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ObjectivesThe study aimed to identify differences and compare anatomical and biomechanical features between elective and ruptured abdominal aortic aneurysms (AAAs).MethodsData (clinical, anatomical, and biomechanical) of 98 patients with AAA, 75 (76.53%) asymptomatic (Group aAAA) and 23 (23.46%) ruptured AAA (Group rAAA), were prospectively collected and analyzed. Anatomical, morphological, and biomechanical imaging markers like peak wall stress (PWS) and rupture risk equivalent diameter (RRED), comorbid conditions, and demographics were compared between the groups. Biomechanical features were assessed by analysis of Digital Imaging and Communication in Medicine images by A4clinics (Vascops), and anatomical features were assessed by 3Surgery (Trimensio). Binary and multiple logistic regression analysis were used and adjusted for confounders. Accuracy was assessed using receiving operative characteristic (ROC) curve analysis.ResultsIn a multivariable model, including gender and age as confounder variables, maximal aneurysm diameter [MAD, odds ratio (OR) = 1.063], relative intraluminal thrombus (rILT, OR = 1.039), and total aneurysm volume (TAV, OR = 1.006) continued to be significant predictors of AAA rupture with PWS (OR = 1.010) and RRED (OR = 1.031). Area under the ROC curve values and correct classification (cc) for the same parameters and the model that combines MAD, TAV, and rILT were measured: MAD (0.790, cc = 75%), PWS (0.713, cc = 73%), RRED (0.717, cc = 55%), TAV (0.756, cc = 79%), rILT (0.656, cc = 60%), and MAD + TAV + rILT (0.797, cc = 82%).ConclusionBased on our results, in addition to MAD, other important predictors of rupture that might be used during aneurysm surveillance are TAV and rILT. Biomechanical parameters (PWS, RRED) as valuable predictors should be assessed in prospective clinical trials. Similar studies on AAA smaller than 55 mm in diameter, even difficult to organize, would be of even greater clinical value.

The aim of this study was to demonstrate how fluid dynamic parameters are affected by aortic geometry and flow condition in two cases. Case A included blood flow analysis in aortic system with abdominal aortic aneurysm and left common iliac aneurysm before stent graft placement, while in case B was included stent graft geometry, at the site of the aneurysms. An individual patient-specific geometry and a 3D finite element meshes were reconstructed, based on Computed tomography (CT) scan images. The analysis was performed using the possibilities of computational fluid dynamics. It uses numeric methods and algorithms for the simulation of blood flow by solving the Navier-Stokes equations on computational meshes. The computational simulations of cardiac cycles were performed for average blood properties and blood flow rate. The velocity field, pressure and shear stress, as main fluid dynamics parameters, were visualized and compared for cases A and B.

We present a unified framework, based on quantum metrology concepts, for defining and quantifying deterministic noiseless quantum amplification of parameter-dependent processes, which plays an important role in increasing the precision of quantum sensing. Recent experiments [Burd et al., Science 364, 1163 (2019)SCIEAS0036-807510.1126/science.aaw2884] can be encompassed by this concept, which also leads to new suggestions of experimental work. The unified view presented here allows the identification of the basic steps for quantum amplification and of the measurements that lead to the best possible precision, beyond the quantum standard limit, in the estimation of parameters involved in the process. This is applied to the estimation of displacements of trapped ions and of the phase in SU(1,1) optical interferometers and atomic interferometry.

We determine quantum precision limits for estimation of damping constants and temperature of lossy bosonic channels. A direct application would be the use of light for estimation of the absorption and the temperature of a transparent slab. Analytic lower bounds are obtained for the uncertainty in the estimation, through a purification procedure that replaces the master equation description by a unitary evolution involving the system and ad hoc environments. For zero temperature, Fock states are shown to lead to the minimal uncertainty in the estimation of damping, with boson-counting being the best measurement procedure. In both damping and temperature estimates, sequential prethermalization measurements, through a stream of single bosons, may lead to huge gain in precision.

We investigate interferometric techniques to estimate the deflection angle of an optical beam and compare them to the direct detection of the beam deflection. We show that quantum metrology methods lead to a unifying treatment for both single photons and classical fields. Using the Fisher information to assess the precision limits of the interferometric schemes, we show that the precision can be increased by exploiting the initial transverse displacement of the beam. This gain, which is present for both Sagnac and Mach-Zehnder-like configurations, can be considerable when compared to noninterferometric methods. In addition to the fundamental increase in precision, the interferometric schemes have the technical advantage that (i) the precision limits can be saturated by a sole polarization measurement on the field, and that (ii) the detection system can be placed at any longitudinal position along the beam. We also consider position-dependent polarization measurements, and show that in this case the precision increases with the propagation distance, as well as the initial transverse displacement.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

There is growing evidence that in utero imbalance immune activity plays a role in the development of neurodevelopmental and psychiatric disorders in children. Mood dysregulation (MD) is a debilitating transnosographic syndrome whose underlying pathophysiological mechanisms could be revealed by studying its biomarkers using the Research Domain Criteria (RDoC) model. Our aim was to study the association between the network of cord serum cytokines, and mood dysregulation trajectories in offsprings between 3 and 8 years of age. We used the data of a study nested in the French birth cohort EDEN that took place from 2003 to 2014 and followed mother-child dyads from the second trimester of pregnancy until the children were 8 years of age. The 2002 mother-child dyads were recruited from the general population through their pregnancy follow-up in two French university hospitals. 871 of them were included in the nested cohort and cord serum cytokine levels were measured at birth. Children's mood dysregulation symptoms were assessed with the Strengths and Difficulties Questionnaire Dysregulation Profile at the ages 3, 5 and 8 years in order to model their mood dysregulation trajectories. Out of the 871 participating dyads, 53% of the children were male. 2.1% of the children presented a high mood dysregulation trajectory whereas the others were considered as physiological variations. We found a significant negative association between TNF-α cord serum levels and a high mood dysregulation trajectory when considering confounding factors such as maternal depression during pregnancy (adjusted Odds Ratio (aOR) = 0.35, 95% Confidence Interval (CI) [0.18-0.67]). Immune imbalance at birth could play a role in the onset of mood dysregulation symptoms. Our findings throw new light on putative immune mechanisms implicated in the development of mood dysregulation and should lead to future animal and epidemiological studies., Competing Interests: We declare none of the authors has any conflict of interest regarding the manuscript “Cord serum cytokines at birth and children's trajectories of mood dysregulation symptoms from 3 to 8 years: the EDEN birth cohort”, (© 2024 The Authors. Published by Elsevier Inc.)

Childhood internalizing disorders refer to inwardly focused negative behaviours such as anxiety, depression, and somatic complains. Interactions between psychosocial, genetic, and environmental risk factors adversely impact neurodevelopment and can contribute to internalizing disorders. While prenatal exposure to single endocrine disruptors (EDs) is associated with internalizing behaviours in infants, the associations with prenatal exposure to EDs in mixture remain poorly addressed. In addition, the biological mediators of EDs in mixture effects on internalizing behaviours remain unexplored. EDs do not only interfere with endocrine function, but also with immune function and inflammatory processes. Based on this body of evidence, we hypothetised that inflammation at birth is a plausible biological pathway through which prenatal exposure to EDs in mixture could operate to influence offspring internalizing behaviours. Based on the EDEN birth cohort, we investigated whether exposure to a mixture of EDs increased the odds of internalizing disorders in 459 boy infants at age 3, and whether the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α measured at birth were mediators of this effect. To determine both the joint and individual associations of prenatal exposure to EDs with infant internalizing behaviours and the possible mediating role of cytokines, we used the counterfactual hierarchical Bayesian Kernel Machine Regression (BKMR) regression-causal mediation analysis. We show that prenatal exposure to a complex mixture of EDs has limited effects on internalizing behaviours in boys at age 3. We also show that IL-1β, IL-6, and TNF-α are unlikely mediators or suppressors of ED mixture effects on internalizing behaviours in boys at age 3. Further studies on larger cohorts are warranted to refine the deleterious effects of EDs in mixtures on internalizing behaviours and identify possible mediating pathways., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Glaichenhaus reports financial support was provided by Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail and Université Côte d'Azur. Davidovic reports financial support was provided by Fondation de France., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: This systematic review with network meta-analysis aimed at comparing the medium-term results of open surgery (OS), fenestrated endovascular repair (FEVAR), and chimney endovascular repair (ChEVAR) in patients with juxta/pararenal abdominal aortic aneurysms (JAAAs/PAAAs). Materials and methods: MEDLINE, SCOPUS, and Web of Science were searched from inception date to 1st July 2022. Any studies comparing the results of two or three treatment strategies (ChEVAR, FEVAR, or OS) on medium-term outcomes in patients with JAAAs/PAAAs were included. Primary outcomes were all-cause mortality, aortic-related reintervention, and aortic-related mortality, while secondary outcomes were visceral stent/bypass occlusion/occlusion, major adverse cardiovascular events (MACEs), new onset renal replacement therapy (RRT), total endoleaks, and type I/III endoleak. Results: FEVAR (OR = 1.53, 95%CrI 1.03-2.11) was associated with higher medium-term all-cause mortality than OS. Sensitivity analysis including only studies that analysed JAAA showed that FEVAR (OR = 1.65, 95%CrI 1.08-2.33) persisted to be associated with higher medium-term mortality than OS. Both FEVAR (OR = 8.32, 95%CrI 3.80-27.16) and ChEVAR (OR = 5.95, 95%CrI 2.23-20.18) were associated with a higher aortic-related reintervention rate than OS. No difference between different treatment options was found in terms of aortic-related mortality. FEVAR (OR = 13.13, 95%CrI 2.70-105.2) and ChEVAR (OR = 16.82, 95%CrI 2.79-176.7) were associated with a higher rate of medium-term visceral branch occlusion/stenosis compared to OS; however, there was no difference found between FEVAR and ChEVAR. Conclusions: An advantage of OS compared to FEVAR and ChEVAR after mid-term follow-up aortic-related intervention and vessel branch/bypass stenosis/occlusion was found. This suggests that younger, low-surgical-risk patients might benefit from open surgery of JAAA/PAAA as a first approach.

Background and Objectives: It has been suggested that intense feelings of fear/anxiety and significant patient concerns may affect the perioperative course. Those findings emphasize the importance of surgical patients' preoperative feelings. Still, current knowledge in this area is based on a limited number of studies. Thus, we think that there is a need to further explore patients' preoperative fears, better characterize risk factors and reasons for their occurrence, and evaluate patients' perspectives associated with anesthesia. Materials and Methods: A total of 385 patients undergoing vascular surgery were preoperatively interviewed using a questionnaire that included demographics and questions related to patients' fears and perceptions of anesthesia. Statistical analyses included descriptive statistics, Pearson's χ 2 and McNemar tests, and multivariate ordinal logistic regression. Results: The main causes of patients' preoperative fear were surgery (53.2%), potential complications (46.5%), and anesthesia (40%). Female sex was a predictor of surgery and anesthesia-related fear (OR = 3.07, p = 0.001; OR = 2.4, p = 0.001, respectively). Previous experience lowered the fear of current surgery (OR = 0.65, p = 0.031) and anesthesia (OR = 0.6, p = 0.017). Type of surgery, type of anesthesia, educational and socioeconomic status, and personal knowledge of an anesthesiologist affected specific anesthesia-related fears. Over 25% of patients did not know that an anesthesiologist is a physician, and only 17.7% knew where anesthesiologists work. Level of education and place of residence influenced patients' perceptions of anesthesia. Conclusions: Anesthesia-related fears are affected by the type of surgery/anesthesia, experience with previous surgery, and personal knowledge of an anesthesiologist. Women, patients with lower education levels, and patients with poorer socioeconomic status are at higher risk of developing those fears. The perception of anesthesiologists is inadequate, and knowledge of anesthesia is poor. Promotion of patient education regarding anesthesia is needed to alleviate those fears and increase understanding of anesthesia.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background and Objectives: Despite the relatively large number of publications concerning the validation of these models, there is currently no solid evidence that they can be used with absolute precision to predict survival. The goal of this study is to identify preoperative factors that influenced 30-day mortality and to create a predictive model after open ruptured abdominal aortic aneurysm (RAAA) repair. Materials and Methods: This was a retrospective single-center cohort study derived from a prospective collected database, between 1 January 2009 and 2016. Multivariate logistic regression analysis was used to identify all significant predictive factors. Variables that were identified in the multivariate analysis were dichotomized at standard levels, and logistic regression was used for the analysis. To ensure that dichotomized variables were not overly simplistic, the C statistic was evaluated for both dichotomized and continuous models. Results: There were 500 patients with complete medical data included in the analysis during the study period. Of them, 37.6% were older than 74 years, and 83.8% were males. Multivariable logistic regression showed five variables that were predictive of mortality: age > 74 years (OR = 4.01, 95%CI 2.43−6.26), loss of consciousness (OR = 2.21, 95%CI 1.11−4.40), previous myocardial infarction (OR = 2.35, 95%CI 1.19−4.63), development of ventricular arrhythmia (OR = 4.54, 95%CI 1.75−11.78), and DAP < 60 mmHg (OR = 2.32, 95%CI 1.17−4.62). Assigning 1 point for each variable, patients were stratified according to the preoperative RAAA mortality risk score (range 0−5). Patients with 1 point suffered 15.3% mortality and 3 points 68.2% mortality, while all patients with 5 points died. Conclusions: This preoperative RAAA score identified risk factors readily assessed at the bedside and provides an accurate prediction of 30-day mortality after open repair of RAAA.

Background: Metabolic syndrome (MetS) is a highly prevalent and harmful medical disorder often comorbid with psychosis where it can contribute to cardiovascular complications. As immune dysfunction is a key shared component of both MetS and schizophrenia (SZ), this study investigated the relationship between immune alterations and MetS in patients with SZ, whilst controlling the impact of confounding clinical characteristics including psychiatric symptoms and comorbidities, history of childhood maltreatment and psychotropic treatments., Method: A total of 310 patients meeting DSM-IV criteria for SZ or schizoaffective disorders (SZA), with or without MetS, were systematically assessed and included in the FondaMental Advanced Centers of Expertise for Schizophrenia (FACE-SZ) cohort. Detailed clinical characteristics of patients, including psychotic symptomatology, psychiatric comorbidities and history of childhood maltreatment were recorded and the serum levels of 18 cytokines were measured. A penalized regression method was performed to analyze associations between inflammation and MetS, whilst controlling for confounding factors., Results: Of the total sample, 25% of patients had MetS. Eight cytokines were above the lower limit of detection (LLOD) in more than 90% of the samples and retained in downstream analysis. Using a conservative Variable Inclusion Probability (VIP) of 75%, we found that elevated levels of interleukin (IL)-6, IL-7, IL-12/23 p40 and IL-16 and lower levels of tumor necrosis factor (TNF)-α were associated with MetS. As for clinical variables, age, sex, body mass index (BMI), diagnosis of SZ (not SZA), age at the first episode of psychosis (FEP), alcohol abuse, current tobacco smoking, and treatment with antidepressants and anxiolytics were all associated with MetS., Conclusion: We have identified five cytokines associated with MetS in SZ suggesting that patients with psychotic disorders and MetS are characterized by a specific "immuno-metabolic" profile. This may help to design tailored treatments for this subgroup of patients with both psychotic disorders and MetS, taking one more step towards precision medicine in psychiatry., Competing Interests: All authors declare that they have no competing interests., (© 2022 The Authors.)

Inflammation appears as a cardinal mediator of the deleterious effect of early life stress exposure on neurodevelopment. More generally, immune activation during the perinatal period, and most importantly elevations of pro-inflammatory cytokines levels could contribute to psychopathology and neurological deficits later in life. Cytokines are also required for normal brain function in homeostatic conditions and play a role in neurodevelopmental processes. Despite these latter studies, whether pro-inflammatory cytokines such as Tumor Necrosis Factor (TNF) impact neurodevelopmental trajectories and behavior during the immediate postnatal period remains to be elucidated. To address this issue, we have injected mouse pups daily with recombinant TNF from postnatal day (P)1 to P5. This yielded a robust increase in peripheral and central TNF at P5, and also an increase of additional pro-inflammatory cytokines. Compared to control pups injected with saline, mice injected with TNF acquired the righting and the acoustic startle reflexes more rapidly and exhibited increased locomotor activity 2 weeks after birth. Our results extend previous work restricted to adult behaviors and support the notion that cytokines, and notably TNF, modulate early neurodevelopmental trajectories., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Paraschivescu, Barbosa, Van Steenwinckel, Gressens, Glaichenhaus and Davidovic.)

Sleep is essential for optimal child development and health during the life course. However, sleep disturbances are common in early childhood and increase the risk of cognitive, metabolic and inflammatory disorders throughout life. Sleep and immunity are mutually linked, and cytokines secreted by immune cells could mediate this interaction. The sleep modulation of cytokines has been studied mostly in adults and adolescents; few studies have focused on school-aged children and none on preschoolers. We hypothesized that night sleep duration affects cytokine levels in preschoolers. In a sample of 687 children from the EDEN French birth cohort, we studied the associations between night sleep duration trajectories from age to 2-5 years old and serum concentrations of four cytokines (Tumor necrosis factor α [TNF-α], Interleukin 6 [IL-6], IL-10, Interferon γ [IFN)-γ] at age 5, adjusting for relevant covariates. As compared with the reference trajectory (≈11h30/night sleep, 37.4% of children), a shorter sleep duration trajectory (<10 ​h/night, 4.5% of children), and changing sleep duration trajectory (≥11h30/night then 10h30/night, 5.6% of children) were associated with higher serum levels of IL-6 and TNF-α, respectively at age 5. We found no associations between sleep duration trajectories and IL-10 or IFN-γ levels. This first longitudinal study among children aged 2-5 years old suggests an impact of sleep duration on immune activity in early childhood. Our study warrants replication studies in larger cohorts to further explore whether and how immune activity interacts with sleep trajectories to enhance susceptibility to adverse health conditions., Competing Interests: None., (© 2022 Published by Elsevier Inc.)

Secreted phospholipase A2-IIA (sPLA2-IIA) hydrolyzes phospholipids to liberate lysophospholipids and fatty acids. Given its poor activity toward eukaryotic cell membranes, its role in the generation of proinflammatory lipid mediators is unclear. Conversely, sPLA2-IIA efficiently hydrolyzes bacterial membranes. Here, we show that sPLA2-IIA affects the immune system by acting on the intestinal microbial flora. Using mice overexpressing transgene-driven human sPLA2-IIA, we found that the intestinal microbiota was critical for both induction of an immune phenotype and promotion of inflammatory arthritis. The expression of sPLA2-IIA led to alterations of the intestinal microbiota composition, but housing in a more stringent pathogen-free facility revealed that its expression could affect the immune system in the absence of changes to the composition of this flora. In contrast, untargeted lipidomic analysis focusing on bacteria-derived lipid mediators revealed that sPLA2-IIA could profoundly alter the fecal lipidome. The data suggest that a singular protein, sPLA2-IIA, produces systemic effects on the immune system through its activity on the microbiota and its lipidome.

Objectives: Preoperative anxiety is common and might affect surgical treatment outcomes. The aim was to translate and validate the Serbian version of the Amsterdam Preoperative Anxiety and Information Scale (APAIS)., Methods: Following translation and initial evaluation, the Serbian version (S-APAIS) was administered to 385 patients. Internal consistency, construct validity, prognostic criteria validity, and concurrent validity between S-APAIS and Visual Analogue Scale for Anxiety (VAS-A) were evaluated., Results: Factor analysis revealed two factors: APAIS-anesthesia (items 1, 2, 3) and APAIS-procedure (items 4, 5, 6). The whole scale, APAIS-anesthesia, and APAIS-procedure subscales showed an adequate level of internal consistency (Cronbach's αs: 0.787, 0.806, and 0.805, respectively). High concurrent validity was observed between APAIS-anesthesia and VAS-A (ρ = 0.628, p < .001). A moderate correlation was found between APAIS-procedure and VAS-A scale (ρ = 0.537, p < .001). At the cut-off point of 9, the area under the curve (AUC) of APAIS-anesthesia was 0.815 (95% CI: 0.77-0.85, p < .001). For the APAIS-procedure, AUC was 0.772 (95% CI: 0.73-0.81, p < .001) at the cut-off point of 8., Conclusion: The structure of S-APAIS substantially differs from the original and allows separate measurement of anesthesia- and procedure-related anxieties. S-APAIS is a comprehensive, valid, and reliable instrument for the measurement of preoperative anxiety., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders defined by impaired social interactions and communication with repetitive behaviors, activities, or interests. Gastrointestinal (GI) disturbances and gut microbiota dysbiosis are frequently associated with ASD in childhood. However, it is not known whether microbiota dysbiosis in ASD patients also occurs in adulthood. Further, the consequences of altered gut microbiota on digestive functions and the enteric nervous system (ENS) remain unexplored. Therefore, we studied, in mice, the ability offecal supernatant (FS) from adult ASD patients to induce GI dysfunctions and ENS remodeling. First, the analyses of the fecal microbiota composition in adult ASD patients indicated a reduced α-diversity and increased abundance of three bacterial 16S rRNA gene amplicon sequence variants compared to healthy controls (HC). The transfer of FS from ASD patients (FS-ASD) to mice decreased colonic barrier permeability by 29% and 58% compared to FS-HC for paracellular and transcellular permeability, respectively. These effects are associated with the reduced expression of the tight junction proteins JAM-A, ZO-2, cingulin, and proinflammatory cytokines TNFα and IL1β. In addition, the expression of glial and neuronal molecules was reduced by FS-ASD as compared to FS-HC in particular for those involved in neuronal connectivity (βIII-tubulin and synapsin decreased by 31% and 67%, respectively). Our data suggest that changes in microbiota composition in ASD may contribute to GI alterations, and in part, via ENS remodeling.

Background: Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice., Results: Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice., Conclusions: The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD. Video abstract.

Bipolar disorder (BD) diagnosis currently relies on assessment of clinical symptoms, mainly retrospective and subject to memory bias. BD is often misdiagnosed as Major Depressive Disorder (MDD) resulting in ineffective treatment and worsened clinical outcome. The primary purpose of this study was to identify blood biomarkers that discriminate MDD from BD patients when in a depressed state. We have used clinical data and serum samples from two independent naturalistic cohorts of patients with a Major Depressive Episode (MDE) who fulfilled the criteria of either BD or MDD at inclusion. The discovery and replication cohorts consisted of 462 and 133 patients respectively. Patients were clinically assessed using standard diagnostic interviews, and clinical variables including current treatments were recorded. Blood was collected and serum assessed for levels of 31 cytokines using a sensitive multiplex assay. A penalized logistic regression model combined with nonparametric bootstrap was subsequently used to identify cytokines associated with BD. Interleukin (IL)-6, IL-10, IL-15, IL-27 and C-X-C ligand chemokine (CXCL)-10 were positively associated with BD in the discovery cohort. Of the five cytokines identified as discriminant features in the discovery cohort, IL-10, IL-15 and IL-27 were also positively associated with BD in the replication cohort therefore providing an external validation to our finding. Should our results be validated in a prospective cohort, they could provide new insights into the pathophysiological mechanisms of mood disorders., Competing Interests: NG, RB, EM, SB, PC and EI are co-inventors of a proprietary (CNRS, Université Côte d’Azur) patent application entitled “A method for diagnosing in vitro a bipolar disorder or a major depressive disorder” filed in the European Patent Office on October 4, 2018 (11115 ​EP). EO, SG, DD and LD reported no biomedical financial interests or conflict of interest., (© 2021 Published by Elsevier Inc.)

Objective: There are currently two treatments available for patients with chronic limb threatening ischaemia (CLTI): open surgical bypass (OSB) and percutaneous transluminal angioplasty with/without stenting (PTA/S). The aim of this study was to compare short and long term outcomes between PTA/S and OSB in CLTI patients with long (GLASS grade III and IV) femoropopliteal disease., Methods: This was a two centre retrospective study including all consecutive patients with CLTI undergoing first time lower extremity intervention at two distinct vascular surgical centres. Between 1 January 2012 and 1 January 2018, 1 545 CLTI consecutive limbs were treated for femoropopliteal GLASS grade III and IV lesions at two vascular surgical centres. Using covariables from baseline and angiographic characteristics, a propensity score was calculated for each limb. Thus, comparable patient cohorts (235 in PTA/S and 235 in OSB group) were identified for further analysis. The primary outcomes were freedom from re-intervention in the treated extremity and major amputation. Secondary outcomes were all hospital complications among the two patient groups., Results: Total overall complication rates were significantly higher in the OSB group (20.42% vs. 5.96%, p < .001), especially wound infection/seroma rate that required prolonged hospitalisation and further treatment (7.65% vs. 0%, p < .001). After the median follow up of 61 months, re-intervention rates were significantly higher in the PTA/S group (log rank test, 44.68% vs. 29.79%, p = .002), but there was no significant difference in terms of major amputation rates between the two group of patients (log rank test, PTA/S 27.23% vs. OSB 22.13%, p = .17)., Conclusion: Bypass surgery seems to be superior to PTA/S for GLASS grade III and IV femoropopliteal lesions in patients with CLTI in terms of long term re-intervention rates, but with considerably higher rates of post-operative complications. A larger cohort of patients in currently ongoing randomised trials, as well as prospective cohort studies are necessary to confirm these findings., Competing Interests: Conflict of interest This article is a part of a scientific research project (No 175008) supported by the Ministry of Education and Science of the Republic of Serbia. The authors declare that there is no conflict of interests., (Copyright © 2020 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Intestinal microbiota plays a key role in shaping host homeostasis by regulating metabolism, immune responses and behavior. Its dysregulation has been associated with metabolic, immune and neuropsychiatric disorders and is accompanied by changes in bacterial metabolic regulation. Although proteomics is well suited for analysis of individual microbes, metaproteomics of fecal samples is challenging due to the physical structure of the sample, presence of contaminating host proteins and coexistence of hundreds of taxa. Furthermore, there is a lack of consensus regarding preparation of fecal samples, as well as downstream bioinformatic analyses following metaproteomics data acquisition. Here we assess sample preparation and data analysis strategies applied to mouse feces in a typical mass spectrometry-based metaproteomic experiment. We show that subtle changes in sample preparation protocols may influence interpretation of biological findings. Two-step database search strategies led to significant underestimation of false positive protein identifications. Unipept software provided the highest sensitivity and specificity in taxonomic annotation of the identified peptides of unknown origin. Comparison of matching metaproteome and metagenome data revealed a positive correlation between protein and gene abundances. Notably, nearly all functional categories of detected protein groups were differentially abundant in the metaproteome compared to what would be expected from the metagenome, highlighting the need to perform metaproteomics when studying complex microbiome samples.

Objective: Popliteal artery aneurysm (PAA) is the second most common arterial aneurysm. Vascunet is an international collaboration of vascular registries. The aim was to study treatment and outcomes., Methods: This was a retrospective analysis of prospectively registered population based data. Fourteen countries contributed data (Australia, Denmark, Finland, France, Hungary, Iceland, Italy, Malta, New Zealand, Norway, Portugal, Serbia, Sweden, and Switzerland)., Results: During 2012-2018, data from 10 764 PAA repairs were included. Mean values with between countries ranges in parenthesis are given. The incidence was 10.4 cases/million inhabitants/year (2.4-19.3). The mean age was 71.3 years (66.8-75.3). Most patients, 93.3%, were men and 40.0% were active smokers. The operations were elective in 73.2% (60.0%-85.7%). The mean pre-operative PAA diameter was 32.1 mm (27.3-38.3 mm). Open surgery dominated in both elective (79.5%) and acute (83.2%) cases. A medial surgical approach was used in 77.7%, and posterior in 22.3%. Vein grafts were used in 63.8%. Of the emergency procedures, 91% (n = 2 169, 20.2% of all) were for acute thrombosis and 9% for rupture (n = 236, 2.2% of all). Thrombosis patients had larger aneurysms, mean diameter 35.5 mm, and 46.3% were active smokers. Early amputation and death were higher after acute presentation than after elective surgery (5.0% vs. 0.7%; 1.9% vs. 0.5%). This pattern remained one year after surgery (8.5% vs. 1.0%; 6.1% vs. 1.4%). Elective open compared with endovascular surgery had similar one year amputation rates (1.2% vs. 0.2%; p = .095) but superior patency (84.0% vs. 78.4%; p = .005). Veins had higher patency and lower amputation rates, at one year compared with synthetic grafts (86.8% vs. 72.3%; 1.8% vs. 5.2%; both p < .001). The posterior open approach had a lower amputation rate (0.0% vs. 1.6%, p = .009) than the medial approach., Conclusion: Patients presenting with acute ischaemia had high risk of amputation. The frequent use of endovascular repair and prosthetic grafts should be reconsidered based on these results., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Disruption of neurodevelopmental trajectories can alter brain circuitry and increase the risk of psychopathology later in life. While preclinical studies have demonstrated that the immune system and cytokines influence neurodevelopment, whether immune activity and in particular which cytokines at birth are associated with psychopathology remains poorly explored in children. We used data and biological samples from 869 mother-child pairs participating in the French mother-child cohort EDEN. As proxies for immune activity at birth, we measured the levels of 27 cytokines in umbilical cord blood sera (CBS). We then explored the association between CBS cytokine levels and five psychopathological dimensions assessed in 5-year-old children using the Strengths and Difficulties Questionnaire (SDQ). Five cytokines were positively associated with psychopathology: C-X-C motif chemokine Ligand (CXCL)10, interleukin (IL)-10 and IL-12p40 with emotional symptoms, C-C motif chemokine Ligand (CCL)11 with conduct problems, and CCL11, and IL-17A with peer relationships problems. In contrast, seven cytokines were negatively associated with psychopathology: IL-7, IL-15 and Tumor Necrosis Factor (TNF)-β with emotional symptoms, CCL4 and IL-6 with conduct problems, CCL26 and IL-15 with peer relationships problems, and CCL26, IL-7, IL-15, and TNF-α with abnormal prosocial behavior. Without implying causation, these associations support the notion that cytokines influence neurodevelopment in humans and the risk of psychopathology later in life., Competing Interests: None., (© 2020 The Author(s).)

Objective: The aim of our study was to compare early and long-term results of open repair of patients with inflammatory abdominal aortic aneurysm (IAAA) with matched cohort of patients with abdominal aortic aneurysm (AAA)., Methods: This retrospective single-center cohort study used prospectively collected data from an institutional registry from 1786 patients between 2009 and 2015. Patients with IAAA and AAA were matched by propensity score analysis controlling for demographics, baseline comorbidities, and AAA parameters in a 1:2 ratio. Patients were followed for 5 years., Results: There were 76 patients with IAAA and 152 patients with AAA. Patients with IAAA had more common intraoperative lesion of intraabdominal organs (P = .04), longer in-hospital (P = .035) and intensive care (P = .048) stays and a higher in-hospital mortality rate (P = .012). There were four patients (5.26%) with in-hospital lethal outcome in IAAA there were no deaths in the AAA group. During the follow-up, there was no difference in survival (χ 2  = 0.07; DF = 1; P = .80) and overall aortic related complications (χ 2  = 1.25; DF = 1; P = .26); however, aortic graft infection was more frequent in IAAA group (P = .04)., Conclusions: Open repair of IAAA is challenging and comparing to AAA carries a higher perioperative risk and long-term infection rate, even in high-volume centers. The main causes of complications are intraoperative injury of adjacent organs, bleeding, and coronary events. Patients with AAA in a matched cohort showed equal long-term survival, which should be assessed in bigger registries., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to determine whether magnetic resonance imaging (MRI) can be used in assessment of biologic activity of intraluminal thrombus (ILT) and proteolytic processes of the abdominal aortic aneurysm wall., Methods: Using MRI, 50 patients with asymptomatic infrarenal abdominal aortic aneurysm were analyzed at the maximum aneurysm diameter on T1-weighted images in the arterial phase after administration of contrast material. Relative ILT signal intensity (SI) was determined as the ratio between ILT SI and psoas muscle SI. During surgery, the full thickness of the ILT and the adjacent part of the aneurysm wall were harvested at the maximal diameter for biochemical analysis. The concentrations of matrix metalloproteinase 9 and neutrophil elastase (NE/ELA) were analyzed in harvested thrombi, and the concentrations of collagen type III, elastin, and proteoglycans were analyzed in harvested aneurysm walls., Results: A significant positive correlation was found between the NE/ELA concentration of the ILT and the relative SI (ρ = 0.309; P = .029). Furthermore, a negative correlation was observed between the elastin content of the aneurysm wall and the relative SI (ρ = -0.300; P = .034). No correlations were found between relative SI and concentration of matrix metalloproteinase 9, NE/ELA, collagen type III, or proteoglycan 4 in the aneurysm wall., Conclusions: These findings indicate a potential novel use of MRI in prediction of thrombus proteolytic enzyme concentrations and the extracellular matrix content of the aneurysm wall, thus providing additional information for the risk of potential aneurysm rupture., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Maternal immune activation (MIA) during pregnancy induces a cytokine storm that alters neurodevelopment and behavior in the progeny. In humans, MIA increases the odds of developing neuropsychiatric disorders such as autism spectrum disorder (ASD). In mice, MIA can be induced by injecting the viral mimic polyinosinic:polycytidylic acid (poly(I:C)) to pregnant dams. Although the murine model of MIA has been extensively studied, it is not clear whether MIA results in cytokine changes in the progeny at early postnatal stages. Further, the murine model of MIA suffers from a lack of reproducibility and high inter-individual variability. Multivariable (MV) statistical analysis is widely used in human studies to control for confounders and covariates such as sex, age and exposure to environmental factors. We therefore reasoned that animal studies in general and studies on the MIA model in particular could benefit from MV analyses to account for complex phenotype interactions and high inter-individual variability. Here, we used MV statistical analysis to identify cytokines associated with MIA after adjustment for covariates. Besides confirming the association between previously described variables and MIA, we identified new cytokines that could play a role in behavioural alterations in the progeny during the early postnatal period., Competing Interests: The authors have declared that no competing interests exist.

Background: Fragile X syndrome (FXS) is the most frequent cause of inherited intellectual disability and the most commonly identified monogenic cause of autism. Recent studies have shown that long-term pathological consequences of FXS are not solely confined to the central nervous system (CNS) but rather extend to other physiological dysfunctions in peripheral organs. To gain insights into possible immune dysfunctions in FXS, we profiled a large panel of immune-related biomarkers in the serum of FXS patients and healthy controls., Methods: We have used a sensitive and robust Electro Chemi Luminescence (ECL)-based immunoassay to measure the levels of 52 cytokines in the serum of n = 25 FXS patients and n = 29 healthy controls. We then used univariate statistics and multivariate analysis, as well as an advanced unsupervised clustering method, to identify combinations of immune-related biomarkers that could discriminate FXS patients from healthy individuals., Results: While the majority of the tested cytokines were present at similar levels in FXS patients and healthy individuals, nine chemokines, CCL2, CCL3, CCL4, CCL11, CCL13, CCL17, CCL22, CCL26 and CXCL10, were present at much lower levels in FXS patients. Using robust regression, we show that six of these biomarkers (CCL2, CCL3, CCL11, CCL22, CCL26 and CXCL10) were negatively associated with FXS diagnosis. Finally, applying the K-sparse unsupervised clustering method to the biomarker dataset allowed for the identification of two subsets of individuals, which essentially matched the FXS and healthy control categories., Conclusions: Our data show that FXS patients exhibit reduced serum levels of several chemokines and may therefore exhibit impaired immune responses. The present study also highlights the power of unsupervised clustering methods to identify combinations of biomarkers for diagnosis and prognosis in medicine.

Objective: Acute lower limb ischaemia (ALI) as a result of popliteal artery aneurysm (PAA) thrombosis represents a significant problem. The aim of this study was to investigate outcome of intra-operative intra-arterial thrombolysis in the treatment of acute ischaemia due to PAA thrombosis in terms of major adverse limb events (MALE), overall survival, and intrahospital complications, especially those associated with bleeding., Methods: A total of 156 patients with Rutherford grade IIa and IIb acute ischaemia resulting from PAA thrombosis were admitted between 1 January 2011 and 1 January 2017. The patients were divided into two groups, those who underwent additional treatment with intra-operative intra-arterial thrombolysis (20 patients), and those who did not (136 patients). By using covariables from baseline and angiographic characteristics, a propensity score was calculated for each patient. Each patient who underwent intra-operative thrombolysis was matched to four patients from the non-thrombolysis group. Thus, comparable patient cohorts (20 in the thrombolysis and 80 in the non-thrombolysis group) were identified for further analysis. The primary end point was MALE and the secondary endpoint all cause mortality., Results: After a median follow up of 55 months, the estimated MALE rate was significantly lower in the thrombolysis group (30% vs. 65%, chi square = 10.86, p < .001, log rank test). Also, patients in the thrombolysis group had a significantly lower mortality rate (20% vs. 42.65%, chi square = 3.65, p = .05, log rank test). The thrombolysis group had wound/haematoma related interventions performed more commonly (25% in thrombolysis vs 8%, in non-thrombolysis group), but the difference was not significant (p=.013). There were no cases of major (intracranial and gastrointestinal) bleeding in either group., Conclusion: The data suggest that intra-operative thrombolysis in the treatment of selected patients with ALI due to PAA thrombosis has long term MALE and overall survival benefits, without a significant risk of major, life threatening bleeding complications., (Copyright © 2019 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability, hyperactivity, and autism. FXS is due to the silencing of the X-linked FMR1 gene. Murine models of FXS, knock-out (KO) for the murine homolog Fmr1 , have been generated, exhibiting CNS-related behavioral, and neuronal anomalies reminiscent of the human phenotypes. As a reflection of the almost ubiquitous expression of the FMR1 gene, FXS is also accompanied by physical abnormalities. This suggests that the FMR1- deficiency could impact skeletal ontogenesis. In the present study, we highlight that Fmr1- KO mice display changes in body composition with an increase in body weight, likely due to both increase of skeleton length and muscular mass along with reduced visceral adiposity. We also show that, while Fmr1- deficiency has no overt impact on cortical bone mineral density (BMD), cortical thickness was increased, and cortical eccentricity was decreased in the femurs from Fmr1- KO mice as compared to controls. Also, trabecular pore volume was reduced and trabecular thickness distribution was shifted toward higher ranges in Fmr1- KO femurs. Finally, we show that Fmr1 -KO mice display increased physical activity. Although the precise molecular signaling mechanism that produces these skeletal and bone microstructure changes remains to be determined, our study warrants further investigation on the impact of FMR1 -deficiency on whole-body composition, as well as skeletal and bone architecture., (Copyright © 2019 Leboucher, Bermudez-Martin, Mouska, Amri, Pisani and Davidovic.)

Objective: The aim of this study was to evaluate the results of endovascular therapy on the treatment of different types of iliac occlusions., Materials and Methods: A bi-center prospective, non-randomized study was conducted on 100 patients (mean age 59.14 ± 8.53; 64 men) who underwent endovascular treatment of iliac occlusive disease between January 2013 and November 2017. We evaluated baseline data, procedure, and follow-up results for the entire group, and according to Trans-Atlantic Inter-Society Consensus (TASC II) classification. The majority of patients (60%) were treated for severe claudication; 56 (56%) patients had TASC B occlusions, 28 patients TASC C, and 16 patients TASC D., Results: The mean length of the occluded segments was 61.41 ± 35.15 mm. Procedural complications developed in 6 patients (6%). Mean ankle-brachial pressure index increased from 0.40 ± 0.12 preoperatively to 0.82 ± 0.16 postoperatively. The mean follow-up was 33.18 ± 15.03 months. After 1 and 5 years, the primary patency rates were 98% and 75.1%, and the secondary patency rate was 97% respectively. Regarding occlusion complexity there were no statistical significant differences in primary patency rates (TASC B vs. C vs. D: p = 0.19). There were no statistically significant differences in primary patency rates between patients in different clinical stages, as well as between the type of stents, and location of the occlusion., Conclusion: In our study, endovascular treatment for iliac artery occlusions proved to be a safe and efficient approach with excellent primary and secondary patency rates regardless of the complexity of occlusions defined by TASC II classification. This study is aligned with the notion that in well selected patients, endovascular therapy can be the treatment of choice even in complex iliac lesions if performed by experienced endovascular interventionists in high volume centers., Competing Interests: The authors have declared that no competing interests exist.

Background: Patients with acute peripheral arterial occlusion (aPAO) are candidates for operative thrombectomy, bypass, or catheter-directed thrombolysis (CDT) using a plasminogen activator. Human plasma-derived plasmin may offer another CDT option. Objectives: To evaluate the efficacy, safety, and tolerability of two intrathrombus delivery methods and two doses of plasmin compared with recombinant tissue plasminogen activator (rtPA) and placebo in patients with aPAO. Patients/methods: This was a phase 2, randomized, open-label study of intra-arterial CDT of plasmin in patients with aPAO. The study used infusion catheters with or without balloon occlusion (BOC) to evaluate 150 mg plasmin (2 and 5 h post-infusion) and 250 mg plasmin (5 h post-infusion). The efficacy of plasmin, rtPA and placebo was assessed. Results: One hundred and seventy-four subjects were enrolled. Overall, the thrombolytic efficacy (>50% thrombolysis) was 59% (58/99) for 150 mg plasmin without BOC, which is comparable to 89% (8/9) for rtPA without BOC ( p  = 0.149) and 40% (2/5) for placebo control ( p =  0.648). The thrombolytic efficacy was 33% of the 250 mg plasmin group. There was no difference ( p  > 0.999) in thrombolytic efficacy with BOC (59%, 58/99) or without BOC (59%, 17/29). Plasmin-treated groups experienced treatment-emergent adverse events (TEAEs) at 71% (76/107) without BOC and 63% (24/38) with BOC; 78% (7/9) of the rtPA-treated group and 89% (8/9) of the placebo group had TEAEs. Serious AEs (SAEs) occurred in 29% (31/107) of the 150 mg plasmin group without BOC and 24% (9/38) with BOC. No SAEs occurred in the 250 mg plasmin group. Conclusions: Plasmin demonstrated less bleeding during catheter-directed administration at 150 mg and 250 mg doses compared to rtPA. BOC utilization did not improve efficacy. CDT with plasmin has a potential thrombolytic benefit in patients presenting with aPAO. ClinicalTrials.gov Identifier: NCT01222117.

Objectives: The Fragile X Mental Retardation Protein (FMRP) is a widely expressed RNA-binding protein involved in translation regulation. Since the absence of FMRP leads to Fragile X Syndrome (FXS) and autism, FMRP has been extensively studied in brain. The functions of FMRP in peripheral organs and on metabolic homeostasis remain elusive; therefore, we sought to investigate the systemic consequences of its absence., Methods: Using metabolomics, in vivo metabolic phenotyping of the Fmr1-KO FXS mouse model and in vitro approaches, we show that the absence of FMRP induced a metabolic shift towards enhanced glucose tolerance and insulin sensitivity, reduced adiposity, and increased β-adrenergic-driven lipolysis and lipid utilization., Results: Combining proteomics and cellular assays, we highlight that FMRP loss increased hepatic protein synthesis and impacted pathways notably linked to lipid metabolism. Mapping metabolomic and proteomic phenotypes onto a signaling and metabolic network, we predicted that the coordinated metabolic response to FMRP loss was mediated by dysregulation in the abundances of specific hepatic proteins. We experimentally validated these predictions, demonstrating that the translational regulator FMRP associates with a subset of mRNAs involved in lipid metabolism. Finally, we highlight that FXS patients mirror metabolic variations observed in Fmr1-KO mice with reduced circulating glucose and insulin and increased free fatty acids., Conclusions: Loss of FMRP results in a widespread coordinated systemic response that notably involves upregulation of protein translation in the liver, increased utilization of lipids, and significant changes in metabolic homeostasis. Our study unravels metabolic phenotypes in FXS and further supports the importance of translational regulation in the homeostatic control of systemic metabolism., (Crown Copyright © 2019. Published by Elsevier GmbH. All rights reserved.)

Advanced renal cell carcinoma accompanied by tumor thrombus in the venous system is present in up to 10% of cases. Extension of tumor thrombus above the diaphragm or into the right atrium represents level IV disease. Level IV tumors are typically treated with sterno-laparotomy approach with or without deep hypothermic circulatory arrest and veno-venous bypass. In this case report, the surgical technique for the resection of advanced RCC were described, with the concomitant use of transesophageal echocardiography for thrombus extraction without the veno-venous or cardiopulmonary bypass.

Early response to first-line antipsychotic treatments is strongly associated with positive long-term symptomatic and functional outcome in psychosis. Unfortunately, attempts to identify reliable predictors of treatment response in first-episode psychosis (FEP) patients have not yet been successful. One reason for this could be that FEP patients are highly heterogeneous in terms of symptom expression and underlying disease biological mechanisms, thereby impeding the identification of one-size-fits-all predictors of treatment response. We have used a clustering approach to stratify 325 FEP patients into four clinical subtypes, termed C1A, C1B, C2A and C2B, based on their symptoms assessed using the Positive and Negative Syndrome Scale (PANSS) scale. Compared to C1B, C2A and C2B patients, those from the C1A subtype exhibited the most severe symptoms and were the most at risk of being non-remitters when treated with the second-generation antipsychotic drug amisulpride. Before treatment, C1A patients exhibited higher serum levels of several pro-inflammatory cytokines and inflammation-associated biomarkers therefore validating our stratification approach on external biological measures. Most importantly, in the C1A subtype, but not others, lower serum levels of interleukin (IL)-15, higher serum levels of C-X-C motif chemokine 12 (CXCL12), previous exposure to cytomegalovirus (CMV), use of recreational drugs and being younger were all associated with higher odds of being non-remitters 4 weeks after treatment. The predictive value of this model was good (mean area under the curve (AUC) = 0.73 ± 0.10), and its specificity and sensitivity were 45 ± 0.09% and 83 ± 0.03%, respectively. Further validation and replication of these results in clinical trials would pave the way for the development of a blood-based assisted clinical decision support system in psychosis.

Introduction: Acute lower limb ischaemia (ALI) is the sudden onset of decreased arterial perfusion with imminent threat to limb viability. Contrast induced acute kidney injury (CI-AKI) is one of the complications that increases mortality in patients who undergo contrast imaging in coronary procedures. The goal of this study is to evaluate the impact of chronic kidney disease (CKD) and CI-AKI on long-term clinical outcomes in patients with ALI undergoing lower limb revascularisation., Methods: A total 1017 consecutive patients with acute lower limb ischaemia who were admitted between July 1, 2006, and January 1, 2017, were retrospectively reviewed. Patients who had end stage renal disease, those who had end stage heart and malignant disease and died within 7 days of limb revascularisation, and those who did not undergo angiography were excluded. Thus 546 patients were included in the final analysis. Patients were classified as with or without CKD and were then subdivided according to the presence or absence of the development of CI-AKI, defined as an increase in serum creatinine of ≥0.5 mg/dL or by ≥25% from the baseline value within the first 72 h after contrast exposure. The primary end point was all cause mortality and secondary major adverse limb event (MALE)., Results: Both CKD and CI-AKI were associated with the highest rate of all cause mortality (chi square = 55.77, d.f. = 1, p < .01, log rank test) and MALE (chi square = 79.07, d.f. = 1, p < .01, log rank test). The presence of CKD and CI-AKI were significant risk factors associated with long-term all cause mortality (HR = 2.61, p < .01) and MALE (HR = 2.87, p < .01)., Conclusion: In patients with ALI undergoing lower limb revascularisation, both CKD and CI-AKI were significantly associated with poor long-term outcomes compared with either CKD or CI-AKI alone. Further studies are required to assess this association and to confirm the combined effect of CKD and CI-AKI on long-term clinical outcomes., (Copyright © 2018 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and a leading cause of autism. FXS is due to the silencing of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein mainly involved in translational control, dendritic spine morphology and synaptic plasticity. Despite extensive studies, there is currently no cure for FXS. With the purpose to decipher the initial molecular events leading to this pathology, we developed a stem-cell-based disease model by knocking-down the expression of Fmr1 in mouse embryonic stem cells (ESCs). Repressing FMRP in ESCs increased the expression of amyloid precursor protein (APP) and Ascl1. When inducing neuronal differentiation, βIII-tubulin, p27 kip1 , NeuN, and NeuroD1 were upregulated, leading to an accelerated neuronal differentiation that was partially compensated at later stages. Interestingly, we observed that neurogenesis is also accelerated in the embryonic brain of Fmr1-knockout mice, indicating that our cellular model recapitulates the molecular alterations present in vivo. Importantly, we rescued the main phenotype of the Fmr1 knockdown cell line, not only by reintroducing FMRP but also by pharmacologically targeting APP processing, showing the role of this protein in the pathophysiology of FXS during the earliest steps of neurogenesis. Our work allows to define an early therapeutic window but also to identify more effective molecules for treating this disorder. Stem Cells 2017;35:374-385., (© 2016 AlphaMed Press.)