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Background Over the past twenty years, progress of cardiac surgery has been such that actual life expectancy of a patient with congenital heart disease (CHD) approaches that of the average for the general population. The current challenge is no longer to decrease cardiac surgery's mortality rate, but rather to manage morbidity and a child's overall development regarding nutrition and neurodevelopment. Malnutrition is a common cause of morbidity in infants with CHD, especially before the age of one. It can easily be explained by an increased metabolic demand linked to cardiac failure, hypoxemia or pulmonary hypertension. Secondly, food intake is frequently not optimal in this population and the infant's growth is insufficiently examined by paediatric cardiologists. Another factor is that much needed therapeutics such as diuretic drugs for example, often lead to weight loss. Ultimately, malnutrition in infants with CHD increases surgical risk, morbidity (infections, …), hospital stay, and alters long-term cognitive development. This study reports prevalence and associated factors of malnutrition on short and long-term follow-up of a large cohort of patients with various CHD, and who underwent cardiac surgery before the age of one. Method We conducted a retrospective and multicentre study that included infants from the North of France with CHD who underwent cardiac surgery before the age of one, between 2013 and 2017. To determine malnutrition, anthropometric measures (weight and height) were collected on the day of the surgery and during follow-up until 3 years after surgery to calculate Z-score for weight, height and weight/height. To test the statistical significance of the association between nutritional status and risk variables, univariate analysis was done applying Chi-square test. All variables significant at 0.1 in univariate analysis were included in the multivariate logistic regression analysis. The study was approved by French national ethic committee Commission national de l’informatique et des libertes (CNIL) and by the GFHGNP ethic committee (Groupe francophone d’hepatologie–gastro-enterologie et nutrition pediatrique). The author declares that he has no competing of interest. Result In total, 331 patients with CHD who underwent their first cardiac surgery (palliation or repair) before the age of one were included. Table 1 lists the cardiac diagnosis of patients included in the study. Demographic and clinical characteristics are summarised in Table 2 . Caesarean section was performed in 23.5% of cases. Only 38% infants were breastfed after maternity stay. An important part of our population was treated with diuretic drugs before surgery for congestive heart failure (38.5%). 69 (21%) infants needed a gastric tube before surgery. Feeding difficulties (including need for dietary enrichment and/or presence of a gastric tube) represented 35% of our population at the day of surgery. Only 39 (12%) were specifically assessed by speech therapist for feeding problems. Concerning surgery, 246 (74.5%) infants had undergone a biventricular repair, 51 (15.5%) infants had undergone a palliative intervention before a biventricular repair and 33 (10%) had a palliative intervention before a univentricular repair. 84 (26%) were cyanotic after their first surgery, 104 (32%) needed at least a second intervention. 49 (15%) infants had postoperative complications and 84 (26%) infants were treated by diuretics for congestive heart failure one month after surgery. 19 (5.9%) infants needed intravenous (IV) nutrition for more than 7 days. There were 19 (6%) deaths. Regarding nutritional status, at the time of the surgery, 14% of the infants presented moderate to severe growth failure (with a Z score weight for age During follow-up, between six months and 12 months after surgery, moderate to severe growth failure persisted in 16% of the study population and minor growth failure in 24%. In other terms, 40% of our cohort presented a persistent minor to severe growth failure. Fig. 1 , Fig. 2 summarize evolution of growth failure and malnutrition respectively during follow-up from 15 days to 3 years after surgery. Nineteen patients died during follow-up. A significant proportion of patients had impaired somatic growth or malnutrition at the end of the follow-up. Several associated factors of persistent growth failure 6 to 12 months after surgery were identified in univariate analysis: prenatal diagnosis, presence of genetic syndrome, birth weight ≤ 3 kg, complex CHD (CHD with 2 or more significative lesions or double outlet right ventricule or single ventricule physiology), surgery after 30 days from birth, and diuretic therapy before surgery and/or still necessary one month after surgery. The results of multivariate logistic regression analysis are summarized in Table 3 . CHD types were divided in 4 groups regarding anatomy and complexity, using TGA, Fallot and coarctation of Aorta as referent CHD with low impact on infant growth away from the day of surgery. The presence of a feeding tube at the day of surgery was not associated with growth failure 6 to 12 months after. Conclusion Growth failure in infants with CHD who undergo cardiac surgery before the age of one persists between 6 and 12 months after surgery. This should be taken into account as it can have serious consequences on children's health and development. Highlighting predictive factors will allow medical staff to identify vulnerable infants at birth and during the period of surgery and therefore increase nutritional care to combat malnutrition and growth failure.

Background Breast cancer is the most common malignancy in woman and hormone receptor positive breast cancer represents approximately 70% of all cases. These patients are treated with endocrine therapies aimed at disrupting hormone receptor signaling and estrogen production which improves survival and allows a cure in early stages. However, recurrent disease, metastatic dissemination and drug resistance limit the survival of patients. The limitations regarding endocrine therapy have prompted the search for new therapeutic targets, such as CDK4/6 Inhibitors. Despite the improved disease control that CDK4/6 Inhibitors offer to patients, not all patients respond to these drugs and some patients whose tumors respond to CDK4/6 Inhibitors eventually develop acquired resistance. No proven biomarkers of CDK4/6 Inhibitors efficacy exist to date, and there is a need for diagnostic tools that could stratify patients to save costs and the burden of unnecessary therapy. Our aim is to perform a quantitative evaluation of marker proteins with a developed multiplexed panel using targeted mass spectrometry (MS)-based proteomics for 25 proteins from the CDK/RB/E2F-pathway which have been shown in the literature to be central to CDK4/6I resistance. Material and Methods We developed Multiple Reaction Monitoring (MRM) MS methods for the 25 target proteins from the CDK/RB/E2F-pathway using synthetic heavy-isotope-labeled standards with the aim of creating MRM assays to enable specific, sensitive and precise quantitation of these proteins in small amounts of cell line and tissue samples. Moreover, we developed a high resolution peptide fractionation system using high-pH micro-flow liquid chromatography (LC) which is required to overcome the problem of small samples amounts while improving analytical assay sensitivity in the analysis of complex biological matrices such as breast cancer biopsies. The MCF-7 human breast cancer cell line was used as model during method development. Proteins from cell lysates were isolated, reduced, alkylated and digested with trypsin. The resulting tryptic peptides were micro-flow fractionated into 70 fractions and the developed nano-LC-MS MRM assays were used for peptide detection and quantification. Data were analyzed using Skyline. Results Our developed micro-flow fractionation method allowed us to work on limited amounts of samples (60ug), and increased the possibility to detecting low abundance proteins such as cell cycle components. Using the MCF-7 cell model, we are able to identify and quantify 17 proteins out of the 25 from our panel: CDK1, CDK2, CDK4, Cyclin B1, Cyclin D1, Cyclin D3, Cyclin E1, RB1, E2F-3, E2F-4, E2F-5, ESR1, TOP2A, TYMS, EZH2, MKI67, BIRC5. Conclusion We have developed a highly specific MS-based multiplexed assay with peptide standards targeting 25 proteins relevant to CDK4/6 Inhibitors breast cancer treatment. Our micro-flow fractionation method increased assay sensitivity and allows for the analysis of small sample amounts. In the future we will apply this workflow to samples such as Patient Derived Xenografts models, breast cancer tissues and FFPE samples in order to identify the predictive value of these potential biomarkers for responsiveness to CDK4/6 Inhibitors. Citation Format: Marta Zurawska, Adriana Aguilar-Mahecha, Mark Basik, Michal Dadlez, Dominik Domanski. Development of a multiplexed protein panel using a targeted proteomics approach for the study of CDK4/6 inhibitors resistance in hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-48.

Millions of people worldwide are affected by traumatic spinal cord injury, which usually results in permanent sensorimotor disability. Damage to the spinal cord leads to a series of detrimental events including ischaemia, haemorrhage and neuroinflammation, which over time result in further neural tissue loss. Eventually, at chronic stages of traumatic spinal cord injury, the formation of a glial scar, cystic cavitation and the presence of numerous inhibitory molecules act as physical and chemical barriers to axonal regrowth. This is further hindered by a lack of intrinsic regrowth ability of adult neurons in the central nervous system. The intracellular signalling molecule, cyclic adenosine 3′,5′-monophosphate (cAMP), is known to play many important roles in the central nervous system, and elevating its levels as shown to improve axonal regeneration outcomes following traumatic spinal cord injury in animal models. However, therapies directly targeting cAMP have not found their way into the clinic, as cAMP is ubiquitously present in all cell types and its manipulation may have additional deleterious effects. A downstream effector of cAMP, exchange protein directly activated by cAMP 2 (Epac2), is mainly expressed in the adult central nervous system, and its activation has been shown to mediate the positive effects of cAMP on axonal guidance and regeneration. Recently, using ex vivo modelling of traumatic spinal cord injury, Epac2 activation was found to profoundly modulate the post-lesion environment, such as decreasing the activation of astrocytes and microglia. Pilot data with Epac2 activation also suggested functional improvement assessed by in vivo models of traumatic spinal cord injury. Therefore, targeting Epac2 in traumatic spinal cord injury could represent a novel strategy in traumatic spinal cord injury repair, and future work is needed to fully establish its therapeutic potential.

Background The health status of newborns is a major concern for parents and medical personnel. Recent studies have provided increasing evidence that factors from the foetal and perinatal periods of life influence health later in life. The “Follow‐up of the Survey of Neonates in Pomerania” (SNiP‐I‐Follow‐up) is the first follow‐up of the population‐based birth cohort study, SNiP‐I, established in north‐east Germany. Objectives The primary aim of SNiP‐I‐Follow‐up study was the collection of longitudinal data on children and adolescents. The associations will be analysed between risk factors in pregnancy and the perinatal period and health status in infancy and later childhood. Population The population‐based cohort study SNiP‐I was conducted in Pomerania in north‐east Germany between February 2002 and November 2008. All mothers from the SNiP‐I birth cohort were recontacted when their children were from 9 to 15 years of age. Design The SNiP‐I‐Follow‐up study was carried out between December 2016 and August 2017 and is a questionnaire‐based survey. Methods Physical development, health status, and social behaviour (school and leisure behaviour) of children were analysed using a questionnaire comprising medical, epidemiological, and socio‐economic data, associated health care risk factors, and life circumstances of newborns, children, and their parents. Preliminary results Out of 5725 children invited to participate in the SNiP‐I‐Follow‐up study between December 2016 and August 2017, 29% (n = 1665) children participated in the SNiP‐I‐Follow‐up study, providing data on 1665 mothers‐child dyads. Responders had higher socio‐economic status, especially in relation to maternal education status. Conclusion As a longitudinal birth cohort from rural Germany, the SNiP cohort will be a resource to address urgent research needs and contribute to overall population health.

Cerebral palsy is a disease that puts a great mental burden on caregivers and generates very high social costs. Children with CP require many years of rehabilitation and medical care. The etiology of the disease is undoubtedly multifactorial, and the pathogenesis is associated with focal damage to the central nervous system. One can find descriptions of well-documented interventions in the literature that reduce the risk of CP in certain groups of pregnant and neonatal patients, and interventions that have a potentially protective effect. In this review, we have analyzed the available literature in terms of prenatal and postnatal interventions that may have an impact on reducing the incidence of this condition in children.

Aims To compare the clinical significance of exercise echocardiography (ExE) and cardiopulmonary exercise testing (CPX) in patients with ≥moderate primary mitral regurgitation (MR) and discrepancy between symptoms and MR severity. Methods and results Patients consulting for ≥moderate discordant primary MR prospectively underwent low (25 W) ExE, peak ExE, and CPX within 2 months in Lille and Rennes University Hospital. Patients with Class I recommendation for surgical MR correction were excluded. Changes in MR severity, systolic pulmonary artery pressure (SPAP), left ventricular ejection fraction (LVEF), and tricuspid annular plane systolic excursion were evaluated during ExE. Patients were followed for major events (ME): cardiovascular death, acute heart failure, or mitral valve surgery. Among 128 patients included, 22 presented mild-to-moderate, 61 moderate-to-severe, and 45 severe MR. Unlike MR variation, SPAP and LVEF were successfully assessed during ExE in most patients. Forty-one patients (32%) displayed reduced aerobic capacity (peak VO2 < 80% of predicted value) with cardiac limitation in 28 (68%) and muscular or respiratory limitation in the 13 others (32%). ME occurred in 61 patients (47.7%) during a mean follow-up of 27 ± 21 months. Twenty-five Watts SPAP [hazard ratio (HR) (95% confidence interval, CI) = 1.03 (1.01–1.06), P = 0.003] and reduced aerobic capacity [HR (95% CI) = 1.74 (1.03–2.95), P = 0.04] were independently predictive of ME, even after adjustment for MR severity. The cut-off of 55 mmHg for 25 W SPAP showed the best accuracy to predict ME (area under the curve = 0.60, P = 0.05). Conclusion In patients with ≥moderate primary MR and discordant symptoms, 25 W exercise pulmonary hypertension, defined as an SPAP ≥55 mmHg, and poor aerobic capacity during CPX are independently associated with adverse events.

Background: Transcatheter Patent Foramen Ovale (PFO) is recommended as a therapy in secondary prevention of cryptogenic stroke. The aim of this study was to report one-year French single-center experience in PFO closure under sole Transthoracic Echocardiography (TTE) and fluoroscopy guidance performed as a day-case procedure versus a 3-day hospitalization. Methods: In 2018, all consecutive patients undergoing PFO closure for stroke were retrospectively included: 108 patients as a day-case procedure (group 1) versus 20 patients performed under a 3-day hospitalization (group 2). A comparison was performed between Occlutech and Amplatzer PFO devices and the impact on hospitalization costs was studied. Results: Occluders included Occlutech (n=81), Amplatzer (n=43), Lifetech (n=2) and PFM (n=2) PFO devices. Implantation succeeded in all. In-group 1, hospital discharge was delayed in only 3 cases. At one-month, 5 patients had Atrial Fibrillation (AF) and 91 patients (84%) had no residual shunt. In-group 2, hospital discharge was delayed in 4 patients. At one month, 1 patient had AF and no shunt was observed in 80%. In the comparative study, no significant statistical difference could be observed between Amplatzer and Occlutech devices. The one-day strategy leaded to a positive balance of 1825 euros per procedure in 2018, with a difference of 3785 euros with group 2. Conclusion: Our experience suggests that day-case PFO closure under fluoroscopy and TTE guidance is safe and effective in the majority of patients leading to a cost reduction and no increased risk of embolization.

Cellular and circuit hyperexcitability are core features of fragile X syndrome and related autism spectrum disorder models. However, the cellular and synaptic bases of this hyperexcitability have proved elusive. We report in a mouse model of fragile X syndrome, glutamate uncaging onto individual dendritic spines yields stronger single-spine excitation than wild-type, with more silent spines. Furthermore, fewer spines are required to trigger an action potential with near-simultaneous uncaging at multiple spines. This is, in part, from increased dendritic gain due to increased intrinsic excitability, resulting from reduced hyperpolarization-activated currents, and increased NMDA receptor signaling. Using super-resolution microscopy we detect no change in dendritic spine morphology, indicating no structure-function relationship at this age. However, ultrastructural analysis shows a 3-fold increase in multiply-innervated spines, accounting for the increased single-spine glutamate currents. Thus, loss of FMRP causes abnormal synaptogenesis, leading to large numbers of poly-synaptic spines despite normal spine morphology, thus explaining the synaptic perturbations underlying circuit hyperexcitability., Fragile X syndrome and autism spectrum disorders are associated with circuit hyperexcitability, however, its cellular and synaptic bases are not well understood. Here, the authors report abnormal synaptogenesis with an increased prevalence of polysynaptic spines with normal morphology in a mouse model of fragile X.

Sensory hypersensitivity is a common and debilitating feature of neurodevelopmental disorders such as Fragile X Syndrome (FXS). How developmental changes in neuronal function culminate in network dysfunction that underlies sensory hypersensitivities is unknown. By systematically studying cellular and synaptic properties of layer 4 neurons combined with cellular and network simulations, we explored how the array of phenotypes in Fmr1-knockout (KO) mice produce circuit pathology during development. We show that many of the cellular and synaptic pathologies in Fmr1-KO mice are antagonistic, mitigating circuit dysfunction, and hence may be compensatory to the primary pathology. Overall, the layer 4 network in the Fmr1-KO exhibits significant alterations in spike output in response to thalamocortical input and distorted sensory encoding. This developmental loss of layer 4 sensory encoding precision would contribute to subsequent developmental alterations in layer 4-to-layer 2/3 connectivity and plasticity observed in Fmr1-KO mice, and circuit dysfunction underlying sensory hypersensitivity., Somatosensory hypersensitivity in Fmr-1 knockout mice is thought to arise from an increase in cortical circuit excitability. Here, the authors report that the loss of precision of sensory encoding in the Layer 4 of barrel cortex is the primary developmental circuit alteration that drives the other compensatory circuit dysfunction.

Introduction: The majority of venomous snake exposures in the United States are due to snakes from the subfamily Crotalinae (pit vipers). There are three types of US pit vipers: rattlesnakes (Crota...

Background The FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial demonstrated that for patients with diabetes mellitus (DM) and multivessel coronary disease (MVD), coronary artery bypass grafting (CABG) is superior to percutaneous coronary intervention with drug-eluting stents (PCI-DES) in reducing the rate of major adverse cardiovascular and cerebrovascular events after a median follow-up of 3.8 years. It is not known, however, whether CABG confers a survival benefit after an extended follow-up period. Objectives The purpose of this study was to evaluate the long-term survival of DM patients with MVD undergoing coronary revascularization in the FREEDOM trial. Methods The FREEDOM trial randomized 1,900 patients with DM and MVD to undergo either PCI with sirolimus-eluting or paclitaxel-eluting stents or CABG on a background of optimal medical therapy. After completion of the trial, enrolling centers and patients were invited to participate in the FREEDOM Follow-On study. Survival was evaluated using Kaplan-Meier analysis, and Cox proportional hazards models were used for subgroup and multivariate analyses. Results A total of 25 centers (of 140 original centers) agreed to participate in the FREEDOM Follow-On study and contributed a total of 943 patients (49.6% of the original cohort) with a median follow-up of 7.5 years (range 0 to 13.2 years). Of the 1,900 patients, there were 314 deaths during the entire follow-up period (204 deaths in the original trial and 110 deaths in the FREEDOM Follow-On). The all-cause mortality rate was significantly higher in the PCI-DES group than in the CABG group (24.3% [159 deaths] vs. 18.3% [112 deaths]; hazard ratio: 1.36; 95% confidence interval: 1.07 to 1.74; p = 0.01). Of the 943 patients with extended follow-up, the all-cause mortality rate was 23.7% (99 deaths) in the PCI-DES group and 18.7% (72 deaths) in the CABG group (hazard ratio: 1.32; 95% confidence interval: 0.97 to 1.78; p = 0.076). Conclusions In patients with DM and MVD, coronary revascularization with CABG leads to lower all-cause mortality than with PCI-DES in long-term follow-up. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450)

Background: The prevalence of obstructive sleep apnea (OSA) is very high in stroke patients, whereas the acceptance of positive airway pressure (PAP) therapy is low. Although telemedicine offers new options to increase acceptance, effective concepts and patient groups are not yet known. Objective: The aim of this study was to investigate the effect of a telemedicine concept consisting of telemonitoring and support when usage time drops. Methods: PAP naive stroke patients with apnea-hypopnea index (AHI) >15 were randomized in a prospective parallel design comparing home therapy with standard care (SC) as opposed to telemedicine care (TC) over a period of 6 months. The TC group received a standardized phone call to offer help and advice if the average weekly usage of PAP fell below 4 h/night. Results: Eighty patients were included, 5 were lost to follow-up, 75 (20 females, age: 57.0 ± 9.9, body mass index: 30.9 ± 6.0 kg/m2, AHI: 39.4 ± 18.6) were evaluated. While inpatient usage was similar in both groups, a significant difference was identified after 6 months of receiving home therapy (TC: 4.4 ± 2.5 h, SC: 2.1 ± 2.2 h; p < 0.000063). On average, 4.7 ± 3.1 interventional phone calls were needed (173 calls in total, ranging from 0 to 10 calls per patient), primarily for the purpose of motivation (61.3%), mask problems (16.2%), nasopharyngeal complaints or humidification issues (11.2%), and technical questions (10.6%). Sleepiness (Epworth Sleepiness Scale [ESS]) differed significantly (TC: 3.7 + 3.2, SC: 6.1 + 4.1; p = 0.008), as well as systolic blood pressure, which was available in a subgroup of 55 patients (TC: 129.5 + 15.2 mm Hg, SC: 138.8 + 16.1 mm Hg; p = 0.034). Conclusion: A concept of telemonitoring and short telephone calls from the sleep lab raised PAP therapy adherence significantly in a group of stroke patients with moderate to severe OSA.

Background Diabetes mellitus (DM) is associated with complex coronary artery disease (CAD), which in turn results in increased morbidity and mortality from cardiovascular disease. Objectives This study sought to evaluate the utility of SYNTAX score (SS) for predicting future cardiovascular events in patients with DM and complex CAD undergoing either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). Methods The FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial randomized patients with DM and multivessel CAD to undergo either PCI with drug-eluting stents or CABG. The SS was calculated retrospectively by a core laboratory. The endpoint of hard cardiovascular events (HCE) was a composite of death from any cause, nonfatal myocardial infarction, and nonfatal stroke, while the endpoint of major adverse cardiac and cerebrovascular events (MACCE) was a composite of HCE and repeat revascularization. Results A total of 1,900 patients were randomized to PCI (n = 953) or CABG (n = 947). The SS was considered an independent predictor of 5-year MACCE (hazard ratio per unit of SS: 1.02; 95% confidence interval: 1.00 to 1.03; p = 0.014) and HCE (hazard ratio per unit of SS: 1.03; 95% confidence interval: 1.01 to 1.04; p = 0.002) in the PCI cohort, but not in the CABG group. There was a higher incidence of MACCE in PCI patients with low, intermediate, and high SS compared with those who underwent CABG (36.6% vs. 25.9%, p = 0.02; 43.9% vs. 26.8%, p Conclusions In DM patients with multivessel CAD, the complexity of CAD evaluated by the SS is an independent risk factor for MACCE and HCE only in patients undergoing PCI. The SS should not be utilized to guide the choice of coronary revascularization in patients with DM and multivessel CAD. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450)

Introduction Histiocytoid cardiomyopathy is a rare life-threatening pediatric condition characterized by incessant ventricular tachyarrhythmia, dilated cardiomyopathy but also sudden cardiac death in over 20% of cases [1] . Management is challenging and aggressive therapy as catheter ablation [2] , [3] , surgical resection [4] and even heart transplantation is reported in the literature [5] . Methods Over the last decade, 4 patients were referred to our institution for incessant ventricular arrythmia consistent with histiocytoid cardiomyopathy (HC) diagnosis. We retrospectively reviewed clinical data in order to highlight the management and document natural history. Results Mean patient age at diagnosis was 7 months [1.5–16], 3 were girls. Mean weight at diagnosis was 6.65 kg [4.8–8.2]. Initial clinical presentation was incessant rapid ventricular tachycardia with right bundle branch block pattern ( Fig. 1 ) associated with dilated cardiomyopathy in 3, 1 presented with resuscitated sudden cardiac arrest (SCA). Despite association of antiarrhythmic drugs including amiodarone, hemodynamic deterioration required intubation for mechanical ventilatory support in 3 and extracorporeal membrane assistance (ECMO) in 2 patients. The patient diagnosed after SCA have implanted with a cardioverter defibrillator (ICD) at 4 months old ( Fig. 2 ). The first patient of this case series diagnosed 10 years ago, for who ECMO was not initiated, died of terminal cardiac failure despite rate control. Arrythmia burden decreased for the 3 others patients, allowing to slowly tapped down medication. Conclusion HC is known to be a rare severe condition affecting mostly girls under 2 years old. Initial management can be dreadful. Still, aggressive therapy such as ECMO and ICD can allow to overcome the acute phase. Based on this small case series and report in the literature [6] , secondary natural history seams favorable.

AIM The aim was to investigate socio-economic risk factors for maternal underweight before pregnancy and then associations of underweight with neonatal outcomes. METHODS Data of 3401 mother-child dyads from the population-based birth cohort Survey of Neonates in Pomerania (SNiP) were analysed. RESULTS Bivariate analysis showed that underweighted mothers were younger, smoked more often, had a lower equivalent income and lower socio-economic status (employment status and/or educational level) compared to women with normal weight. The final prediction model revealed that only younger maternal age (OR = 0.93; 95%-CI = 0.90-0.97) and maternal smoking during pregnancy (OR = 2.52; 95%-CI = 1.74-3.66) were associated with underweight. Compared to women with normal pre-pregnancy BMI, underweight women had an increased chance of premature labour (OR = 1.73; 95% CI: 1.29-2.31) and a reduced placental weight. The offspring of underweight women had an increased risk of late preterm birth (OR = 1.82; 95% CI: 1.21-2.74) and birthweight

International audience; BACKGROUND: Although recommendations encourage daily moderate activities in post aortic dissection, very little data exists regarding cardiopulmonary exercise testing (CPET) to personalize those patient's physical rehabilitation and assess their cardiovascular prognosis.METHODS: We aimed at testing the prognostic insight of CPET regarding aortic and cardiovascular events by exploring a prospective cohort of patients followed-up after acute aortic dissection.METHODS: Patients referred to our department after an acute (type A or B) aortic dissection were prospectively included in a cohort between September 2012 and October 2017. CPET was performed once optimal blood pressure control was obtained. Clinical follow-up was done after CPET for new aortic event and major cardio-vascular events (MCE) not directly related to the aorta.RESULTS: Among the 165 patients who underwent CPET, no adverse event was observed during exercise testing. Peak oxygen pulse was 1.46(1.22-1.84) mlO2/beat, that is, 97 (83-113) % of its predicted value, suggesting cardiac exercise limitation in a population under beta blockers (92% of the population). During a follow-up of 39(20-51) months from CPET, 42 aortic event recurrences and 22 MCE not related to aorta occurred. Low peak oxygen pulse (

Background: Conflicting data exist regarding the benefit of urgent coronary angiogram and percutaneous coronary intervention (PCI) after sudden cardiac arrest, particularly in the absence of ST-segment elevation. We hypothesized that the type of lesions treated (stable versus unstable) influences the benefit derived from PCI. Methods: Data were taken between May 2011 and 2014 from a prospective registry enrolling all sudden cardiac arrest in Paris and suburbs (6.7 million inhabitants). Patients undergoing emergent coronary angiogram were included. Decision to perform PCI was left to the discretion of local teams. We assessed the impact of emergent PCI on survival at discharge according to whether the treated lesion was angiographically unstable or stable, and we investigated the predictive factors for unstable coronary lesions. Results: Among 9265 sudden cardiac arrests occurring during the study period, 1078 underwent emergent coronary angiogram (median age: 59.6 years, 78.3% males): 463 (42.9%) had an unstable lesion, 253 (23.5%) only stable lesions, and 362 (33.6%) no significant lesions. Emergent PCI was performed in 478 patients (91.4% of unstable and 21.7% of stable lesions). At discharge, PCI of unstable lesions was associated with twice-higher survival rate compared with untreated unstable lesions (47.9% versus 25.6%, P =0.013), while stable lesions PCI did not improve survival (25.5% versus 26.3%, P =1.00). After adjustment, PCI of unstable coronary lesions was independently associated with improved survival (odds ratio, 2.09 [95% CI, 1.42–3.09], P P =0.824). Angina, initial shockable rhythm, ST-segment elevation, and absence of known coronary artery disease were independent predictors of unstable lesions. Conclusions: Emergent PCI of unstable lesions is associated with improved survival after sudden cardiac arrest, contrary to PCI of stable lesions. Accordingly, early PCI should only be performed in patients with unstable lesions. Four factors (chest pain, ST-elevation, absence of coronary artery disease history, and shockable initial rhythm) could help identify patients with unstable lesions who would, therefore, benefit from emergent coronary angiogram.

Treatment of advanced pulmonary emphysema with endobronchial coils can improve clinical outcomes like quality of life (QOL). Yet, patients with chronic obstructive pulmonary disease (COPD) are also known to suffer from reduced sleep quality. The effect of coil therapy on sleep has not yet been investigated. The primary aim of this study was to investigate sleep efficiency before and after coil treatment. Secondly, we investigated the effects on nocturnal breathing pattern, QOL, and physical activity. Polysomnography (PSG) testing was performed before (T0), 6 month after (T3), and 12 months after (T4) treatment with endobronchial coils. Further examinations included QOL by St George’s Respiratory Questionnaire (SGRQ) and COPD assessment test (CAT), and physical activity using an accelerometer for 1 week after each visit. Of 21 patients, 14 completed the study: 6 women; mean age 58.0 ± 4.9 years; BMI 22.6 ± 4.6 kg/m2; FEV1 28.6 ± 7.1% predicted; residual volume (RV) 278.2 ± 49.4% predicted. Sleep efficiency did not vary between baseline and follow-up examinations (T0 69.0 ± 15.8%; T3 70.9 ± 16.0%; T4 66.8 ± 18.9%). Non-REM respiratory rate decreased compared to baseline (T0 19.4 ± 3.9/min; T3 17.8 ± 3.5/min; T4 17.1 ± 3.1/min (p = 0.041; p = 0.030) and QOL improved meeting the minimal clinically important difference (MCID) (SGRQ, T3 −12.8 units; T4 −7.1 units; CAT: T3 −5.6 units; T4 −3.4 units). No increase in physical activity was recorded (light activity T0 31.9 ± 9.9; T3 30.8 ± 16.9; T4 26.3 ± 10.6 h/week). Treatment with endobronchial coils did not influence objectively measured sleep quality or physical activity, but reduced nocturnal breathing frequency and improved QOL in severe emphysema patients. ClinicalTrials.gov Identifier: NCT02399514, First Posted: March 26, 2015

Fine needle aspiration cytology (FNAC) is a widely accepted safe, simple and rapid diagnostic procedure used in the examination of neoplastic and non-neoplastic lesions of various locations. Since its introduction, FNAC has developed into an effective diagnostic tool practiced in a large majority of medical centres evaluating and treating oncological patients. The role of FNAC has been limited in the examination of primary soft tissue lesions, however, as many physicians working in this area recommended against using FNAC. An increasing use of minimally invasive diagnostic procedures in the last decade has resulted in a better acceptance of FNAC as a first-line approach or as a complementary tool to core needle biopsy in the diagnosis of musculoskeletal lesions. This review discusses the role and value of FNAC in the evaluation and treatment of soft tissue tumours based on the experience gathered over the course of 48 years at the Sarcoma Center in Lund, Sweden. FNAC reports most often provide diagnostic information allowing the initiation of treatment or, when definitive diagnosis cannot be rendered from a cytological examination, guiding the continued diagnostic investigation. The main advantages of soft tissue FNAC are good sensitivity and specificity, low morbidity, speed of diagnosis, and low cost/benefit ratio. The most important disadvantages stem from limited experience in cytological diagnosis of soft tissue tumours and a lack of standardised and uniform reporting system for soft tissue FNAC.

Case details A 51-year-old man presented with rapid onset encephalopathy and respiratory failure after a suspected intravascular envenomation from a North American pit viper. The patient received antivenom and was transferred to a tertiary care facility where he had cardiovascular collapse and persistent coagulopathy requiring 28 vials of Crotalidae polyvalent immune Fab antivenom for initial control and six vials for maintenance. The patient's coagulopathy was monitored using “traditional” measures (platelets, fibrinogen, and prothrombin time/international normalized ratio) and rotational thromboelastometry (ROTEM®). The patient also subsequently developed intestinal necrosis requiring exploratory laparotomy with ileum and colonic resections, and anuric renal failure requiring continuous renal replacement therapy. After coordinated multidisciplinary management, he was discharged to an acute inpatient rehabilitation on hospital day 25 and has since made a full recovery. Discussion In the setting of a severe intravascular pit viper envenomation, thromboelastometry correlated well with “traditional” measures. During recovery, ROTEM® demonstrated measurable improvements in the extrinsic coagulation pathway while the INR remained between 1.5 and 1.6. Patient's intestinal necrosis may have resulted from microvascular thrombosis due to Crotalinae venom. The patient's ultimate recovery necessitated a coordinated multidisciplinary effort. ROTEM® abnormalities after North American pit viper envenomation may be more sensitive than “traditional” measures and may have prognostic value to determine the severity of envenomation, but further research to define its utility is required.

BACKGROUND: Coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are used for coronary revascularization in patients with multivessel and left main coronary artery disease. Stroke is among the most feared complications of revascularization. Due to its infrequency, studies with large numbers of patients are required to detect differences in stroke rates between CABG and PCI.OBJECTIVES: This study sought to compare rates of stroke after CABG and PCI and the impact of procedural stroke on long-term mortality.METHODS: We performed a collaborative individual patient-data pooled analysis of 11 randomized clinical trials comparing CABG with PCI using stents; ERACI II (Argentine Randomized Study: Coronary Angioplasty With Stenting Versus Coronary Bypass Surgery in Patients With Multiple Vessel Disease) (n = 450), ARTS (Arterial Revascularization Therapy Study) (n = 1,205), MASS II (Medicine, Angioplasty, or Surgery Study) (n = 408), SoS (Stent or Surgery) trial (n = 988), SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial (n = 1,800), PRECOMBAT (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease) trial (n = 600), FREEDOM (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes) trial (n = 1,900), VA CARDS (Coronary Artery Revascularization in Diabetes) (n = 198), BEST (Bypass Surgery Versus Everolimus-Eluting Stent Implantation for Multivessel Coronary Artery Disease) (n = 880), NOBLE (Percutaneous Coronary Angioplasty Versus Coronary Artery Bypass Grafting in Treatment of Unprotected Left Main Stenosis) trial (n = 1,184), and EXCEL (Evaluation of Xience Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial (n = 1,905). The 30-day and 5-year stroke rates were compared between CABG and PCI using a random effects Cox proportional hazards model, stratified by trial. The impact of stroke on 5-year mortality was explored.RESULTS: The analysis included 11,518 patients randomly assigned to PCI (n = 5,753) or CABG (n = 5,765) with a mean follow-up of 3.8 ± 1.4 years during which a total of 293 strokes occurred. At 30 days, the rate of stroke was 0.4% after PCI and 1.1% after CABG (hazard ratio [HR]: 0.33; 95% confidence interval [CI]: 0.20 to 0.53; p < 0.001). At 5-year follow-up, stroke remained significantly lower after PCI than after CABG (2.6% vs. 3.2%; HR: 0.77; 95% CI: 0.61 to 0.97; p = 0.027). Rates of stroke between 31 days and 5 years were comparable: 2.2% after PCI versus 2.1% after CABG (HR: 1.05; 95% CI: 0.80 to 1.38; p = 0.72). No significant interactions between treatment and baseline clinical or angiographic variables for the 5-year rate of stroke were present, except for diabetic patients (PCI: 2.6% vs. CABG: 4.9%) and nondiabetic patients (PCI: 2.6% vs. CABG: 2.4%) (p for interaction = 0.004). Patients who experienced a stroke within 30 days of the procedure had significantly higher 5-year mortality versus those without a stroke, both after PCI (45.7% vs. 11.1%, p < 0.001) and CABG (41.5% vs. 8.9%, p < 0.001).CONCLUSIONS: This individual patient-data pooled analysis demonstrates that 5-year stroke rates are significantly lower after PCI compared with CABG, driven by a reduced risk of stroke in the 30-day post-procedural period but a similar risk of stroke between 31 days and 5 years. The greater risk of stroke after CABG compared with PCI was confined to patients with multivessel disease and diabetes. Five-year mortality was markedly higher for patients experiencing a stroke within 30 days after revascularization.

Aim To describe our initial experience with the Occlutech Duct Occluder (ODO) for percutaneous closure of patent ductus arteriosus (PDA). Methods Retrospective review of patients undergoing transcatheter PDA closure with the ODO in 2 academic centers. Results From April 2013 to September 2017, 42 patients underwent PDA closure. Median age at implantation was 34 months (range 4 months–68 years) and median weight was 12 kg (range 4.1–57 kg). Ducts were Krichenko type A duct ( n = 34), type E ( n = 6), and type C ( n = 2). The mean duct diameter was 3.76 mm (range 1.69 to 9.95 mm, median 3.1 mm). Implantation succeeded in all. There was neither device embolization nor hemolysis. At device release, immediate angiogram showed a small residual shunt in 54.7%. During follow-up, Doppler echocardiography demonstrated 71% of full occlusion at day one, rising to 95% at one month and 100% at one year and half after implantation. The mean maximal systolic pressure gradient in left pulmonary artery was 4.2 ± 4.3 mm and across the distal aortic arch 5.4 ± 4.7 mm Hg. No patient had any significant stenosis with clinical relevance. Conclusions ODO is safe and effective in transcatheter closure of PDA including relatively large sized ducts. The results are satisfactory with a high level of full occlusion and a low rate of complications. Further evaluation with larger studies and longer follow-up will be required to confirm these preliminary good results.

Objectives Published reports have suggested that the concurrent use of alcohol or drugs occurs among some snakebite victims, but no national assessment of such data exists. Methods We used data from US poison control centers collected during telephone calls in calendar years 2000-2013 to compare snake envenomations with concomitant use of drugs, alcohol, or both to snakebites lacking such use. Results A total of 608 snakebites with 659 instances of concomitant alcohol/drug use were reported, which represent approximately 1% of 92,751 snakebites reported to US poison control centers. An annual mean of 48 snakebites with concomitant use of alcohol/drugs was reported, compared with a mean of 6625 snakebites per year with no concomitant use of alcohol/drugs. Most cases involved men, peaked during the summer months, and involved copperheads or rattlesnakes, which mirrored overall trends. Snakebite victims who also used alcohol/drugs were more likely than victims with only a snakebite reported to be bitten by rattlesnakes, to be admitted to the hospital, and die. Alcohol was the most common reported concomitant substance, but other substances were reported. Conclusions Snakebites with concomitant use of alcohol/drugs are uncommon, accounting for approximately 1% of the snakebite envenomations reported annually to US poison control centers; however, snakebite victims also reporting alcohol/drug use are more likely to be bitten by rattlesnakes, be admitted to a healthcare facility, and die.

BACKGROUND: Numerous randomised trials have compared coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) for patients with coronary artery disease. However, no studies have been powered to detect a difference in mortality between the revascularisation strategies.METHODS: We did a systematic review up to July 19, 2017, to identify randomised clinical trials comparing CABG with PCI using stents. Eligible studies included patients with multivessel or left main coronary artery disease who did not present with acute myocardial infarction, did PCI with stents (bare-metal or drug-eluting), and had more than 1 year of follow-up for all-cause mortality. In a collaborative, pooled analysis of individual patient data from the identified trials, we estimated all-cause mortality up to 5 years using Kaplan-Meier analyses and compared PCI with CABG using a random-effects Cox proportional-hazards model stratified by trial. Consistency of treatment effect was explored in subgroup analyses, with subgroups defined according to baseline clinical and anatomical characteristics.FINDINGS: We included 11 randomised trials involving 11 518 patients selected by heart teams who were assigned to PCI (n=5753) or to CABG (n=5765). 976 patients died over a mean follow-up of 3·8 years (SD 1·4). Mean Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score was 26·0 (SD 9·5), with 1798 (22·1%) of 8138 patients having a SYNTAX score of 33 or higher. 5 year all-cause mortality was 11·2% after PCI and 9·2% after CABG (hazard ratio [HR] 1·20, 95% CI 1·06-1·37; p=0·0038). 5 year all-cause mortality was significantly different between the interventions in patients with multivessel disease (11·5% after PCI vs 8·9% after CABG; HR 1·28, 95% CI 1·09-1·49; p=0·0019), including in those with diabetes (15·5% vs 10·0%; 1·48, 1·19-1·84; p=0·0004), but not in those without diabetes (8·7% vs 8·0%; 1·08, 0·86-1·36; p=0·49). SYNTAX score had a significant effect on the difference between the interventions in multivessel disease. 5 year all-cause mortality was similar between the interventions in patients with left main disease (10·7% after PCI vs 10·5% after CABG; 1·07, 0·87-1·33; p=0·52), regardless of diabetes status and SYNTAX score.INTERPRETATION: CABG had a mortality benefit over PCI in patients with multivessel disease, particularly those with diabetes and higher coronary complexity. No benefit for CABG over PCI was seen in patients with left main disease. Longer follow-up is needed to better define mortality differences between the revascularisation strategies.FUNDING: None.

Importance Modern data regarding incidence and modes of death of patients with aortic stenosis (AS) are restricted to tertiary centers or studies of aortic valve replacement (AVR). Objective To provide new insights into the natural history of outpatients with native AS based on a large regionwide population study with inclusion by all cardiologists regardless of their mode of practice. Design, Setting, and Participants Between May 2016 and December 2017, consecutive outpatients with mild (peak aortic velocity, 2.5-2.9 m/s), moderate (peak aortic velocity, 3-3.9 m/s), and severe (peak aortic velocity, ≥4 m/s) native AS graded by echocardiography were included by 117 cardiologists from the Nord-Pas-de-Calais region in France. Analysis took place between August and November 2020. Main Outcomes and Measures Natural history, need for AVR, and survival of patients with AS were followed up. Indications for AVR were based on current guideline recommendations. Results Among 2703 patients (mean [SD] age, 76.0 [10.8] years; 1260 [46.6%] women), 233 (8.6%) were recruited in a university public hospital, 757 (28%) in nonuniversity public hospitals, and 1713 (63.4%) by cardiologists working in private practice. A total of 1154 patients (42.7%) had mild, 1122 (41.5%) had moderate, and 427 (15.8%) had severe AS. During a median (interquartile range) of 2.1 (1.4-2.7) years, 634 patients underwent AVR and 448 died prior to AVR. Most deaths were cardiovascular (200 [44.7%]), mainly associated with congestive heart failure (101 [22.6%]) or sudden death (60 [13.4%]). Deaths were noncardiovascular in 186 patients (41.5%) and from unknown causes in 62 patients (13.8%). Compared with patients with mild AS, there was increased cardiovascular mortality in those with moderate (hazard ratio, 1.47 [95% CI, 1.07-2.02]) and severe (hazard ratio, 3.66 [95% CI, 2.52-5.31]) AS. The differences remained significant when adjusted for baseline characteristics or in time-dependent analyses considering AS progression. In asymptomatic patients, moderate and mild AS were associated with similar cardiovascular mortality (hazard ratio, 0.99 [95% CI, 0.44-2.21]). Conclusions and Relevance While patients in this study with moderate AS had a slightly higher risk of cardiovascular death than patients with mild AS, this risk was much lower than that observed in patients with severe AS. Moreover, in asymptomatic patients, moderate and mild AS were associated with similar cardiovascular mortality.

Objectives This study sought to examine the associations between heart failure (HF)-related hospital length of stay and 30-day readmissions and HF hospital length of stay and mortality rates. Background Although reducing HF readmission and mortality rates are health care priorities, how HF-related hospital length of stay affects these outcomes is not fully known. Methods A population-level, multicenter cohort study of 58,230 patients with HF (age >65 years) was conducted in Ontario, Canada between April 1, 2003 and March 31, 2012. Results When length of stay was modeled as continuous variable, its association with the rate of cardiovascular readmission was nonlinear (p Conclusions A short length of stay after hospitalization for HF is associated with increased rates of cardiovascular and HF readmissions but lower rates of noncardiovascular readmissions. A long length of stay is associated with increased rates of all types of readmission and mortality.

Tetralogy of Fallot is a frequent congenital heart disease that has been repaired since the mid-1950s. The follow-up after repair is good despite a persistent risk of sudden death. The risk factors in long-term follow-up are advanced age at repair, hemodynamic status of the right ventricle, QRS duration≥180ms, left ventricular dysfunction, and existence of sustained or not ventricular tachycardia. In the presence of significant pulmonary regurgitation, it is necessary to perform revalvulation either by classic surgery or cardiac catheterization. To correct the risk of ventricular arrhythmia, some have proposed radiofrequency ablation of critical isthmus, or cryo-application during surgery. However, the use of implantable cardioverter defibrillator is another therapeutic option that is more and more employed as secondary or primary prevention in patients at risk of sudden death.

Georg Nilius,1 Ulrike Domanski,1 Maik Schroeder,1 Karl-Josef Franke,1 Anke Hogrebe,1 Laurent Margarit,2 Maria Stoica,2 Marie-Pia d’Ortho2,3 1HELIOS-Klinik Ambrock, Universität Witten-Herdecke, Hagen, Germany; 2Service de Physiologie – Explorations Fonctionnelles DHU FIRE, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique-Hopitaux de Paris, 3Université Denis DiderotParis 7, Paris, France Background: Obstructive sleep apnea (OSA) is a highly prevalent condition; however, the majority of patients remain undiagnosed. There is a potential to expand the diagnostic capacity of sleep laboratories. The study objective was to validate a portable respiratory monitoring device (Alice PDX) against polysomnography (PSG) in the laboratory and to assess its reliability at home.Methods: A total of 85 patients with suspected OSA (80% male, mean age 49.1±13.5 years, body mass index 29.7±6.9 kg/m2, Epworth Sleepiness Scale 10.0±5.1) were randomized to 3 diagnostic nights: 1 night simultaneous in-laboratory PSG and PDX recording; 1 night self-applied PDX at home, and 1 night in-laboratory PSG. Study data were manually scored according to American Academy of Sleep Medicine criteria.Results: The Alice PDX was in diagnostic agreement with simultaneously recorded reference PSG in 96.4% of studies. In 2.4% of studies the in-laboratory PDX underestimated and in 1.2% of studies it overestimated the apnea hypopnea index (AHI). The difference between the AHI from the reference PSG and the home study was similar to the difference between the PSGs (2.79 vs 0.79, p=0.08).Conclusion: In a population with a high suspicion of OSA, the Alice PDX showed a high level of diagnostic agreement with a simultaneous PSG and performed valid home diagnostic studies for OSA. If manually scored, the portable device can be used by sleep specialists for diagnosing moderate-to-severe obstructive sleep apnea in cases with a high pretest probability for the disease over a wide range of disease severity. The technology can be deployed reliably outside of the sleep laboratory setting. Keywords: sleep apnea, diagnostic, portable device, ambulant monitoring, polysomnography

Associations of early creatine phosphokinase-MB (CK-MB) elevation and new Q waves and their association with cardiovascular death (CVD) after coronary artery bypass grafting (CABG) have been reported, but this association has not been studied in a large population of patients with diabetes mellitus. In this study, we examine the association of periprocedural CK-MB elevations and new Q waves with CVD in the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease trial. Cox proportional hazards regression was used to assess the relation of CK-MB elevations and new Q waves in the first 24 hours after procedure and their relation to CVD; logistic regression was used to assess odds ratios of these variables. Hazard ratios, 95% confidence intervals, and p values associated with Wald chi-square test are reported. CK-MB elevation in first 24 hours after procedure was independently associated with CVD. CVD hazard increased by 6% (p0.001) with each multiple of CK-MB above the upper reference limit (URL); odds of new post-CABG Q waves increased by a factor of 1.08 (p0.001); at 7× CK-MB URL, HR was2. CK-MB URL multiples of 7, 12, and 15 were associated with new Q-wave odds ratios of 9, 16, and 27 times, respectively (p ≤0.001, C-statistic0.70). New Q waves were independently associated with survival in the multivariate model only when CK-MB was excluded (p = 0.01). In conclusion, independent associations included (1) CVD and early post-CABG CK-MB elevation; (2) new Q waves with early post-CABG CK-MB elevation; (3) CVD with new Q waves only when CK-MB elevation is excluded from analysis.

Liquid-liquid phase separation (LLPS) of proteins and RNAs has emerged as the driving force underlying the formation of membrane-less organelles. Such biomolecular condensates have various biological functions and have been linked to disease. One of the best studied proteins undergoing LLPS is Fused in Sarcoma (FUS), a predominantly nuclear RNA-binding protein. Mutations in FUS have been causally linked to Amyotrophic Lateral Sclerosis (ALS), an adult-onset motor neuron disease, and LLPS followed by aggregation of cytoplasmic FUS has been proposed to be a crucial disease mechanism. In spite of this, it is currently unclear how LLPS impacts the behaviour of FUS in cells, e.g. its interactome. In order to study the consequences of LLPS on FUS and its interaction partners, we developed a method that allows for the purification of phase separated FUS-containing droplets from cell lysates. We observe substantial alterations in the interactome of FUS, depending on its biophysical state. While non-phase separated FUS interacts mainly with its well-known interaction partners involved in pre-mRNA processing, phase-separated FUS predominantly binds to proteins involved in chromatin remodelling and DNA damage repair. Interestingly, factors with function in mitochondria are strongly enriched with phase-separated FUS, providing a potential explanation for early changes in mitochondrial gene expression observed in mouse models of ALS-FUS. In summary, we present a methodology that allows to investigate the interactome of phase-separating proteins and provide evidence that LLPS strongly shapes the FUS interactome with important implications for function and disease.

Karl-Josef Franke,1,2 Ulrike Domanski,1 Maik Schroeder,1 Volker Jansen,3 Frank Artmann,4 Uwe Weber,5 Rainer Ettler,6 Georg Nilius1,2 1Department of Pneumology and Critical Care Medicine, HeliosKlinik Ambrock, Hagen, 2Witten/Herdecke University, Witten, 3Lung Practice Jansen, Menden, 4Aeroprax Wuppertal,Wuppertal, 5Lung PracticeWitten, Witten, 6Lung Practice Ettler, Hagen, Germany Background: Regular physical activity is associated with reduced mortality in patients with chronic obstructive pulmonary disease (COPD). Interventions to reduce time spent in sedentary behavior could improve outcomes. The primary purpose was to investigate the impact of telemonitoring with supportive phone calls on daily exercise times with newly established home exercise bicycle training. The secondary aim was to examine the potential improvement in health-related quality of life and physical activity compared to baseline. Methods: This prospective crossover-randomized study was performed over 6 months in stable COPD patients. The intervention phase (domiciliary training with supporting telephone calls) and the control phase (training without phone calls) were randomly assigned to the first or the last 3 months. In the intervention phase, patients were called once a week if they did not achieve areal-time monitored daily cycle time of 20 minutes. Secondary aims were evaluated at baseline and after 3 and 6 months. Health-related quality of life was measured by the COPD Assessment Test (CAT), physical activity by the Godin Leisure Time Exercise Questionnaire (GLTEQ). Results: Of the 53 included patients, 44 patients completed the study (forced expiratory volume in 1 second 47.5%±15.8% predicted). In the intervention phase, daily exercise time was significantly higher compared to the control phase (24.2±9.4 versus 19.6±10.3 minutes). Compared to baseline (17.6±6.1), the CAT-score improved in the intervention phase to 15.3±7.6 and in the control phase to 15.7±7.3units. The GLTEQ-score increased from 12.2±12.1 points to 36.3±16.3 and 33.7±17.3. Conclusion: Telemonitoring is a simple method to enhance home exercise training and physical activity, improving health-related quality of life. Keywords: telehealthcare, physical activity, COPD assessment test, telephone support

Pleural effusion (PE), excess fluid in the pleural space, is often observed in lung cancer patients and also forms due to many benign ailments. Classifying it quickly is critical, but this remains an analytical challenge often lengthening the diagnosis process or exposing patients to unnecessary risky invasive procedures. We tested the analysis of PE using a multiplexed cytokeratin (CK) panel with targeted mass spectrometry–based quantitation for its rapid classification. CK markers are often assessed in pathological examinations for cancer diagnosis and guiding treatment course. We developed methods to simultaneously quantify 33 CKs in PE using peptide standards for increased analytical specificity and a simple CK enrichment method to detect their low amounts. Analyzing 121 PEs associated with a variety of lung cancers and noncancerous causes, we show that abundance levels of 10 CKs can be related to PE etiology. CK-6, CK-7, CK-8, CK-18, and CK-19 were found at significantly higher levels in cancer-related PEs. Additionally, elevated levels of vimentin and actin differentiated PEs associated with bacterial infections. A classifier algorithm effectively grouped PEs into cancer-related or benign PEs with 81% sensitivity and 79% specificity. A set of undiagnosed PEs showed that our method has potential to shorten PE diagnosis time. For the first time, we show that a cancer-relevant panel of simple-epithelial CK markers currently used in clinical assessment can also be quantitated in PEs. Additionally, while requiring less invasive sampling, our methodology demonstrated a significant ability to identify cancer-related PEs in clinical samples and thus could improve patient care in the future.

Introduction The purpose of this work is to report one-year experience in day case transcatheter closure of PFO using different occluders. A comparison study is also performed between the Figulla Flex II and PFO Amplatzer devices. Methods From January to December 2018, 106 patients suffering from a stroke underwent transcatheter PFO closure as day-case procedure. Results Devices employed included: Figulla Flex II (Occlutech, n = 66), PFO AmplatzerTM (AGA, Saint Jude medical) (n = 36), CeraFlex PFO Occluder (Lifetech scientific, n = 2) and Nit-occlude PFO (PFM medical, n = 2). Procedure was performed under local anaesthesia with fluoroscopic and transthoracic echocardiographic (TTE) guidance. Implantation succeeded in all. The complications included transient ST deviation in 10 patients due to air embolism with no permanent damage. In 2 cases, the hospital discharge was delayed: one because femoral fistula requiring compression (day 5) and the other because of pericardial effusion requiring no drainage (day 2). At the one-month control, 5 patients complained of chest tightness, 8 reported palpitations, 5 had AF. Eighty-eight patients had no shunt on contrast TTE, 17 had a persistent shunt, and 1 was lost on follow-up. At the 6-month control, 8 of these 17 patients had no persistent shunt. In the comparative study between Occlutech and Amplatzer devices, patient were older in-group Amplatzer but had a similar weight. No significant difference could be observed between the 2 groups concerning time of fluoroscopy, dose of radiation, ST deviation, and persistence of shunt at one month (P = NS). No recurrence of stroke was noticed during follow-up (127 ± 98 days). Conclusion Transcatheter PFO closure as a day case procedure is safe and effective. This approach is not more risky for the patients in terms of embolisation and final results. No significant difference could be observed between the Occlutech and Amplatzer PFO devices.

Background The Coaguchek INRange® is a self testing meter to measure the INR, that is reimbursed by French Social Security since August 2017 for patients with mechanical valve. Methods We evaluated the use of this anticoagulation method in a French population of GUCH (Grown-Up patients with Congenital Heart Disease) with mechanical valve. Results Since September 2018, 52 patients of 37 ± 11 years old were asked to attend a training of 2 hours on anticoagulation and Coaguchek INRange® use, provided by specialized nurses, before getting home with the machine. Patients had to attend a 3 months re-evaluation appointment. Twenty-nine (56%) patients had an aortic mechanical valve, 12 (23%) a mitral one, 8 (15%) a double aortic and mitral one, 2 (4%) a double aortic and pulmonary one and 1 (2%) a tricuspid one. 28 patients (54%) had a mechanical valve for ≥ 10 years (group 1). In group 1, patients were older (41 ± 10 years old vs. 34 ± 10, P = 0.01). Fluindione was the preferred oral anticogulant (30 patients, 57%), and more frequent in group 1 (18 patients, 64%). In group 1, 61% of patients usually managed themselves dosage adjustment whereas in the other group, 52% of patients referred to their doctor. Thirty-one patients (62%) had a higher target of INR than recommended in the last European guidelines. Concerning follow-up, 26 patients (50%) did not attend the 3 months appointment and had to be rescheduled or contacted by phone. Eight patients (15%) did not use the device at 3 months: 5 for variation > 15% compared to laboratory plasma technique and 3 for not trusting the new device. INR at 3 months was obtained in only 40 (77%) patients, and was in the attended target in 62% of cases. Conclusion GUCH patients with mechanical valves, especially when present for ≥ 10 years, seem to validate Coaguchek, even though evaluation is hard since a great proportion of them did not attend follow-up appointment, stick to their old INR target and did not use the device as often as recommended.

Background: Patients with type 2 diabetes (T2D) are at high risk of cardiovascular (CV) morbidity/mortality. The ACCORD trial (NCT00000620) tested intensive glycemic, lipid and blood pressure interventions on major CV events in 10,251 T2D patients with baseline HbA1c concentration >7.5%. Despite its landmark findings, a data-driven systematic evaluation of predictors for major cardiovascular events among hundreds of ACCORD variables has not been conducted. Methods: Random Survival Forest (RSF), a machine-learning method for survival analysis, identified important predictors for total mortality (TM), CV death (CVd), hospitalization/death due to heart failure (hdHF), fatal/non-fatal stroke (CVA), non-fatal myocardial infarction (MI) and MACE (composite of CVd, MI and CVA). Among 378 risk factors, including some highly correlated features, the top-ranked predictors (collected at baseline or derived from repeated measures prior to events) were selected, resulting in a hierarchy of predictive variables. Effects of RSF-selected predictors were then evaluated by multivariate Cox Proportional Hazards Models. Results: Table 1 presented the top ten predictors for six major events. Variables associated with changes in renal function predicted TM, CVd, and hdHF with ~90% accuracy. Insulin use was an important predictor along with predefined composite renal microvascular events for MI, CVA and MACE (74-79% accuracy). The Cox regression models based on RSF variable selection yielded similar findings for these important predictors of events. Conclusions: RSF approach revealed that insulin use and overt renal microvascular events were predictors for the occurrence of MI, stroke, and MACE in T2D patients. Moreover, dynamic changes in urinary renal function biomarkers had additional predictive values for fatal events. These results provide important clinical insights for reducing CV events in Type 2 diabetes patients.

A large panorama of lesions is accessible to fine-needle aspiration cytology (FNAC). This chapter focuses on lesions of the salivary glands, as well as tumors of the tongue and oral and nasal cavities. Some unusual lesions of the neck will also be presented. Aspiration cytology of thyroid, parathyroid, and lymph nodes is dealt with in other chapters. When confronted with a mass lesion in the head and neck area, it is not always obvious which organ or structure is involved or where a tumor originates. The widespread distribution of minor salivary glands, for instance, implies that tumors originating from these glands may present in unexpected sites. Aspiration cytology therefore can play an important role in clarifying the basic question of tumor origin.

Background Gestational diabetes mellitus (GDM) is the most frequent complication during pregnancy. Untreated GDM is a severe threat to maternal and neonatal health. Based on recent evidence, up to 15% of all pregnancies may be affected by GDM. We hypothesized that in a rural birth cohort, higher maternal BMI and adverse socioeconomic conditions would promote GDM, which in turn would lead to adverse effects on pregnancy outcomes. Methods The current study is a part of a population-based cohort study examining the health and socioeconomic information from 5801 mothers and their children. The study, titled the Survey of Neonates in Pomerania (SNiP), was based in northeastern Pomerania, Germany (2002–2008). Results The cumulative incidence of GDM was 5.1%. Multiple logistic regression revealed prepregnancy overweight (OR 1.84 (95% CI 1.27–2.68)), prepregnancy obesity (OR 3.67 (2.48–5.44)) and maternal age (OR 1.06 (1.03–1.08)) as risk factors for GDM (p = 0.001). Alcohol use during pregnancy (OR 0.61 (0.41–0.90), a higher monthly income (OR 0.62 (0.46–0.83)), and the highest level of education (OR 0.44 (0.46–0.83)) decreased the risk of GDM. Newborns of GDM mothers had an increased risk of hypoglycaemia (OR 11.71 (7.49–18.30)) or macrosomia (OR 2.43 (1.41–4.18)) and were more often delivered by primary (OR 1.76 (1.21–2.60)) or secondary C-section (OR 2.00 (1.35–2.97)). Moreover, they were born 0.78 weeks (95% CI -1.09 – -0.48 weeks) earlier than infants of mothers without diabetes, resulting in higher percentage of late preterm infants with a gestational age of 32–36 weeks (11.1% vs. 6.96%). Conclusions Age and BMI before pregnancy were the predominant mediators of the increased risk of GDM, whereas a higher income and educational level were protective. GDM affected relevant perinatal and neonatal outcomes based on its association with an increased risk of delivery by C-section, preterm birth, macrosomia at birth and neonatal hypoglycaemia.

Sensory hypersensitivity is a common and debilitating feature of neurodevelopmental disorders such as Fragile X Syndrome (FXS). However, how developmental changes in neuronal function ultimately culminate in the network dysfunction that underlies sensory hypersensitivities is not known. To address this, we studied the layer 4 barrel cortex circuit inFmr1knockout mice, a critical sensory processing circuit in this mouse model of FXS. By systematically studying cellular and synaptic properties of layer 4 neurons and combining with cellular and network simulations, we explored how the array of phenotypes inFmr1knockout produce circuit pathology during development that result in sensory processing dysfunction. We show that many of the cellular and synaptic pathologies inFmr1knockout mice are antagonistic, mitigating circuit dysfunction, and hence can be regarded as compensatory to the primary pathology. Despite this compensation, the layer 4 network in theFmr1knockout exhibits significant alterations in spike output in response to ascending thalamocortical input that we show results in impaired sensory encoding. We suggest that it is this developmental loss of layer 4 sensory encoding precision that drives subsequent developmental alterations in layer 4 – layer 2/3 connectivity and plasticity observed in theFmr1knockout, and is a critical process producing sensory hypersensitivity.

This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the US Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

Background The Coaguchek INRange® is a self-testing meter to measure the INR, that is reimbursed in France since August 2017 for patients with mechanical valve. Methods We evaluated the use of this anticoagulation method in a French population of GUCH (Grown-Up patients with Congenital Heart Disease) with mechanical valve. Results Since September 2018, 52 patients of 37 ± 11 years old were asked to attend a training course of 2 hours on anticoagulation and Coaguchek INRange® use, provided by specialized nurses, before getting home with the device. Patients had to attend a 3 months’ medical re-evaluation appointment. 29 (56%) patients had an aortic mechanical valve, 12 (23%) a mitral one, 8 (15%) a double aortic and mitral one, 2 (4%) a double aortic and pulmonary one and 1 (2%) a tricuspid one. 28 patients (54%) had a mechanical valve for ≥ 10 years (group 1). In group 1, patients were older (41 ± 10 years old vs. 34 ± 10, P = 0.01). Fluindione was the preferred oral anticoagulant (30 patients, 57%), and was more frequent in group 1 (18 patients, 64%). In group 1, 61% of patients usually managed themselves dosage adjustment whereas in the other group, 52% of patients referred to their doctor. Thirty-one patients (62%) had a higher target of INR than recommended in last European guidelines. Concerning follow-up, 26 patients (50%) did not attend the 3 months appointment and had to be rescheduled or contacted by phone. 8 patients (15%) did not use the device at 3 months: 5 for variation > 15% compared to laboratory plasma technique and 3 for not trusting the new device. INR at 3 months was obtained in only 40 (77%) patients, and was in the attended target in 62% of cases. Conclusion GUCH patients with mechanical valves, especially when present for ≥ 10 years, seem to validate Coaguchek, even though evaluation remains hard since a great proportion of them did not attend follow-up appointment, stick to their old INR target and did not use the device as often as recommended.

Porous alloplastic materials such as titanium mesh and porous polyethylene allow for the ingrowth of fibrovascular tissues into the implant; stabilizing the implant and reducing the risk of extrusion and extrusion-related complications (such as hematoma formation). The literature contains 2 specific reports of delayed atraumatic orbital hematomas occurring 8 months and 3 years after orbital floor reconstruction with porous polyethylene implants. In this study, an atraumatic orbital hematoma occurring 16 years after orbital floor reconstruction with a porous polyethylene implant was presented. The hematoma was evacuated and the implant was removed without replacement of a secondary implant. The remaining fibrovascular tissue on the underside of the implant provided enough support of the orbital soft tissues to achieve excellent anatomic and physiologic outcomes.

Atherosclerotic cardiovascular disease (ASCVD) events, including coronary heart disease and stroke, are the most frequent cause of death and major disability in the world. Current American College of Cardiology/American Heart Association primary prevention guidelines are mainly on the basis of randomized controlled trials of statin-based low-density lipoprotein cholesterol (LDL-C)-lowering therapy for primary prevention of ASCVD events. Despite the clear demonstration of statin-based LDL-C lowering, substantial 10-year and lifetime risks of incident ASCVD continue. Although the 10-year risk is low in young and middle-aged adults who would not be treated according to current guidelines, they ultimately account for most incident ASCVD. If statin-based LDL-C lowering were initiated in them at an age before complex coronary plaques are common in the population, a substantial reduction in lifetime risk of incident coronary heart disease might be achieved. We examine this hypothesis and introduce the design of a currently recruiting trial to address it. (Eliminate Coronary Artery Disease [ECAD]; NCT02245087).

Increasingly frequent, it is clinically indicated to obtain tissue from a peripheral lung lesion (PLL) to yield a pathological diagnosis. The aim of the present study was to evaluate the diagnostic sensitivity of transbronchial needle aspiration (TBNA) and transbronchial catheter aspiration (TBCA) in addition to transbronchial forceps biopsy (TBB) at conventional bronchoscopy. Eligible patients showing a PLL on computed tomography scans were included in the study. In all patients, following TBB, TBNA and TBCA were employed in randomised order under fluoroscopy. Fourty-eight patients were enrolled, of whom 46 patients with 46 PLLs were included in the analysis. The mean ± SD diameter of the PLL was 27.0 ± 13.3 mm. The overall sensitivity for all modalities was 69.6 %; PLL ≤20 or >20 and ≤30 mm in diameter showed a sensitivity of 60.0 and 72.2 %, respectively. For malignant PLL (n = 33), the combined sensitivity of TBNA + TBCA versus TBB was significantly higher (63.6 vs. 33.3 %, p ≤ 0.05), and could not further be improved by TBB. For benign PLL, TBB was superior to TBNA + TBCA (76.9 vs. 38.5 %). TBB, TBNA and TBCA are complementary to one another. Combining the three techniques, even allows transbronchial specimen collection of PLL

Heart failure patients supported with left ventricular assist devices (LVAD) enjoy improvements in functional capacity and quality of life. We reasoned that such improvements in exercise capacity should be reflected in an objective increase in peak oxygen consumption as measured by cardiopulmonary exercise testing (CPET). We performed a retrospective review of all recipients of a HeartMate II LVAD at our center from June 2009 to June 2012 who completed CPET. Thirty-seven patients completed CPET an average of 6 months after implantation. Of these, 10 patients had CPET performed before LVAD implantation. Overall, 91.4% of patients improved by at least two New York Heart Association classes, with 34.3% improving by three classes. Postimplant VO2 max was significantly less than predicted (14.7 ± 3.1 vs. 29.8 ± 6.6 ml/kg/min, p < 0.001; percent-predicted 51% ± 12%). For 10 patients with pre- and post-implant studies, VO2 max increased significantly from 11.6 ± 5.0 to 15.4 ± 3.9 ml/kg/min (p = 0.009). VO2 max improves significantly with LVAD support but fails to normalize to predicted values, in spite of improvements in functional class. The severity of preimplantation heart failure does not associate with the degree of VO2 max improvement.

Objective: The use of cytological specimens to evaluate tumour biomarkers in metastatic breast cancer lesions has attracted increased interest because of the considerable number of reports that have shown discordance between the primary tumour and metastatic lesion. Oestrogen receptor (ER) and progesterone receptor (PgR) assays are crucial for the management of patients with breast cancer, in both adjuvant and palliative settings. The aim of this study was to compare the ER and PgR immunocytochemical analysis of fine needle aspiration (FNA) samples with the immunohistochemistry (IHC) of surgical specimens and core biopsies from primary breast cancers. Methods: The FNA specimens were prepared as cell blocks (n = 25) or ThinPreps (n = 258) for the immunocytochemistry (IC) ER and PgR analyses. Sixteen patients were excluded because of lack of follow-up (n = 1), neoadjuvant therapy (n = 3) or cell counts in their fine needle aspirates that were too low (n = 12). The results of IC on 25 cell blocks and 242 ThinPreps were compared with IHC on the corresponding core needle biopsies (n = 16) or excised tumours (n = 251). The ER and PgR status was defined as negative (when less than 10% of the nuclei were stained) or positive (when equal or more than 10% of the nuclei were stained). Kappa statistics were used to evaluate the concordance. Results: The ER concordance was 98% with ThinPrep (κ = 0.93) and 92% with cell block (κ = 0.82). The corresponding values for PgR were 96% (κ = 0.91) and 96% (κ = 0.92). Conclusions: Our results confirm that, in cases in which biopsies or surgical specimens are not available, IC (with either cell block or ThinPrep techniques) is a reliable method for the determination of the ER and PgR status performed under strict conditions using primary breast carcinomas, and is therefore potentially useful in metastatic settings.

Patients with coronary artery disease (CAD) who have a history of myocardial infarction (MI) are at increased risk of MI compared to patients with CAD and no such history [(1)][1]. This results, at least in part, from increased platelet activation of uncertain, but prolonged, duration. The

In adults, membranous nephropathy is the second most common cause of nephrotic syndrome. In contrast, minimal change disease and focal segmental glomerulosclerosis constitute the most common forms of nephrotic syndrome in children, while membranous nephropathy accounts for 5% of cases. In adults, causes of membranous nephropathy include autoantibodies directed against phospholipase A