 5 mmol/L (OR 5.27, 95% CI 1.48 - 18.77; p = 0.010) CONCLUSION: High dose of norepinephrine infusion is associated with deleterious effects as attested by a higher SOFA score at 24 h and likely hypovolemia as measured by reduced non-blood resuscitation volume. We did not find any significant difference in mortality over the long term.

The relevance of circulating tumor DNA (ctDNA) analysis as a liquid biopsy and minimal residual disease tool in the management of classical Hodgkin lymphoma (cHL) patients was demonstrated in retrospective settings and remains to be confirmed in a prospective setting. We developed a targeted Next-Generation sequencing (NGS) panel for fast analysis (AmpliSeq® technology) of nine commonly mutated genes in biopies and ctDNA of cHL patients. We then conducted a prospective trial to assess ctDNA follow-up at diagnosis and after two cycles (C2) of chemotherapy. Sixty cHL patients treated by first line conventional chemotherapy (BEACOPPescalated [21.3%], ABVD/ABVD-like [73.5%] and other regimens [5.2%, for elderly patients]) were assessed in this noninterventional study. The median age of the patients was 33.5 years (range: 20-86). Variants were identified in 42 (70%) patients. Mutations of NFKBIE, TNFAIP3, STAT6, PTPN1, B2M, XPO1, ITPKB, GNA13 and SOCS1 were found in 13.3%, 31.7%, 23.3%, 5%, 33.3%, 10%, 23.3%, 13.3% and 50% of patients, respectively. ctDNA concentration and genotype were correlated with clinical characteristics and presentation. Regarding early therapeutic response, 45 patients (83%, not available [NA] =6) had a negative positron emission tomography (PET) after C2 (Deauville Score 1-3). The mean of DeltaSUVmax after C2 was -78.8%. ctDNA after C2 was analysed in 54 patients (90%). ctDNA became rapidly undetectable in all cases after C2. Variant detection in ctDNA is suitable to depict the genetic features of cHL at diagnosis and may help to assess early treatment response, in association with PET. Clinical Trial reference: NCT02815137.

We describe an as yet undescribed complication, namely, the perforation of the balloon at a distance from its introduction and the use of EtCO2 to suspect the diagnosis. Following a high-kinetic motorcycle accident, a 25-year-old patient was admitted in our level 1 trauma center, and benefited from a resuscitation thoracotomy followed by a REBOA catheter in zone 3. The use of a small caliber introducer could be responsible for balloon injury. EtCO2 is not only a marker of cardiac output and its sudden increase in this situation should raise questions about the recirculation of ischemia product and therefore the effectiveness of the occlusion balloon.

International audience; The spacecraft industry is facing a new challenge: new missions and customers require always more on-board performance. The current satellite network technologies will not be able to handle this increasing demand for long which leads the spacecraft industry to consider an upgrade of their satellite on-board networks. One opportunity has appeared through the use of Ethernet technologies to benefit from COTS components of a mass market. In this paper we discuss the suitability of several Ethernet technologies/standards with respect to the requirements of a satellite network in a qualitative approach. We will compare Ethernet, ARINC 664, TTEthernet and Time Sensitive Networking under three properties i.e. their quality of service capabilities, their synchronization capabilities and their fault tolerance capabilities.; L’industrie aérospatiale fait face à un nouveau challenge : les nouvelles missions et les nouveaux clients réclament tous les jours plus de performances à bord. Les technologies de réseaux embarqués actuelles ne pourront pas continuer à répondre à cette demande très longtemps. Cela amène les acteurs industriels à aujourd’hui considérer une amélioration de leurs réseaux embarqués à bord de leurs gammes de produits satellites. Une première opportunité est apparue via l’utilisation d’Ethernet et de ses composants COTS provenant d’un marché de masse. Dans ce papier, nous discutons, de manière qualitative, de la compatibilité de plusieurs technologies de la famille Ethernet avec des exigences d’un réseau satellite nouvelle génération. Nous comparons Ethernet, ARINC 664, TTEthernet et Time Sensitive Networking à l’aide de trois propriétés i.e. leurs capacités de qualité de service, leurs capacités de synchronisation et leurs capacités de tolérances au fautes.

Synchronous Hodgkin Lymphoma and Primary Mediastinal B‐cell Lymphoma is possible, with molecular analyses proving the absence of clonal filiation between both entities. This suggests a common etiology but the existence of two divergent clones.

Background: The CRASH-3 trial provides a high level of evidence on the question whether to administer Tranexamic Acid (TXA) for Traumatic brain injury (TBI). For numerous other research questions, the available evidence will not correspond to such a level of evidence and will rely on observational evidence only. The development of methodological alternatives to analyze observational data is necessary. The Crash-3trial provided the opportunity to explore the effect of TXA on TBI mortality with two distinct causal inference methods using incomplete observational data. Methods: Two causal inference techniques, inverse propensity weighting (IPW) and doubly robust method (DR), associated with machine learning method techniques to handle missing data, explored the effect of TXA administration on 30-day head injury related death expressed in registry data. The effect was expressed as Average Treatment Effect (ATE). TBI was defined as a head Abbreviated Injury Score >2. The hypothesis expected the results to concur with the results obtained with the CRASH-3 benchmark trial. Results: Between September 2010 and February 2019, from a total of 20037 registry cases 8269 corresponded to the definition of TBI. A total of 683 received TXA and 7565 did not. The observed head-injury related 30-day hospital mortality rate in the group TXA was 30% (205/683) compared to 15% in the group no-TXA (1102/7565, pConclusions: This study demonstrated the feasibility to apply causal inference techniques in incomplete observational data. DR based on a stronger theoretical background compared to IPW, did not show a significant association of TXA administration with in-hospital mortality. This result provides a strong incentive to explore augmented causal inference techniques on incomplete observational data coupled with techniques to handle missing values.

BackgroundFrom a series of penetrating head and neck trauma managed in a level-1 Trauma Center, the main aim of this study was to determine predictive factors for early definitive airway management, during pre-hospital time or in the emergency room. The secondary objective was to perform a descriptive epidemiological analysis of the series.MethodsA single-center retrospective study was conducted between January 1 2012 and June 30 2020. in a French Level 1 Trauma Center. The patients included were adults treated for penetrating head and neck trauma, regardless of the mechanism and the causal agent.Results 56 patients were included. Ballistic origin, Shock Index >0.9 and active bleeding in the emergency room were predictive criteria for definitive airway management during pre-hospital time or in the emergency room. 78.6% of patients were male. Median age was 54 years. The trauma followed a suicide attempt in 50% of cases, an accident in 26.7% and an assault in 23.2%, with use of a knife in 42.9% and firearm in 26.8%. Mortality was 10.7%. 16.1% of patients had undergone pre-hospital intubation and 19.1% intubation in the emergency room. CT scan was performed in 87.5% of cases, surgery in 96.4% and tracheotomy in 37.5%. A laryngotracheal lesion was seen in 14.2%. In 50% of patients, primary admission was to intensive care. Conclusions Ballistic origin, Shock Index >0.9 and active bleeding in the emergency room were predictive criteria for early definitive airway management. This study established the profile of patients suffering from penetrating head and neck trauma managed in a Trauma Center over a period of 9 years.

Ubiquilin-2 (UBQLN2) is a member of the ubiquilin family, actively implicated in the degradation of misfolded and redundant proteins through the ubiquitin-proteasome system and macroautophagy. UBQLN2 received much attention after the discovery of gene mutations in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). The abnormal presence of positive UBQLN2 inclusion in the cytosol of degenerating motor neurons of familial and sporadic forms of ALS patients has been newly related to neurodegeneration. Only recently, data have emerged on its role in liquid-liquid phase separation, in stress granule development and in the formation of secondary amyloid structures. Furthermore, several animal models are available to investigate its involvement in TDP-43 pathology and neuroinflammation in ALS. This review addresses the molecular pathogenetic pathways involving UBQLN2 abnormalities which are converging toward defects in clearance mechanisms. UBQLN2.

Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes.

A 54-year-old male outpatient complained of dyspnoea, asthenia, anorexia, and significant weight loss (10%), all in accordance with New York Heart Association (NYHA) Class II. His medical history i...

Vascular dementia is one of the most common forms of dementia in aging population. However, the molecular mechanisms involved in development of disease and the link between the cerebrovascular pathology and the cognitive impairments remain elusive. Currently, one common and/or converging neuropathological pathway leading to dementia is the mislocalization and altered functionality of the TDP-43. We recently demonstrated that brain ischemia triggers an age-dependent deregulation of TDP-43 that was associated with exacerbated neurodegeneration. Here, we report that chronic cerebral hypoperfusion in mice (CCH) produced by unilateral common carotid artery occlusion induces cytoplasmic mislocalization of TDP-43 and formation of insoluble phosho-TDP-43 aggregates reminiscent of pathological changes detected in cortical neurons of human brain samples from patients suffering from vascular dementia. Moreover, the CCH in mice caused chronic activation of microglia and innate immune response, development of cognitive deficits, and motor impairments. Oral administration of a novel analog (IMS-088) of withaferin A, an antagonist of nuclear factor-κB essential modulator (NEMO), led to mitigation of TDP-43 pathology, enhancement of autophagy, and amelioration of cognitive/motor deficits in CCH mice. Taken together, our results suggest that targeting TDP-43 pathogenic inclusions may have a disease-modifying effect in dementia caused by chronic brain hypoperfusion. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01015-8.

Elderly patients with symptomatic benign intracranial tumours such as meningioma pose particular problems in decision making. We report on the outcome, morbidity and mortality in patients aged over 80 years after undergoing cranial surgery for meningiomas.In this retrospective study, 37 patients aged more than 80 years underwent surgery at our neurosurgery department. The Karnofsky Performance Scale (KPS) was used to assess functional status. The American Society of Anesthesiologists (ASA) classification system, the Geriatric Scoring System, the Clinical-Radiological Grading System and the Sex, Karnofsky, ASA, Location and Edema score were used to define clinical status and tumour characteristics. The Charlson Comorbidity Index and Clavien-Dindo classification scores reflected therapeutic morbidity.Preoperative KPS scores were generally higher than 60 (Historically, surgery for intracranial meningiomas in patients aged80 years has been feasible; this series demonstrated decreasing rates of postoperative mortality. Functional benefit should be the main goal of surgery. Perioperative morbidity should be better assessed and predicted because it significantly influences functional outcomes.

Increasing demand for antiretroviral treatment (ART) together with a reduction in international funding during the last decade may jeopardize access to ART. Using data from a cross-sectional survey conducted in 2014 in 19 HIV services in the Centre and Littoral regions in Cameroon, we investigated the role of healthcare supply-related factors in time to ART initiation in HIV-positive patients eligible for ART at HIV diagnosis. HIV service profiles were built using cluster analysis. Factors associated with time to ART initiation were identified using a multilevel Cox model. The study population included 847 HIV-positive patients (women 72%, median age: 39 years). Median (interquartile range) time to ART initiation was 1.6 (0.5–4.3) months. Four HIV service profiles were identified: (1) small services with a limited staff practising partial task-shifting (n = 4); (2) experienced and well-equipped services practising task-shifting and involving HIV community-based organizations (n = 5); (3) small services with limited resources and activities (n = 6); (4) small services providing a large range of activities using task-shifting and involving HIV community-based organizations (n = 4). The multivariable model showed that HIV-positive patients over 39 years old [hazard ratio: 1.26 (95% confidence interval) (1.09–1.45), P = 0.002], those with disease symptoms [1.21 (1.04–1.41), P = 0.015] and those with hepatitis B co-infection [2.31 (1.15–4.66), P = 0.019] were all more likely to initiate ART early. However, patients in the first profile were less likely to initiate ART early [0.80 (0.65–0.99), P = 0.049] than those in the second profile, as were patients in the third profile [association only significant at the 10% level; 0.86 (0.72–1.02), P = 0.090]. Our findings provide a better understanding of the role played by healthcare supply-related factors in ART initiation. In HIV services with limited capacity, task-shifting and support from community-based organizations may improve treatment access. Additional funding is required to relieve healthcare supply-related barriers and achieve the goal of universal ART access.

International audience; Objective: The study aimed to explore longitudinal interactions between homonegativity and sexual behaviors with female partners among HIV-negative West African men who have sex with men and women (MSMW).Design and method: The community-based cohort CohMSM ANRS 12324 - Expertise France enrolled MSM in Togo, Burkina Faso, Côte d'Ivoire and Mali. Sociobehavioral data were collected every 6 months. Using 30-month follow-up data, a multiprobit analysis was performed to investigate the relationship between psychosocial and behavioral variables ex-ante (t - 1) and ex-post (t).Results: MSMW (n = 326) accounted for half of all participants in CohMSM. They reported inconsistent condom use with women in 39% of visits. Perceived and internalized homonegativity at t - 1 tended to lead to sexual violence toward women at t (P < 0.1), which was associated with inconsistent condom use with them at t (P < 0.05).Conclusion: Given the high HIV prevalence in West African MSM, widespread condom-less sex with women in MSMW, and the aggravating effect of social and internalized homonegativity, more research in the MSMW subpopulation is needed to assess the risk of HIV bridging to women and to design support activities.

To the Editor: We read with interest the comments from Sarc et al[1][1] about our previous study on ![Formula][2] delivered by noninvasive ventilation (NIV) compared with long-term oxygen therapy at the same flow.[2][3] We want to give some precision in response to their comments. Sarc et al

People who inject drugs (PWID) are disproportionately impacted by hepatitis C virus (HCV). Despite the availability and efficacy of direct-acting antiviral (DAA) HCV therapies, treatment rates remain low among PWID. Among PWID, those who are young (under age 30) experience high rates of HCV and also face distinct barriers to care. The objective of this study is to identify facilitators and barriers to navigating various facets of the HCV cascade of care, including DAA treatment access, among young PWID.We draw on data from in-depth, semi-structured interviews conducted between May and November 2019 with a sample of 11 young, street-involved PWID who have lived experience of HCV and who live in Metro Vancouver, Canada. Informed by a social constructivist epistemology, data were thematically analyzed using an equity-oriented theoretical framework.Our analysis yielded two key themes. First, participants described facilitators to HCV care access, including individual factors (e.g., desire to be cured, knowledge of side effects) and healthcare and socio-contextual factors (e.g., peer supports, supportive youth-specific services). Second, participants described a contrasting set of barriers to HCV care access, including concerns over treatment side effects and (in)eligibility, complex healthcare system navigation, substance use- and housing-related stigma, and clinician gatekeeping of DAAs.Findings from this study underscore the need for HCV-related knowledge-building efforts among young PWID and clinicians. Also needed are structural policy interventions to facilitate access to DAAs, including anti-stigma efforts, access to safe housing, and the scale-up of low-barrier youth-specific services and decentralized HCV care.RéSUMé: OBJECTIFS: Les personnes qui font usage de drogues par injection (PUDI) sont démesurément touchées par le virus de l’hépatite C (VHC). Malgré la disponibilité et l’efficacité potentielle des traitements antiviraux à action directe (AAD) contre le VHC, les taux de traitement demeurent faibles chez les PUDI. Les jeunes PUDI (moins de 30 ans) présentent des taux élevés de VHC tout en faisant face à des obstacles distincts pour se faire soigner. Notre étude vise à cerner les éléments qui favorisent ou qui entravent la négociation des divers aspects de la cascade des soins du VHC, dont l’accès aux traitements par AAD, chez les jeunes PUDI. MéTHODE: Nos données proviennent d’entretiens semi-directifs approfondis menés entre mai et novembre 2019 auprès d’un échantillon de 11 jeunes PUDI de la rue ayant une expérience vécue du VHC et vivant dans le District régional du Grand Vancouver, au Canada. Éclairées par une épistémologie constructiviste sociale, les données ont été analysées thématiquement à l’aide d’un cadre théorique orienté sur l’équité. RéSULTATS: Deux grands thèmes se sont dégagés de notre analyse. Premièrement, les participants ont décrit les éléments qui favorisent l’accès aux soins du VHC, dont les facteurs individuels (p. ex. le désir de guérir, la connaissance des effets secondaires) et les facteurs socio-contextuels et liés aux soins de santé (p. ex. l’entraide des pairs, les services de soutien pour les jeunes). Deuxièmement, les participants ont décrit un ensemble opposé d’obstacles à l’accès aux soins du VHC, dont les craintes par rapport aux effets secondaires des traitements et à l’(in)admissibilité aux traitements, le parcours complexe du système de soins de santé, la stigmatisation associée à l’usage de substances et au logement, ainsi que la protection de l’accès aux AAD par les cliniciens. CONCLUSION: Les constatations de l’étude confirment la nécessité de renforcer les connaissances sur le VHC, tant chez les jeunes PUDI que chez les cliniciens. Sont aussi nécessaires des interventions stratégiques structurelles pour faciliter l’accès aux AAD, dont la lutte contre la stigmatisation, la sécurité du logement, l’augmentation des services jeunesse « à bas seuil » et la décentralisation des soins du VHC.

We describe the case of a 75-year-old man presenting to the emergency with a stage III dyspnoea evolving for several months. His main medical history was an aortic valve replacement 8 years ago, a ...

Objective To examine the associations between risk of pre-eclampsia and pregnancy levels of maternal 25-hydroxyvitamin D (25[OH]D) and oxidative stress biomarkers. Methods A nested case-control study (n = 99; 34 cases; 65 controls) within a prospective pregnancy cohort. Maternal 25(OH)D and oxidative stress markers (six isomers of F2 -isoprostanes; F2 -isoPs) were measured in plasma at 12-18 and 24-26 gestational weeks. Vitamin D deficiency was defined as 25[OH]D less than 50 nmol/L. Results Maternal vitamin D deficiency was associated with increased 8-iso-PGF2α (P = 0.037), 15(R)-PGF2α (P = 0.004), (±)5-iPF2α -VI (P = 0.026) at 12-18 weeks. Vitamin D deficiency was inversely associated with 8-iso-PGF2α (P = 0.019) and (±)5-iPF2α -VI isomer (P = 0.010) at 24-26 weeks. Both maternal vitamin D deficiency (adjusted odds ratio [aOR], 4.79; 95% confidence interval [CI], 1.67-13.75) and increased (±)5-iPF2α -VI (aOR, 2.46; 95% CI, 1.16-5.22) at 24-26 weeks were associated with risk of pre-eclampsia. However, the interaction test between 25(OH)D and (±)5-iPF2α -VI was not significant (P = 0.143). Conclusion Plasma 25(OH)D below 50 nmol/L was associated with increased oxidative stress levels during pregnancy as measured by two F2 -isoP isomers, including the well-studied marker 8-iso-PGF2α . Whether vitamin D-induced oxidative stress mediates the risk of pre-eclampsia warrants future study.

Importance Maternal docosahexaenoic acid (DHA) supplementation may prevent bronchopulmonary dysplasia, but evidence remains inconclusive. Objective To determine whether maternal DHA supplementation during the neonatal period improves bronchopulmonary dysplasia–free survival in breastfed infants born before 29 weeks of gestation. Design, Setting, and Participants Superiority, placebo-controlled randomized clinical trial at 16 Canadian neonatal intensive care units (June 2015-April 2018 with last infant follow-up in July 2018). Lactating women who delivered before 29 weeks of gestation were enrolled within 72 hours of delivery. The trial intended to enroll 800 mothers, but was stopped earlier. Interventions There were 232 mothers (273 infants) assigned to oral capsules providing 1.2 g/d of DHA from randomization to 36 weeks’ postmenstrual age and 229 mothers (255 infants) assigned to placebo capsules. Main Outcomes and Measures The primary outcome was bronchopulmonary dysplasia–free survival in infants at 36 weeks’ postmenstrual age. There were 22 secondary outcomes, including mortality and bronchopulmonary dysplasia. Results Enrollment was stopped early due to concern for harm based on interim data from this trial and from another trial that was published during the course of this study. Among 461 mothers and their 528 infants (mean gestational age, 26.6 weeks [SD, 1.6 weeks]; 253 [47.9%] females), 375 mothers (81.3%) and 523 infants (99.1%) completed the trial. Overall, 147 of 268 infants (54.9%) in the DHA group vs 157 of 255 infants (61.6%) in the placebo group survived without bronchopulmonary dysplasia (absolute difference, –5.0% [95% CI, –11.6% to 2.6%]; relative risk, 0.91 [95% CI, 0.80 to 1.04],P = .18). Mortality occurred in 6.0% of infants in the DHA group vs 10.2% of infants in the placebo group (absolute difference, –3.9% [95% CI, –6.8% to 1.4%]; relative risk, 0.61 [95% CI, 0.33 to 1.13],P = .12). Bronchopulmonary dysplasia occurred in 41.7% of surviving infants in the DHA group vs 31.4% in the placebo group (absolute difference, 11.5% [95% CI, 2.3% to 23.2%]; relative risk, 1.36 [95% CI, 1.07 to 1.73],P = .01). Of 22 prespecified secondary outcomes, 19 were not significantly different. Conclusions and Relevance Among breastfed preterm infants born before 29 weeks of gestation, maternal docosahexaenoic acid supplementation during the neonatal period did not significantly improve bronchopulmonary dysplasia–free survival at 36 weeks’ postmenstrual age compared with placebo. Study interpretation is limited by early trial termination. Trial Registration ClinicalTrials.gov Identifier:NCT02371460

Objective Examine the levels of plasma antioxidant vitamins before and during a treatment with placebo or vitamin E + C supplement to prevent preeclampsia (PE). Study design Per-protocol analysis of a subset group of pregnant women (n = 295) from the International Trial of Antioxidants for the Prevention of PE (INTAPP) randomized case-control study. Normotensive receiving placebo or vitamins (n = 115 and 87 respectively) were compared to gestational hypertension (GH) without proteinuria (n = 30 and 27) and PE (n = 21 and 15). Vitamin quantification was performed at 12–18, 24–26 and 32–34 weeks of gestation. Main outcome measures Coenzyme (Co) Q10, β-carotene and vitamins E (α and γ forms) plasma levels. Results Vitamin E + C supplementation was found to increase the α-tocopherol levels by 40% but was associated with a 57% decrease in the γ-tocopherol isoform for all study groups (p Conclusions A more personalized approach that target the suboptimal levels of specific antioxidants without disturbing the α/γ-tocopherol ratio could be a more successful approach to counteract oxidative stress in PE.

Context Small-for-gestational-age (SGA) is an indicator of poor fetal growth “programming” an elevated risk of type 2 diabetes in adulthood. Little is known about early-life endocrine characteristics in SGA subtypes. Stunting (short) and wasting (skinny) are considered distinct SGA phenotypes in neonatal prognosis. Objectives This work aimed to assess whether SGA infants with stunting or wasting have similar alterations in neonatal endocrine metabolic health biomarkers. Methods This was a nested case-control study based on the 3D (Design, Develop, and Discover) birth cohort in Canada. The study subjects were 146 SGA (birth weight Results Comparing to OGA infants adjusted for maternal and neonatal characteristics, SGA infants with either stunting only or wasting only had lower cord plasma IGF-I and leptin concentrations. HMW adiponectin concentrations were lower in SGA infants with wasting only (P = .004), but similar in SGA infants with stunting only (P = .816). Only SGA infants with both stunting and wasting had substantially lower proinsulin (P Conclusion This study is the first to demonstrate that SGA infants with wasting only are characterized by low HMW adiponectin concentrations, whereas those with stunting only are not. SGA with both stunting and wasting are characterized by low proinsulin and high ghrelin concentrations.

Background Arthroscopic surgery has earned its place as the reference standard treatment for rotator cuff calcific tendinopathy refractory to conservative medical treatment. Adhesive capsulitis of the shoulder is the most common complication (12%). Standard practice involves routine gleno-humeral exploration before calcification removal. The objective of this study was to identify risk factors for adhesive capsulitis. Hypothesis The development of adhesive capsulitis is associated with gleno-humeral exploration. Methods We conducted a multicentre, multi-surgeon, retrospective cohort study of 340 consecutive patients who underwent arthroscopic removal of rotator cuff calcifications between 1 January 2012 and 1 January 2018. We collected epidemiological data (age, sex, work-related physical activity), the history of previous treatments (local injections, needling), the type and location of the calcifications as assessed radiologically, the clinical findings (Constant score before and 6 months after surgery, diagnosis of adhesive capsulitis defined as shoulder pain with motion range limitation in all directions), and the surgical details (type of anaesthesia, gleno-humeral exploration). Results Of the 340 patients, 251 underwent routine gleno-humeral exploration and 89 did not. Adhesive capsulitis developed in 40 (12%) patients. By multivariate analysis, gleno-humeral exploration was an independent risk factor for adhesive capsulitis (p = 0.022; odds ratio, 5.60). Of the 251 gleno-humeral explorations, 8% identified concomitant lesions and only 4% led to a curative procedure. Conclusion Given our results and the data in the literature, we believe that routine gleno-humeral exploration during the arthroscopic treatment of rotator cuff calcific tendinopathy is inadvisable. Level of evidence III; case-control study.

To test the hypothesis that the cerebrospinal fluid (CSF) could provide a spreading route for pathogenesis of amyotrophic lateral sclerosis (ALS), we have examined the effects of intraventricular infusion during 2 weeks of pooled CSF samples from sporadic ALS patients or control CSF samples into transgenic mice expressing human TDP43WT which do not develop pathological phenotypes. Infusion of ALS-CSF, but not of control CSF, triggered motor and cognitive dysfunction, as well as ALS-like pathological changes including TDP43 proteinopathy, neurofilament disorganization and neuroinflammation. In addition, the neuron-specific translational profiles from peptide analyses of immunoprecipitated ribosomes revealed dysregulation of multiple protein networks in response to ALS-CSF altering cytoskeletal organization, vesicle trafficking, mitochondrial function, and cell metabolism. With normal mice, similar ALS-CSF infusion induced mild motor dysfunction but without significant TDP43 pathology in spinal neurons. We conclude that the CSF from sporadic ALS contains factors that can transmit and disseminate disease including TDP43 proteinopathy into appropriate recipient animal model expressing human TDP43. These findings open new research avenues for the discovery of etiogenic factors for sporadic ALS and for the testing of drugs aiming to neutralize the ALS-CSF toxicity.

Non-Hodgkin B-cell lymphomas (B-NHLs) are a highly heterogeneous group of mature B-cell malignancies. Their classification thus requires skillful evaluation by expert hematopathologists, but the risk of error remains higher in these tumors than in many other areas of pathology. To facilitate diagnosis, we have thus developed a gene expression assay able to discriminate the seven most frequent B-cell NHL categories. This assay relies on the combination of ligation-dependent RT-PCR and next-generation sequencing, and addresses the expression of more than 130 genetic markers. It was designed to retrieve the main gene expression signatures of B-NHL cells and their microenvironment. The classification is handled by a random forest algorithm which we trained and validated on a large cohort of more than 400 annotated cases of different histology. Its clinical relevance was verified through its capacity to prevent important misclassification in low grade lymphomas and to retrieve clinically important characteristics in high grade lymphomas including the cell-of-origin signatures and the MYC and BCL2 expression levels. This accurate pan-B-NHL predictor, which allows a systematic evaluation of numerous diagnostic and prognostic markers, could thus be proposed as a complement to conventional histology to guide the management of patients and facilitate their stratification into clinical trials.

INTRODUCTIONManagement of Oxygen supplies is a recurring problem for the intensivists and anesthesiologists working in an austere environment. The French military health service has chosen oxygen concentrators (OC) as the primary source of oxygen.OBJECTIVESThe main objective was to evaluate the feasibility of using OC as the main source of 02for intensive care patients. We assess the need to use pressurized 02during the ICU hospitalization. The secondary objectives were to identify the causes of the use of pressurized 02.MATERIAL AND METHODWe realize an interventional cohort study at the French role 3 hospitals located in the Republic of Djibouti. The criteria of inclusion were all patients aged over 18 years, requiring oxygen and admitted to intensive care.RESULTSWe include 35 patients over 6-month period for 251 days of oxygenation, including 142 days of invasive mechanical ventilation. The population include 21 (60%) men, aged of 35 (30 - 49) years. Twenty-eight (80%) patients benefits of invasive ventilation. Median 02administration duration was 6 (3-10) days, and the median duration of mechanical ventilation was 3 (1-5) days. Nineteen pressurized O2 treatments were required over 251 days of oxygen therapy, or 7.5% of the total oxygen therapy time. The causes of recourse were in 10 cases (52.6%) severe ARDS, in 6 cases (31.6%) an emergency orotracheal intubation and in 3 cases (15.8%) a transfer. Only one OC dysfunction occurred during the study.CONCLUSIONOC can be used as a primary source for intensive care patients in an austere environment. The use of pressurized 02remains imperative in the event of an electrical failure and the need to use high Fi02over 60%.

International audience

International audience; Background: Molecular biology has emerged as a potential companion to histology for the diagnosis of rejection after heart transplantation. Reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) is a technique of targeted gene expression analysis suitable for formalin-fixed paraffin-embedded (FFPE) biopsies. Our aim was to assess RT-MLPA for the diagnosis of allograft rejection in heart transplantation.Methods: We performed a cross-sectional, case-control, multicenter study. After the selection of a 14-transcript panel (endothelial burden, Natural killer cells, interferon-γ pathway, effector T-cells, and antigen presentation), RT-MLPA was applied to 183 FFPE endomyocardial biopsies (EMB), randomized into a training (n = 113) and a validation (n = 70) series. A two-step class prediction analysis was developed (Linear prediction score-LPS1: rejection vs non-rejection; LPS2: antibody-mediated rejection [AMR] vs acute cellular rejection [ACR]). A study of the agreement between pathology and RT-MLPA was performed.Results: Overall, 48 ACR, 82 AMR, 5 mixed rejection, and 48 non-rejection EMBs were analyzed. Three molecular clusters were delineated by unsupervised hierarchical analysis (molecular non-rejection, ACR, and AMR). AMR was characterized by the high expression of CCL4, GNLY, FCGR3, CXCL11 and ACR by the high expression of CCL18 and ADAMdec. RT-MLPA and histopathology agreed in the final diagnosis in 82.2%, 67.7%, and 76.8% of the EMB in the test, validation, and overall cohort, respectively. Disagreement cases were more common in the case of histologic low-grade rejection and early post-transplant EMB.Conclusions: RT-MLPA is a suitable technique for targeted gene expression analysis on FFPE EMB with a good overall agreement with the histologic diagnosis of heart allograft rejection.

BACKGROUND: Long-term home mechanical ventilation is increasingly used by patients with chronic respiratory failure. Storage of medical data in the cloud is expanding, and ventilation can be monitored remotely. The aim of this bench study was to determine whether tidal volume (VT) can be affected by the location of supplemental oxygen placement. METHODS: We tested 4 home ventilators in a bench test using a dual-chamber test lung to test the addition of supplemental oxygen placement via a connector in the circuit (ie, front intake port) versus via the manufacturer9s rear intake port, with different oxygen supply flows of 2, 4, 6, and 8 L/min. We compared the effectively delivered VT as measured with a pneumotachograph (ie, measured VT) versus the VT reported by each home ventilator (ie, monitored VT). RESULTS: For all of the home ventilators, the monitored VT and measured VT were comparable when the rear oxygen intake was used, regardless of oxygen flow. However, when the front oxygen intake was used, the monitored VT as measured by the ventilators was significantly lower than the measured VT, with the greatest difference reaching 29% for the highest oxygen flow tested (8 L/min). CONCLUSIONS: The monitored VT may be inaccurate if oxygen is added with a connector in the circuit, which may have consequences on both the individual level and collective level (ie, big data analysis). Physicians who analyze data from home ventilators should be aware of the site of oxygen supplementation and promote use of only the rear oxygen intake.

Objective: Endovascular treatment (EVT) is the first-line treatment for ruptured and unruptured intracranial aneurysms (IA). EVT may be performed by interventional neuroradiologist (INR) with different levels of experience. This study aimed at evaluating clinical and anatomic results of IA embolisations performed by a INR with a short experience. Materials and Methods: Within a 26-month period, 35 IA embolisations were managed by a young INR, 26 of these IA being ruptured. Different EVT techniques were used: coiling alone, stent-assisted coiling and remodeling techniques. Initial angiographic results, clinical outcomes and mid-term anatomic results were evaluated. Results: Out of 35 procedures, there were seven per-procedural complications leading to one ischemic stroke and one death. Immediate post-procedural complete occlusion was obtained in 91% of procedures (32/35). Good clinical results (modified Rankin Scale Score of 0 or 1) were obtained in 79% of patients (26/33). In a mean follow-up time of 9.5 months, stable occlusion was shown in 88% of IA (21/24). Conclusion: This study suggests that IA embolisation may be performed by a recently trained INR with good clinical and anatomical outcomes., SCOPUS: ar.j, info:eu-repo/semantics/published

In this chapter we describe how the introduction of environmental education and education for sustainable development (ESD) has affected the French education system in terms of changes to formal curricula and teaching practices. In France, these two new types of education have disrupted traditional teaching and the relationships between the different disciplines, and triggered the creation of Eco-Schools, School Agendas 21 and Sustainable Development Schools (E3Ds). Posing a challenge to teachers and educational researchers alike, they promote particular educational aims, such as critical thinking, complex thinking or citizen engagement, mainly through project pedagogies and partnerships. In the first part of this chapter, we look at how international issues have influenced the formal curriculum, showing how the French education system has gradually taken these new educational issues on board. In the second part, we describe the debates and studies that have taken place in France on ESD. The third and final part explains how these educational issues translate at the level of individual schools, many of which now have Eco-School or E3D status. We then discuss the levers for implementing these approaches in schools, as well as the obstacles and particular points to bear in mind.

BACKGROUND: Management of critically ill patients requiring mechanical ventilation in austere environments or during disaster response is a logistic challenge. Availability of oxygen cylinders for mechanically ventilated patient may be difficult in such a context. A solution to ventilate patients requiring high fraction of inspired oxygen (FiO2) is to use a ventilator able to be supplied by a low-pressure oxygen source connected with two oxygen concentrators (OCs). We tested the Elisee 350 (ResMedBella Vista, Australia) ventilator paired with two Newlife Intensity 10 (Airsep, Ball Ground, Georgia) OCs and evaluated the delivered FiO2 across a range of minute volumes and combinations of ventilator settings. METHODS: The ventilators were attached to a test lung, OC flow was adjusted with a Certifier FA ventilator test systems from 2 to 10 L/min and injected into the oxygen inlet port of the Elisee 350. The FiO2 was measured by the analyzer integrated in the ventilator, controlled by the ventilator test system. Several combinations of ventilator settings were evaluated to determine the factors affecting the delivered FiO2. RESULTS: The Elisee 350 ventilator is a turbine ventilator able to deliver high FiO2 when functioning with two OCs. However, modifications of the ventilator settings such as an increase in minute ventilation affect delivered FiO2 even if oxygen flow is constant on the OC. CONCLUSION: The ability of two OCs to deliver high FiO2 when used with a turbine ventilator makes this method of oxygen delivery a viable alternative to cylinders to ventilate patients requiring an FiO2 of ≥80% in austere place or during disaster response. LEVEL OF EVIDENCE: Feasibility study on test bench, level V.

ObjectivesWhether regular HIV testing and counselling reduce risky sexual behaviours in African men who have sex with men (MSM) is still a matter for debate. We aimed to identify behavioural trajectories based on HIV risk exposure (HRE) and factors affecting their evolution.MethodsData were collected from 621 HIV-negative West African MSM (Mali, Cote d'Ivoire, Burkina Faso and Togo) included in a community-based cohort providing quarterly HIV testing and counselling. Sociobehavioural data were collected every 6 months. HRE was defined as reporting inconsistent condom use during receptive anal sex with male partners of unknown HIV status in the previous 6 months. Using 18-month follow-up data, group-based trajectory modelling helped identify behavioural trajectories and determine the factors associated with their evolution. HIV seroconversions (n=67) were specified in each group trajectory.ResultsTwo distinct group trajectories were identified: medium-risk exposure MSM (ME-MSM) (61%, 6.4% of whom having seroconverted) and high-risk exposure MSM (HE-MSM) (39%, 17.5% of whom having seroconverted). A significant declining trend in the probability of reporting HRE over time ((95% CI)) was observed for HE-MSM (from 0.59 (0.48 to 0.70) at M0 to 0.31 (0.22 to 0.41) at M18), while it remained constant for ME-MSM (0.034 (0.0 to 0.079)). This can be explained by a progressive use of risk reduction strategies (less receptive anal sex, better knowledge of their partners’ status and increasing condom use). Being younger, living in Burkina Faso, self-considering both a man and a woman and reporting a higher level of depression were all associated with HE membership. Among HE-MSM, HRE was higher in those practising transactional or group sex and those experiencing psychological harassment.ConclusionsQuarterly HIV testing and counselling seem to reduce risky sexual behaviours in HIV-negative MSM at greatest risk of infection. Specific support for young MSM, focusing on identity and mental health, is needed to strengthen HIV prevention in West African MSM.

Hypocapnia induces cerebral vasoconstriction leading to a decrease in cerebral blood flow, which might precipitate cerebral ischemia. Hypocapnia can be intentional to treat intracranial hypertension or unintentional due to a spontaneous hyperventilation (SHV). SHV is frequent after subarachnoid hemorrhage. However, it is understudied in patients with severe traumatic brain injury (TBI). The objective of this study was to describe the incidence and consequences on outcome of SHV after severe TBI. We conducted a retrospective, observational study including all intubated TBI patients admitted in the trauma center and still comatose 24 h after the withdrawal of sedation. SHV was defined by the presence of at least one arterial blood gas (ABG) with both PaCO2 7.45. Patient characteristics and outcome were extracted from a prospective registry of all intubated TBI admitted in the intensive care unit. ABG results were retrieved from patient files. A multivariable logistic regression model was developed to determine factors independently associated with unfavorable outcome (defined as a Glasgow Outcome Scale between 1 and 3) at 6-month follow-up. During 7 years, 110 patients fully respecting inclusion criteria were included. The overall incidence of SHV was 69.1% (95% CI [59.9–77]). Patients with SHV were more severely injured (median head AIS score (5 [4–5] vs. 4 [4–5]; p = 0.016)) and exhibited an elevated morbidity during their stay. The proportion of patients with an unfavorable functional neurologic outcome was significantly higher in patients with SHV: 40 (52.6%) versus 6 (17.6%), p = 0.0006. After adjusting for confounders, SHV remains an independent factor associated with unfavorable outcome at the 6-month follow-up (OR 4.1; 95% CI [1.2–14.4]). SHV is common in patients with a persistent coma after a severe TBI (overall rate: 69%) and was independently associated with unfavorable outcome at 6-month follow-up.

Accurate short-term power forecasts are crucial for the reliable and efficient integration of wind energy in power systems and electricity markets. Typically, forecasts for hours to days ahead are based on the output of numerical weather prediction models, and with the advance of computing power, the spatial and temporal resolutions of these models have increased substantially. However, high-resolution forecasts often exhibit spatial and/or temporal displacement errors, and when regarding typical average performance metrics, they often perform worse than smoother forecasts from lower-resolution models. Recent computational advances have enabled the use of large-eddy simulations (LESs) in the context of operational weather forecasting, yielding turbulence-resolving weather forecasts with a spatial resolution of 100 m or finer and a temporal resolution of 30 seconds or less. This paper is a proof-of-concept study on the prospect of leveraging these ultra high-resolution weather models for operational forecasting at Horns Rev I in Denmark. It is shown that temporal smoothing of the forecasts clearly improves their skill, even for the benchmark resolution forecast, although potentially valuable high-frequency information is lost. Therefore, a statistical post-processing approach is explored on the basis of smoothing and feature engineering from the high-frequency signal. The results indicate that for wind farm forecasting, using information content from both the standard and LES resolution models improves the forecast accuracy, especially with a feature selection stage, compared with using the information content solely from either source.

Introduction Non-Hodgkin B-cell lymphomas (B-NHLs) are a highly heterogeneous group of mature B-cell malignancies associated with very diverse clinical behaviors. They rely on the activation of different signaling pathways for proliferation and survival which might be amenable to targeted therapies, increasing the need for precision diagnosis. Unfortunately, their accurate classification can be challenging, even for expert hemato-pathologists, and secondary reviews recurrently differ from initial diagnosis. To address this issue we have developed a pan-B-NHL classifier based on a middle throughput gene expression assay coupled with a random forest algorithm. Material and Methods Five hundred ten B-NHL diagnosed according to the WHO criteria were studied, with 325 diffuse large B-cell lymphomas (DLBCL), 43 primary mediastinal B-cell lymphomas (PMBL), 55 follicular lymphomas (FL), 31 mantle cell lymphomas (MCL), 17 small lymphocytic lymphomas (SLL), 20 marginal zone lymphomas (MZL), 11 marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) and 8 lymphoplasmacytic lymphomas (LPL). To train and validate the predictor the samples were randomly split into a training (2/3) and an independent validation cohort (1/3). A panel of 137 genes was designed by purposely selecting the differentiation markers identified in the WHO classification for their capacity to provide diagnostic and prognostic information in NHLs. Gene expression profiles were generated by ligation dependent RT-PCR applied to RNA extracted from frozen or FFPE tissue and analyzed on a MiSeq sequencer. For analysis, the sequencing reads were de-multiplexed, aligned with the sequences of the LD-RTPCR probes and counted. Results were normalized using unique molecular indexes counts to correct PCR amplification biases. Results In DLBCL, unsupervised gene expression analysis retrieved the expected GCB, ABC and PMBL signatures (Fig A). These tumors also showed higher expressions of the KI67 (proliferation), CD68 and CD163 (tumor associated macrophages), and PD-L1/2 (immune response) markers. We also observed that the dual expression of MYC and BCL2 at the mRNA level significantly associates with inferior PFS and OS, independent from the International Prognostic Index and from the GCB/ABC cell-of-origin signature, validating the capacity of the assay to identify these highly aggressive lymphomas (Fig C). Overall, low-grade lymphomas were characterized by a significant T cell component. FLs associated with the GCB (BCL6, MYBL1, CD10 and LMO2) and Tfh (CD3, CD5, CD28, ICOS, CD40L, CXCL13) signatures. Other small B-cell lymphomas tended to overexpress activated B-cell markers (LIMD1, TACI, IRF4,FOXP1...), and the expected CD5, CD10, CD23 and CCND1 differential expressions in SLL, MCL and MZL were correctly retrieved (Fig B). Surprisingly, our analysis revealed that the Ie-Ce sterile transcript, expressed from the IGH locus during IgE isotype switching, is almost exclusively expressed by FLs, constituting one of the most discriminant markers for this pathology. We next trained a random forest classifier to discriminate the 7 principal subtypes of B-NHLs. The training cohort comprised 162 DLBCLs (ABC or GCB), 28 PMBL, 35 FLs (grade 1-3A), 21 MCLs, 12 SLLs, and 25 NHLs grouped into the MZL category (13 MZLs, 8 MALT and 4 LPLs). The independent validation series comprised 90 DLBCLs classified as GCB or ABC DLBCLs by the Lymph2Cx assay, 15 PMBLs, 12 FLs (grade 1-3A), 10 MCLs, 5 SLLs and 14 MZLs (7 MZL, 3 MALT and 4 LPL). The RF algorithm classified all cases of the training series into the expected subtype, as well as 94.5% samples of the independent validation cohort (Fig D). For ABC and GCB DLBCLs, the concordance with the Lymph2Cx assay in the validation cohort was 94.3%. Conclusion We have developed a comprehensive gene expression based solution which allows a systematic evaluation of multiple diagnostic and prognostic markers expressed by the tumor and by the microenvironment in B-NHLs. This assay, which does not require any specific platform, could be implemented in complement to histology in many diagnostic laboratories and, with the current development of targeted therapies, enable a more accurate and standardized B-NHL diagnosis. Together, our data illustrate how the integration of gene expression profiling and artificial intelligence can increase precision diagnosis in cancers. Figure Disclosures Oberic: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees. Haioun:Miltenyi: Honoraria; Takeda: Honoraria; Servier: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Salles:Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Karyopharm: Consultancy; BMS: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Jardin:celgene: Honoraria; roche: Honoraria; amgen: Honoraria; Servier: Honoraria; janssen: Honoraria.

Background Several lines of evidence suggest effects of dietary fat on prostate cancer (PCa) development and progression. Targeting omega (ω)-3:ω6 fatty acids (FA) ratio could be beneficial against PCa by favorably modulating inflammation. Here, we studied the effects of ω3- and ω6-enriched diets on prostate tumor growth and inflammatory response in androgen-deprived and non-deprived conditions. Methods Immune-competent eugonadal and castrated C57BL/6 mice were injected with TRAMP-C2 prostate tumor cells and daily fed with ω3- or ω6-enriched diet. FA and cytokine profiles were measured in blood and tumors using gas chromatography and multiplex immunoassay, respectively. Immune cell infiltration in tumors was profiled by multicolor flow cytometry. Results ω3-enriched diet decreased prostate TRAMP-C2 tumor growth in immune-competent eugonadal and castrated mice. Cytokines associated with Th1 immune response (IL-12 [p70], IFN-γ, GM-CSF) and eosinophil recruitment (eotaxin-1, IL-5, and IL-13) were significantly elevated in tumors of ω3-fed mice. Using in vitro experiments, we confirmed ω3 FA-induced eotaxin-1 secretion by tumor cells and that eotaxin-1 secretion was regulated by androgens. Analysis of immune cell infiltrating tumors showed no major difference of immune cells' abundance between ω3- and ω6-enriched diets. Conclusions ω3-enriched diet reduces prostate tumor growth independently of androgen levels. ω3 FA can inhibit tumor cell growth and induce a local anti-tumor inflammatory response. These findings warrant further examination of dietary ω3's potential to slow down the progression of androgen-sensitive and castrate-resistant PCa by modulating immune cell function in tumors.

From a liquid biopsy, cell-free DNA (cfDNA) can provide information regarding basal tumoral genetic patterns and changes upon treatment. In a prospective cohort of 30 diffuse large B-cell lymphomas (DLBCL), we determined the clinical relevance of cfDNA using targeted next-generation sequencing and its correlation with PET scan imaging at the time of diagnosis and during treatment. Using a dedicated DLBCL panel, mutations were identified at baseline for 19 cfDNAs and profiles were consistent with expected DLBCL patterns. Tumor burden-related clinical and PET scan features (LDH, IPI, and metabolic tumor volume) were significantly correlated with the quantity of tumoral cfDNA. Among the four patients presenting additional mutations in their cfDNAs, three had high metabolic tumor volumes, suggesting that cfDNA more accurately reflects tumor heterogeneity than tissues biopsy itself. Mid-treatment, four patients still had basal mutations in their cfDNAs, including three in partial response according to their Deauville scores. Our study highlights the major interests in liquid biopsy, in particular in the context of bulky tumors where cfDNA allows capturing the entire tumoral mutation profile. Therefore, cfDNA analysis in DLBCL represents a complementary approach to PET scan imaging.

Background Diabetes and pregnancy are both associated with oxidative stress, characterized by an increase of F2-isoprostanes from the non-enzymatic oxidation of arachidonic acid, a n − 6 polyunsaturated fatty acid (PUFA). We hypothesized that pregnant women with pre-existing diabetes will be characterized by elevated levels of specific F2-isoPs isomers and altered PUFA composition in plasma early pregnancy when compared to normoglycemic controls. Methods Plasma samples from 23 women with uncomplicated pregnancies and 11 women with pre-existing diabetes in pregnancy were collected between 12 and 18 weeks of pregnancy (MIROS cohort). Six F2-isoprostanes isomers were measured by high-performance liquid chromatography coupled to tandem mass spectrometry. Fatty acids concentrations in plasmatic phospholipids were measured by gas chromatography coupled to a flame ionization detector. Results F2-isoprostanes, specifically the 8-iso-15(R)-PGF2α levels, were 67% higher in diabetic than normoglycemic pregnancies (p = 0.026). The total n − 6 PUFA and arachidonic acid level did not differ between study groups. In contrast, total n − 3 level was 32% lower in diabetic pregnancies than in controls (p = 0.002); EPA(20:5) and DHA(22:6) being specifically reduced (p = 0.035 and p = 0.003 respectively). Delta-6-desaturase (D6D) activity index, calculated using fatty acid ratios, was 9% lower in pre-existing diabetes than in controls (p = 0.042). Conclusions Pre-existing diabetes in early pregnancy displays a distinctive F2-isoprostanes profile when compared to other pathologies of pregnancy, such as preeclampsia, as previously assessed in the same cohort.

OBJECTIVE To determine whether pre-eclampsia is associated with polymorphisms in superoxide dismutase (SOD) genes among mother-father-infant triads. METHODS We did this follow-up cohort study at 17 urban hospitals in Canada between October 1, 2008, and September 30, 2010. We recruited Canadian participants who had participated in the International Trial of Antioxidant Supplementation for the Prevention of Pre-eclampsia. Saliva specimens were collected for DNA extraction. The SOD1 +35A/C (rs2234694) and SOD2 Ala16Val C/T (rs4880) single-nucleotide polymorphisms (SNPs) were genotyped. RESULTS Dual presence of the SOD2 Ala16Val TT variant among mother-father pairs (n=657) was associated with an increased risk of pre-eclampsia when compared with the absence of the TT variant among the mother-father pairs (7/48 [14.6%] vs 11/339 [3.2%]; adjusted odds ratio 6.80, 95% confidence interval 2.32-19.95; P

BACKGROUND Early transfusion of high ratio of fresh frozen plasma (FFP) and red blood cells (RBC) is associated with mortality reduction. However, time to reach high ratio is limited by the need to thaw the FFP. French lyophilized plasma (FLYP) used by French army and available in military teaching hospital does not need to be thawed and is immediately available. We hypothesize that the use of FLYP may reduce time to reach a plasma/RBC ratio of 1:1. METHODS A retrospective study performed in a Level 1 trauma center between January 2012 and December 2015. Severe trauma patients who received 2 U of RBC in the emergency room were included and assigned to two groups according to first plasma transfused: FLYP group and FFP group. RESULTS Forty-three severe trauma patients in the FLYP group and 29 in the FFP group were included. The time until first plasma transfusion was shorter in the FLYP group than in the FFP group, respectively 15 min (10-25) versus 95 min (70-145) (p < 0.0001). Time until a 1:1 ratio was shorter in the FLYP group than in the FFP group. There were significantly fewer cases of massive transfusion in the FLYP group than in the FFP group with respectively 7% vs. 45% (p < 0.0001). CONCLUSION The use of FLYP provided significantly faster plasma transfusions than the use of FFP as well as a plasma and RBC ratio superior to 1:2 that was reached more rapidly in severe trauma patients. These results may explain the less frequent need for massive transfusion in the patients who received FLYP. These positive results should be confirmed by a prospective and randomized evaluation. LEVEL OF EVIDENCE Therapeutic, level IV.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which presently does not have any efficient therapeutic approach. Pimozide, a Food and Drug Administration (FDA)-approved neuroepileptic drug, has been recently proposed as a promising treatment for ALS patients based on apparent stabilization of right hand muscles after a short-time administration. A new clinical trial started at the end of 2017 to recruit patients with a prolonged drug delivery schedule. Here, our aim was to investigate the effects of chronic administration of pimozide on disease progression and pathological events in two mouse models of ALS. Pimozide was administered every 2 days to transgenic mice bearing the ALS-linked A315T mutation on the human TAR DNA-binding protein 43 (TDP-43) gene and to mice carrying the human superoxide dismutase 1 (SOD1) gene with the ALS-linked G93A mutation. Chronic administration of pimozide exacerbated motor performances in both animal models and reduced survival in SOD1G93A mice. In TDP-43A315T, it decreased the percentage of innervated neuromuscular junctions (NMJs) and increased the accumulation of insoluble TDP-43. In SOD1G93A mice, pimozide had no effects on NMJ innervation or motoneuron loss, but it increased the levels of misfolded SOD1. We conclude that a chronic administration of pimozide did not confer beneficial effects on disease progression in two mouse models of ALS. In light of a new clinical trial on ALS patients with a chronic regime of pimozide, these results with mouse models suggest prudence and careful monitoring of ALS patients subjected to pimozide treatment. Electronic supplementary material The online version of this article (10.1007/s13311-018-0634-3) contains supplementary material, which is available to authorized users.

IMPORTANCE: An intraoperative higher level of positive end-expiratory positive pressure (PEEP) with alveolar recruitment maneuvers improves respiratory function in obese patients undergoing surgery, but the effect on clinical outcomes is uncertain. OBJECTIVE: To determine whether a higher level of PEEP with alveolar recruitment maneuvers decreases postoperative pulmonary complications in obese patients undergoing surgery compared with a lower level of PEEP. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 2013 adults with body mass indices of 35 or greater and substantial risk for postoperative pulmonary complications who were undergoing noncardiac, nonneurological surgery under general anesthesia. The trial was conducted at 77 sites in 23 countries from July 2014-February 2018; final follow-up: May 2018. INTERVENTIONS: Patients were randomized to the high level of PEEP group (n = 989), consisting of a PEEP level of 12 cm H(2)O with alveolar recruitment maneuvers (a stepwise increase of tidal volume and eventually PEEP) or to the low level of PEEP group (n = 987), consisting of a PEEP level of 4 cm H(2)O. All patients received volume-controlled ventilation with a tidal volume of 7 mL/kg of predicted body weight. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of pulmonary complications within the first 5 postoperative days, including respiratory failure, acute respiratory distress syndrome, bronchospasm, new pulmonary infiltrates, pulmonary infection, aspiration pneumonitis, pleural effusion, atelectasis, cardiopulmonary edema, and pneumothorax. Among the 9 prespecified secondary outcomes, 3 were intraoperative complications, including hypoxemia (oxygen desaturation with Spo(2) ≤92% for >1 minute). RESULTS: Among 2013 adults who were randomized, 1976 (98.2%) completed the trial (mean age, 48.8 years; 1381 [69.9%] women; 1778 [90.1%] underwent abdominal operations). In the intention-to-treat analysis, the primary outcome occurred in 211 of 989 patients (21.3%) in the high level of PEEP group compared with 233 of 987 patients (23.6%) in the low level of PEEP group (difference, −2.3% [95% CI, −5.9% to 1.4%]; risk ratio, 0.93 [95% CI, 0.83 to 1.04]; P = .23). Among the 9 prespecified secondary outcomes, 6 were not significantly different between the high and low level of PEEP groups, and 3 were significantly different, including fewer patients with hypoxemia (5.0% in the high level of PEEP group vs 13.6% in the low level of PEEP group; difference, −8.6% [95% CI, −11.1% to 6.1%]; P