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The most frequent germline mutations responsible for non syndromic congenital sideroblastic anemia are identified in ALAS2 and SLC25A38 genes. Iron overload is a key issue and optimal chelation therapy should be used to limit its adverse effects on the development of children. Our multicentre retrospective descriptive study compared the strategies for diagnosis and management of congenital sideroblastic anemia during the follow-up of six patients with an ALAS2 mutation and seven patients with an SLC25A38 mutation. We described in depth the clinical, biological and radiological phenotype of these patients at diagnosis and during follow-up and highlighted our results with a review of available evidence and data on the management strategies for congenital sideroblastic anemia. This report confirms the considerable variability in manifestations among patients with ALAS2 or SLC25A38 mutations and draws attention to differences in the assessment and the monitoring of iron overload and its complications. The use of an international registry would certainly help defining recommendations for the management of these rare disorders to improve patient outcome., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To describe the characteristics, management, and outcome of patients admitted to ICUs for pheochromocytoma crisis., Design: A 16-year multicenter retrospective study., Setting: Fifteen university and nonuniversity ICUs in France., Patients: Patients admitted in ICU for pheochromocytoma crisis., Interventions: None., Measurement and Main Results: We included 34 patients with a median age of 46 years (40-54 yr); 65% were males. At admission, the median Sequential Organ Failure Assessment score was 8 (4-12) and median Simplified Acute Physiology Score II 49.5 (27-70). The left ventricular ejection fraction was consistently decreased with a median value of 30% (15-40%). Mechanical ventilation was required in 23 patients, mainly because of congestive heart failure. Vasoactive drugs were used in 23 patients (68%) and renal replacement therapy in eight patients (24%). Extracorporeal membrane oxygenation was used as a rescue therapy in 14 patients (41%). Pheochromocytoma was diagnosed by CT in 33 of 34 patients. When assayed, urinary metanephrine and catecholamine levels were consistently elevated. Five patients underwent urgent surgery, including two during extracorporeal membrane oxygenation. Overall ICU mortality was 24% (8/34), and overall 90-day mortality was 27% (9/34). Crude 90-day mortality was not significantly different between patients managed with versus without extracorporeal membrane oxygenation (22% vs 30%) (p = 0.7) despite higher severity scores at admission in the extracorporeal membrane oxygenation group., Conclusions: Mortality is high in pheochromocytoma crisis. Routinely considering this diagnosis and performing abdominal CT in patients with unexplained cardiogenic shock may allow an earlier diagnosis. Extracorporeal membrane oxygenation and adrenalectomy should be considered as a therapeutic in most severe cases.

Background: Pneumonia is a dreaded complication of varicella-zoster virus (VZV) infection in adults; however, the data are limited. Our objective was to investigate the clinical features, management, and outcomes of critically ill patients with VZV-related community-acquired pneumonia (VZV-CAP)., Methods: This was an observational study of patients with VZV-CAP admitted to 29 intensive care units (ICUs) from January 1996 to January 2015., Results: One hundred and two patients with VZV-CAP were included. Patients were young (age 39 years (interquartile range 32-51)) and 53 (52%) were immunocompromised. Time since respiratory symptom onset was 2 (1-3) days. There was a seasonal distribution of the disease, with more cases during spring and winter time. All but four patients presented with typical skin rash on ICU admission. Half the patients received mechanical ventilation within 1 (1-2) day following ICU admission (the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO 2 /FiO 2 ) = 150 (80-284), 80% with acute respiratory distress syndrome (ARDS)). Sequential Organ Failure Assessment (SOFA) score on day 1 (odds ratio (OR) 1.90 (1.33-2.70); p < 0.001), oxygen flow at ICU admission (OR 1.25 (1.08-1.45); p = 0.004), and early bacterial co-infection (OR 14.94 (2.00-111.8); p = 0.009) were independently associated with the need for mechanical ventilation. Duration of mechanical ventilation was 14 (7-21) days. ICU and hospital mortality rates were 17% and 24%, respectively. All patients were treated with aciclovir and 10 received adjunctive therapy with steroids. Compared to 60 matched steroid-free controls, patients treated with steroids had a longer mechanical ventilation duration, ICU length of stay, and a similar hospital mortality, but experienced more ICU-acquired infections., Conclusions: Severe VZV-CAP is responsible for an acute pulmonary involvement associated with a significant morbidity and mortality. Steroid therapy did not influence mortality, but increased the risk of superinfection.

Background: There is currently no recommendation for the mean arterial pressure target in the particular setting of Extracorporeal Cardiopulmonary Resuscitation (ECPR) in the first hours following cardiogenic shock complicated by cardiac arrest. This study aimed to assess the effects of two different levels of mean arterial pressure on macrocirculatory, microcirculatory, and metabolic functions., Design: Randomized animal study., Setting: University research laboratory., Intervention: Ventricular fibrillation was induced in 14 male pigs by surgical ligature of the interventricular coronary artery. After 20 min of cardiopulmonary resuscitation, Extracorporeal Life Support (ECLS) was initiated to restore circulatory flow. Thereafter, animals were randomly allocated to a high mean arterial pressure group (High-MAP, 80-85 mm Hg) or to a standard mean arterial pressure group (Standard-MAP, 65-70 mm Hg). Assessments conducted at baseline, immediately following and 6 h after ECLS initiation were focused on lactate evolution, amount of infused fluid, and microcirculatory parameters., Results: There was no significant difference between the two groups at the time of ECLS initiation and at 6 h with regard to lactate levels (High-MAP vs. Standard-MAP: 8.8 [6.7-12.9] vs. 9.6 [9.1-9.8] mmol·l, P = 0.779 and 8.9 [4.3-11.1] vs. 3.3 [2.4-11] mmol·l, P = 0.603). Infused fluid volume did not significantly differ between the two groups (4,000 [3,500-12,000] vs. 5,000 [2,500-18,000] mL, P = 0.977). There was also no significant difference between the two groups regarding renal and liver functions, and sublingual capillary microvascular flow index assessed by Sidestream Dark Field imaging., Conclusion: Compared with a standard mean arterial pressure regimen, targeting a high mean arterial pressure in the first hours of an experimental ECPR model did not result in any hemodynamic improvement nor in a decrease in the amount of infused fluid.

Chronic GvHD-related keratoconjunctivitis sicca (cGvHD-related KCS) can significantly alter the quality of life of patients after allogeneic hematopoietic stem cell transplantation. The aim of this work was to assess the efficacy and tolerability of scleral lenses to treat severe cGvHD-related KCS. In this retrospective, multicenter study, we included 60 consecutive patients diagnosed with cGvHD-related KCS and fitted with scleral lenses. Patients were evaluated at baseline and at 2 months with the following tests: the Ocular Surface Disease Index (OSDI) to assess quality of life, the Oxford score to grade corneal damage and the logarithm of minimal angle of resolution (Log MAR) scale to determine visual acuity. We observed improvement in quality of life in 58 patients (97%). All parameters improved at 2 months. We observed significant differences at 2 months compared with baseline for the mean OSDI (86 versus 30, respectively, P<0.001), the mean Oxford score (3.2 versus 1.3, respectively, P<0.001) as well as visual acuity (Log MAR of 0.33 versus 0.10, respectively, P<0.001). Treatment with scleral lenses was discontinued in only 5 patients (8%) with a median follow-up of 20.5 months (range: 2-125 months). Scleral lenses were very efficient and well tolerated in patients with severe cGvHD-related KCS.

Research on human immunology has been hindered by the lack of optimal small animal models, given that the protective immune responses of human and non-human species show significant differences. However, due to ethical constraints[1] and the high cost of clinical trials, it is urgent to improve the current animal models that can mimic faithfully human physiology, particularly the human immune system (HIS). HIS mice had been generated recently by engrafting human hematopoietic stem cells (hHSCs) or human peripheral mononuclear cells (hPBMCs) into highly immuno-deficient mice such as NSG, NOG or NRG mice. However, a major experimental drawback for studies using these models is the rapid onset of Graft-versus-Host Disease (GvHD). In the present study, we overcome this limitation by generating new immuno-deficient mice named "HUMAMICE" (HLA-A2+/+/DR1+/+/H-2-β2m-/-/IAβ-/-/Rag2-/-/IL2rγ-/-/Perf-/- mice), which expressed human HLA molecules instead of mouse MHC molecules (H-2), and whose immuno-deficient status was reversed by transferring functional HLA-matched PBMCs thus producing mice with an immuno-competent status with a functional human immune system. We showed that in this HLA-matched context, the hPBMC-transfer led to high lymphocytes engraftment rates without GvHD over three months in this novel mouse model. Furthermore, to evaluate the utility of the hPBMC-HUMAMICE, we immunized them with commercial vaccine of Hepatitis B virus (HBsAg, Hepvac@) which resulted in robust and reproducible production of high levels of HBsAg-specific antibodies, implying that both transferred T and B lymphocytes were functional in HUMAMICE. These responses are comparable to those observed in human clinical trials with this identical vaccine. In conclusion, these findings indicated that the HLA-matched-hPBMC-HUMAMICE represents a promising model for dissecting human immune responses in various human diseases, including infectious diseases, cancers and tumors, and to facilitate the development of novel vaccines and cellular therapies.

Purpose: The two life-threatening signs of anaphylactic shock (AS) are severe arterial hypotension and bronchospasm. Guidelines recommend epinephrine as first-line treatment. Arginine vasopressin (AVP) has been proposed as an alternative if epinephrine does not correct arterial hypotension. These two drugs may have beneficial, neutral or deleterious effects on airflow either directly or by modifying factors that regulate vasodilatation and/or edema in the bronchial wall., Aim of the Study: To compare the effects of epinephrine and AVP on airflow and airway leakage in a rat model of AS., Materials and Methods: Thirty-two ovalbumin-sensitized rats were randomized into four groups: control (CON), AS without treatment (OVA), AS treated with epinephrine (EPI), and AS treated with AVP (AVP). Mean arterial pressure (MAP), respiratory resistance and elastance and microvascular leakage in the airways were measured., Results: All OVA rats died within 20 minutes following ovalbumin injection. Ovalbumin induced severe arterial hypotension and airway obstruction (221 ± 36 hPa.s.L -1 vs. vehicle 52 ± 8 hPa.s.L -1 ; p < 0.0001) associated with microvascular leakage distributed throughout the trachea, bronchi and intra-pulmonary airways. EPI and AVP extended survival time; EPI restored a higher level of MAP than AVP. Airway obstruction was attenuated by epinephrine (146 ± 19 hPa.s.L -1 ; p < 0.0001), but not by AVP (235 ± 58 hPa.s.L -1 ; p = 0.42)., Conclusions: Epinephrine was superior to AVP for alleviating the airway response in a rat model of AS. When bronchospasm and severe arterial hypotension are present during AS, epinephrine should be the drug of choice.

Cardiogenic shock (CS) patients treated with extracorporeal membrane oxygenation (ECMO) have severe cardiac failure, associated with ischemia-reperfusion. The use of moderate hypothermia during ischemia-reperfusion syndrome is supported by experimental data. We therefore studied the effects of moderate hypothermia on cardiac and vascular function in pig ischemic CS treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). CS was induced in 12 anesthetized pigs by coronary ligation. After 1 h of CS, VA-ECMO was initiated and pigs were randomized to normothermia (38°C) or moderate hypothermia (34°C) during 8 h. Intrinsic cardiac function was measured using a left ventricular conductance catheter. At the end of the experiment, tissues were harvested for Western blotting. ECMO associated with norepinephrine infusion and volume resuscitation increased mean arterial pressure, mixed venous oxygen saturation as well as carotid, renal, and coronary blood flow without any differences between normothermia and hypothermia. Hypothermia was associated with less fluid and less norepinephrine infusion, lower lactate level, and higher urinary output. Vascular reactivity was superior in hypothermia comparatively to normothermia as expressed using norepinephrine dose-response curves. Pressure development during isovolumic contraction, left ventricular ejection fraction, and prerecruitable stroke work index were higher in the hypothermia group. There were no differences between normothermia and hypothermia with regard to carotid and mesenteric protein expression for iNOs, eNOS, and phospho AKt/AKt measured at the end of the experimentation. The incidence of surgical bleeding and coagulation disorders was the same in both groups. In conclusion, moderate and rapid hypothermia improves hemodynamics and cardiac and vascular function in a pig model of ischemic CS treated with ECMO.

Objective: To assess incidence and prognostic significance of bacterial infections (BIs) occurring in compensated viral cirrhosis., Design: This prospective study involved 35 French centres. Inclusion criteria were biopsy-proven HCV or HBV cirrhosis, Child-Pugh A and no previous hepatic complications. Cumulative incidence (CumI) of events was estimated in a competing risks framework., Results: 1672 patients were enrolled (HCV 1323, HBV 318, HCV-HBV 31). During a median follow-up of 43 months, 234 BIs occurred in 171 patients (5 year CumI: 12.9%), among whom 14.6% had septic shock. Main localisations included the urinary tract (27.4%), lung (25.2%) and peritoneum (10.7%) (other, 86 (36.7%)). Most BIs occurred as a first event prior to liver decompensation (n=140, 81.8%) and were community-acquired (CA, 84.2%). The risk of BI was higher in patients with HCV than in patients with HBV (5 year CumI: 15.2% vs 5.5%, p=0.0008). Digestive localisation, concomitant interferon-based treatment, isolation of resistant bacteria and non-CA BIs were associated with lowest probability of resolution. The occurrence of a first BI impaired survival in patients infected with HCV (5 year survival: 60.2% vs 90.4%, p<0.001) and patients infected with HBV (5 year survival: 69.2% vs 97.6%, p<0.001). BIs represented the third cause of death (14.1%) after liver failure and liver cancer. BI risk factors comprised older age, lower albumin, proton pump inhibitor intake and absence of virological eradication/control., Conclusion: BI mostly occurs as a first complication and represents a turning point in the course of compensated viral cirrhosis. Its occurrence impacts long-term prognosis and may define a subgroup of patients in whom adaptation of management is warranted., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

This prospective multi-center observational survey describes causes of death and their trends from 2000 to 2010 among treated HIV-infected patients with immunovirologic success (PIVS) in France. In 90 clinical sites providing HIV care and treatment, representing a cohort of 82,000 patients in 2010, the underlying causes of death and characteristics of deceased patients were prospectively recorded in 2000, 2005, and 2010 by using a standardized form. We provide data on PIVS, define as patients with a CD4+ T cell value above 500/mm3 and a plasma HIV-1 RNA below 50 copies/ml at their last periodic checkup before death, compare them with immunovirologic uncontrolled patients, and describe trends in these data from 2000 onward. The main underlying causes of death of the 120 PIVS recorded in 2010 were: a non-AIDS/nonviral hepatitis-related malignancy (19%), suicide (12.5%), cardiovascular disease (11.5%), and liver disease (11%). Only three PIVS died of an AIDS-related event. Socioeconomic difficulty was identified in 41% of PIVS in 2010. This percentage had constantly grown since 2000 (p < .001). Median age at death also increased (40, 46, and 52 years in 2000, 2005, and 2010, respectively; p < .001). The distribution of the main causes of death of PIVS was statistically different from that of uncontrolled patients (p < .001). Although immunovirologic control is fundamental, a parallel multidisciplinary approach to care is essential to accurately detect and treat comorbidities, particularly cancer, psychiatric disorders, and cardiovascular disease. Psychosocial aspects must be considered.

Background: Regadenoson, a selective A2a receptor agonist, is a vasodilator increasingly used in myocardial perfusion imaging. Adjunction of isometric exercise is a simple method that could improve side effect profile while providing better image quality., Methods: Patients undergoing SPECT MPI were prospectively enrolled in handgrip-Regadenoson (HG-Reg test, N = 20) and Regadenoson (Reg) stress test (N = 40). Investigator blinded to stress test analyzed clinical data and images., Results: Heart rate (HR) increase was statistically higher in the HG-Reg group (27 vs 22 bpm, P = .019). Decrease in SBP was less frequent in the HG-Reg group than in the Reg group (55% vs 85.5%, P = .005), there were less drops >10 mmHg (45% vs 77.7%, P = .012). During stress testing, fewer subjects reported at least one side effect in the HG-Reg compared to Reg group (70% vs 92.5%, P = .021). Images were more often classified as good in the HG-Reg group (75% vs 52.5% in the Reg group, P = .25)., Conclusions: Adjunction of handgrip exercise to Regadenoson administration is a well-tolerated and easy method, without loss of time. Furthermore, image quality seems to be better.

Background: The impact of the use of anti-thymocyte globulin (ATG) in allogeneic stem cell transplantation performed with HLA-identical sibling donors following fludarabine and 4 days intravenous busulfan myeloablative conditioning regimen has been poorly explored., Methods: We retrospectively analyzed 566 patients who underwent a first HLA-identical allogeneic stem cell transplantation with this conditioning regimen for acute myeloid leukemia in first complete remission between 2006 and 2013 and compared the outcomes of 145 (25.6%) patients who received ATG (ATG group) to 421 (74.4%) who did not (no-ATG group). The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate., Results: Patients in the ATG group were older, received more frequently peripheral blood stem cell grafts from older donors, and were transplanted more recently. With a median follow-up of 19 months, patients in the ATG group had reduced 2-year cumulative incidence of chronic graft-versus-host disease (GVHD) (31 vs. 52%, p = 0.0002) and of its extensive form (8 vs. 26%, p < 0.0001) but similar relapse incidence (22 vs. 27%, p = 0.23) leading to improved GVHD and relapse-free survival (GRFS) (60 vs. 40%, p = 0.0001). In multivariate analyses, the addition of ATG was independently associated with lower chronic GVHD (HR = 0.46, p = 0.0001), improved leukemia-free survival (HR = 0.67, p = 0.027), overall survival (HR = 0.65, p = 0.027), and GRFS (HR = 0.51, p = 4 × 10 -5 ). Recipient age above 50 years was the only other factor associated with worse survivals., Conclusions: These results suggest that the use of ATG with fludarabine and 4 days intravenous busulfan followed by HLA-identical sibling donor allogeneic stem cell transplantation for acute myeloid leukemia improves overall transplant outcomes due to reduced incidence of chronic GVHD without increased relapse risk.

Background/objectives: Little information is available on the prevalence and clinical aspects of nail involvement in children with psoriasis. The objective of this study was to evaluate the prevalence and clinical aspects of and the risk factors for nail involvement in French children with psoriasis., Methods: We performed a multicenter, cross-sectional study in 23 French dermatology centers. All children seen during the 1-year study were systematically included. Clinical features of the nails were collected. Association with clinical aspects of the disease and comorbidities were evaluated., Results: Of 313 children with psoriasis (mean age 9.1 ± 4.2 yrs; 149 boys, 164 girls), 31.1% had familial psoriasis and 30% had severe psoriasis. The mean age at onset was 6.1 ± 3.7 years. Nails were involved in 32.3% of children. The main clinical aspects were pitting (69.1%) for fingernails and onycholysis (40.0%) and pachyonychia (27.5%) for toenails. All of the fingers were involved at similar frequencies, whereas the big toe was involved twice as often as the others (p < 0.005). Nail involvement was associated with male sex (p < 0.001), palmoplantar psoriatic (p < 0.001), severity of disease (p = 0.003), and psoriatic arthritis (p = 0.03)., Conclusion: The prevalence of nail involvement was 32.3% in children with psoriasis. Clinical aspects in children are reported, as well as clinical associations. As in adults, nail psoriasis is closely associated with psoriatic arthritis., (© 2016 Wiley Periodicals, Inc.)

Background: Administration of a selective β1-blocker, such as esmolol, in human septic shock has demonstrated cardiovascular protective effects related to heart rate reduction. Certain experimental data also indicate that esmolol exerts systemic anti-inflammatory and beneficial effects on vascular tone. Thus, the present study aimed to determine whether a non-chronotropic dose of esmolol maintains its protective cardiovascular and anti-inflammatory effects in experimental septic shock., Methods: Four hours after cecal ligation and puncture (CLP), Wistar male rats were randomly allocated to the following groups (n = 8): CLP, CLP + E-1 (esmolol: 1 mg.kg -1 .h -1 ), CLP + E-5 (esmolol: 5 mg.kg -1 .h -1 ), CLP + E-18 (esmolol: 18 mg.kg -1 .h -1 ). An additional eight rats underwent sham operation. All rats received a continuous infusion of saline, analgesic and antibiotics 4 hours after the surgery. Assessment at 18 hours included in vivo cardiac function assessed by echocardiography and ex vivo vasoreactivity assessed by myography. Circulating cytokine levels (IL-6 and IL-10) were measured by ELISA. Cardiac and vascular protein expressions of p-NF-κB, IκBα, iNOS, p-AKT/AKT and p-eNOS/eNOS were assessed by western blotting., Results: CLP induced tachycardia, hypotension, cardiac output reduction, hyperlactatemia and vascular hypo-responsiveness to vasopressors. Compared to CLP animals, heart rate was unchanged in CLP + E-1 and CLP + E-5 but was reduced in CLP + E-18. Stroke volume, cardiac output, mean arterial pressure and lactatemia were improved in CLP + E-1 and CLP + E-5, while vascular responsiveness to phenylephrine was only improved in CLP + E-5 and CLP + E-18. Plasma IL-6 levels were decreased in all esmolol groups. p-NF-κB was decreased in both cardiac and vascular tissues in CLP + E-5 and CLP + E-18., Conclusion: In experimental septic shock, low doses of esmolol still improved cardiac function and vasoreactivity. These benefits appear to be associated with a modulation of inflammatory pathways.

Background: Acute respiratory failure (ARF) is the most frequent complication in patients with hematological malignancies and is associated with high morbidity and mortality. ARF etiologies are numerous, and despite extensive diagnostic workflow, some patients remain with undetermined ARF etiology., Methods: This is a post-hoc study of a prospective multicenter cohort performed on 1011 critically ill hematological patients. Relationship between ARF etiology and hospital mortality was assessed using a multivariable regression model adjusting for confounders., Results: This study included 604 patients with ARF. All patients underwent noninvasive diagnostic tests, and a bronchoscopy and bronchoalveolar lavage (BAL) was performed in 155 (25.6%). Definite diagnoses were classified into four exclusive etiological categories: pneumonia (44.4%), non-infectious diagnoses (32.6%), opportunistic infection (10.1%) and undetermined (12.9%), with corresponding hospital mortality rates of 40, 35, 55 and 59%, respectively. Overall hospital mortality was 42%. By multivariable analysis, factors associated with hospital mortality were invasive pulmonary aspergillosis (OR 7.57 (95% CI 3.06-21.62); p < 0.005), use of invasive mechanical ventilation (OR 1.65 (95% CI 1.07-2.55); p = 0.02), a SOFA score >7 (OR 3.32 (95% CI 2.15-5.15); p < 0.005) and an undetermined ARF etiology (OR 2.92 (95% CI 1.71-5.07); p < 0.005)., Conclusions: In patients with hematological malignancies and ARF, up to 13% remain with undetermined ARF etiology despite comprehensive diagnostic workup. Undetermined ARF etiology is independently associated with hospital mortality. Studies to guide second-line diagnostic strategies are warranted. ClinicalTrials.Gov NCT01172132.

Objective: The objective of this study was to evaluate the reliability of recognising structural lesions on MRI (erosions, fatty lesions, ankylosis) of the sacroiliac joints (MRI-SIJ) in clinical practice compared to a central reading in patients with a possible recent axial spondyloarthritis (axSpA)., Methods: Patients aged 18-50 years, with recent (<3 years) and chronic (≥3 months) inflammatory back pain, suggestive of axSpA were included in the DEvenir des Spondyloarthrites Indifférenciées Récentes (DESIR) cohort. MRI-SIJ structural lesions were scored by non-trained local readers, and by two trained central readers. Local readers scored each SIJ as normal, doubtful or definite lesions. Central readers scored separately each type of lesion. The central reading (mean of the two central readers' scores) was the external standard. Agreement (κ) was calculated first between local (3 definitions of a positive MRI-SIJ) and central readings (9 definitions), and then between the two central readers., Results: 664/708 patients with complete available images were included. Agreements between local and central readings were overall 'fair', except when considering at least 2 or 3 fatty lesions and at least 3 erosions and/or fatty lesions where agreement was 'moderate'. Agreement between central readers was similar. MRI-SIJ was positive for 52.6% of patients according to central reading (at least 1 structural lesion) and for 35.4% of patients according to local reading (at least unilateral 'doubtful' or 'definite' structural lesions)., Conclusions: Agreement on a positive structural MRI-SIJ was fair to moderate between local and central readings, as well as between central readers. The reliability improved when fatty lesions were considered., Trial Registration Number: NCTO 164 8907., Competing Interests: Conflicts of Interest: None declared.

Haploidentical hematopoietic stem cell transplantation (HSCT) is being increasingly used due to improvement of the transplantation procedures allowing a reduction of graft-versus-host-disease (GVHD) and of transplant-related mortality (TRM). Such improvements have been particularly observed after administration of T-replete HSCT graft associated to an in vivo T cell depletion by the administration of high-doses of cyclophosphamide (HD-Cy) after transplantation. Here, we have analyzed the results of haplo-identical T replete HSC transplants, in particular, when performed with post-transplant HD-Cy in order to provide recommendations for the clinical practice. Criteria of choice for a haploidentical donor by priority order are absence of donor-specific antibodies (DSA) and to prioritize: CMV seronegative recipient/donor couples, ABO matching in case of deserythrocytation, male donor for a male recipient, the youngest donor. There is no clear argument in favor of the use of bone marrow versus peripheral blood stem cells (PBSC) after non myeloablative conditioning regimen, while after ablative conditioning PBSC seem to be associated with higher risks of GVHD without obvious impact on survival. Results of haploidentical HSCT, confirmed by several groups, are interesting in lymphomas (in particular Hodgkin disease) and for acute leukemia. Outcomes of patients rely on age, disease status at transplant and conditioning intensity. At equivalent disease risk, results of haploidentical HSCT seem comparable to those of HLA matched HSCT, raising the question of the classification of such transplants as alternatives. In all cases, we recommend to include patients in prospective clinical trials., (Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: The design of continuous training programs in therapeutic patient education (ETP) should be inspired by needs shown by the professionals concerned in terms of mobilization or acquisition of skills in this domain. The objective of this study is to analyze needs expressed by healthcare professionals (HP) involved in patients' management presenting a type 2 diabetes (T2D) and/or obesity and to compare them with the existing recommendations., Methods: One hundred and five PS (general practitioners, dietitians and nurses) of 3 frontier regions of French-speaking European countries (France, Belgium and Grand duchy of Luxembourg) were questioned in 12 monodisciplinary groups according to the technique of the nominal group. Needs expressed by the participants were classified in the categories of the reference table of skills to dispense TPE (National Institute for Health Prevention and Education [INPES], 2013)., Results/discussion: Among needs expressed by HP, 52 % of the votes targeted relational skills, 10 % of the skills relative to the biomedical techniques, 20 % of the skills relative to the educational techniques and 11 %, those of organization and the coordination. Seven percent of the proposals were out of the categories of the INPES. Results do not allow to establish profiles of skills according to the studied region or profession. The recognition of the TPE by the French legislation does not seem to influence in a major way the data., Conclusion: The needs expressed by PS in the context of this study are focused on the relation HP/patient that is the heart of the TPE. It would however be necessary to raise awareness among HP in the acquisition of the other skills which concern in particular the animation of group, the interprofessional coordination, the consideration of the environment or more generally the procedures., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: The efficacy and safety of intra-venous (i.v.) sodium benzoate for treating acute episodes of hyperammonemia in urea cycle enzyme disorders (UCD) is well known. However, published data do not provide a clear picture of the benefits and risks of this drug. We report a retrospective multicentre study on the use of i.v. sodium benzoate in patients treated for UCD between 2000 and 2010 in the 6 French reference centres for metabolic diseases., Results: Sixty-one patients with UCDs - 22 ornithine transcarbamylase (20 confirmed, 2 suspected), 18 arginino-succinate synthetase, 15 carbamoyl phosphate synthetase, 3 arginosuccinate lyase, 1 arginase deficiency, 1 N-acetylglutamate synthetase, 1 HHH syndrome - required i.v. sodium benzoate over the course of 95 acute episodes (NH3 > 100 μmol/L or high-risk situations, i.e., gastroenteritis, surgery). Forty out of 61 patients experienced only one episode of decompensation (neonatal coma, 68.6 %). The most frequent cause of late decompensation was infection (55.5 %). A loading dose of i.v. sodium benzoate (median 250 mg/kg over 2 h) was administered for 41/95 acute episodes. The median maintenance dose was 246.1 mg/kg/day, administered via peripheral venous infusion in all cases except one via a central line. The total median duration of i.v. sodium benzoate treatment per episode was 2 days (0-13 days). The median durations of hospitalization in intensive care and metabolic units were 4 days (0-17 days) and 10 days (0-70 days), respectively. Eight patients died during the neonatal coma (n = 6) or surgery (n = 2). The median plasma ammonium level before treatment was 245.5 μmol/L (20.0-2274.0 μmol/L); it decreased to 40.0 μmol/L in patients who were alive (13.0-181.0 μmol/L) at the end of treatment with i.v. sodium benzoate. A decrease in ammonium level to ≤ 100 μmol/L was obtained in 92.8 % of episodes (64/69 of the episodes recorded for the 53 surviving patients). Five patients required another treatment for hyperammonemia (sodium phenylacetate + sodium benzoate, haemofiltration). Eighteen side effects were reported related to the i.v. infusion (local diffusion, oedema)., Conclusion: This 10-year retrospective study shows that i.v. sodium benzoate associated with an emergency regimen is an effective and safe treatment for acute episodes of UCD.

Objective: Previous studies have suggested that lowering heart rate (HR) by selective β1-blockers improves sepsis-induced cardiac and vascular dysfunction primarily by decreasing proinflammatory pathways. However, the impact of isolated heart rate reduction (HRR) on hemodynamics and inflammatory pathways remains unknown. The present study was designed to assess the effects of HRR by ivabradine, an If channel inhibitor, on cardiovascular function and inflammatory pathways in peritonitis-induced septic shock in rats., Design: Randomized animal study., Setting: University research laboratory., Interventions: Four hours after cecal ligation and puncture (CLP), Wistar rats were randomly allocated to the following groups: CLP (n = 8) and CLP + ivabradine (n = 8, administered per os 4 h after the surgery). Another eight Wistar male rats underwent sham operation. All rats received a continuous infusion of saline (10 mL kg h), analgesic (nalbuphine: 0.2 mg kg h), and antibiotics (imipenem and cilastatin sodium: 10 mg kg) 4 h after the surgery. Assessment at 18 h included hemodynamics, in vivo cardiac function by echocardiography, and ex vivo vasoreactivity by myography. Circulating cytokine levels (TNF-α, IL-6, and IL-10) were measured by ELISA, whereas cardiac and vascular protein expressions of NF-κB/IκBα/iNOS and Akt/eNOS were assessed by Western blotting., Results: Compared with sham animals, CLP induced tachycardia, hypotension, decreased cardiac output, hyperlactatemia, and vascular hyporesponsiveness to vasopressors. Compared with the CLP group, adjunction of ivabradine decreased the HR without any impact on blood pressure, lactatemia, or vascular responsiveness to vasopressors. Adjunction of ivabradine to CLP rats had no impact on TNF-α, IL-6, and IL-10 cytokines, or on the protein expression levels of phosphorylated forms of NF-κB, Akt, eNOS, and degradation of IκBα in cardiac and vascular tissues., Conclusion: Isolated HRR by ivabradine in an experimental model of septic shock does not appear to be associated with any effect on the tested parameters of cardiac function or on vascular responsiveness to vasopressors. Moreover, in this setting, ivabradine does not alter the circulating levels of selected pro/anti-inflammatory cytokines or cardiac and vascular NF-κB/IκBα protein expression levels.

Objective: We aimed to assess the acceptability of antibiotic stewardship measures by family physicians., Material and Methods: We conducted an online cross-sectional survey in 2015 with a sample of family physicians practicing in a specific French region., Results: Overall, 283 of 1171 family physicians (24%) completed the questionnaire. Decision-support tools for antibiotic prescribing and educational measures were well accepted by family physicians: 71% strongly agreed with a free distribution of urine dipstick tests and 54% with incentives to participate in antibiotic training sessions. Almost all family physicians did not agree with restrictive measures: 68% were for instance opposed to having to justify the prescription's compliance with guidelines on the prescription itself. Physicians also did not agree with restrictive measures when they only applied to physicians prescribing many antibiotics., Conclusion: Participants were probably the most motivated and aware of the topic physicians, but they were particularly hostile to the introduction of restrictive measures related to antibiotic prescribing. Our survey was conducted with a large sample of family physicians and could help orientate our country's antibiotic stewardship policy. However, family physicians are likely to oppose any measure aiming at restricting their freedom of prescription., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Multiple Endocrine Neoplasia type 1 (MEN1) patients often undergo multiple pancreatic operations at a young age., Objective: To describe robot-assisted and laparoscopic spleen-preserving pancreatic surgery in MEN1 patients, and to compare both techniques., Methods: Robot-assisted pancreatectomies of the DutchMEN1 study group and the Université de Lorraine, Nancy, France were compared to a historical cohort of laparoscopic treated MEN1 patients. Perioperative outcomes were compared., Results: A total of 21 MEN1 patients underwent minimally invasive pancreatic surgery for pancreatic neuroendocrine tumors, seven patients were subjected to robot-assisted surgery, and 14 patients underwent laparoscopic surgery. Demographics and clinical characteristics did not differ between the cohorts and no significant differences in operative outcomes were found. A high number of ISGPS grade B/C pancreatic fistulas were observed in both cohorts (38%), and no conversions were seen in the robot-assisted cohort (respectively 0% vs. 43%, P = 0.06). In one laparoscopic and one robot-assisted case the primary tumor was not resected., Conclusions: Minimally invasive spleen-preserving surgery in MEN1 patients is safe and feasible. Patients who underwent robot-assisted surgery did not require conversion to open surgery. J. Surg. Oncol. 2016;114:456-461. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Data comparing fully matched and mismatched-unrelated-donor (M- and mM-URD) allogeneic hematopoietic stem cell transplant (allo-SCT) following reduced intensity conditioning regimens for acute myeloid leukemia are limited., Methods: We retrospectively compared the outcome of 3398 patients above the age of 50 years who underwent 10/10 M-URD (n = 2567), 9/10 (n = 723), or 8/10 (n = 108) mM-URD allo-SCT for acute myeloid leukemia after reduced intensity conditioning regimen between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate., Results: HLA matching had no impact on engraftment (p = 0.31). In univariate analysis, in comparison to 10/10 M-URD, mM-URD was associated with higher incidence of grade II-IV acute graft-versus-host disease (GVHD) (p = 0.0002), similar rates of chronic GVHD (p = 0.138) but increased incidence of its extensive form (p = 0.047). Compared to 10/10 M-URD, patients transplanted in the first complete remission (CR1) with a 9 or an 8/10 mM-URD had decreased 2-year leukemia free (LFS) (p = 0.005) and overall survivals (OS) (56.7, 46.1, and 50.2 %, respectively, p = 0.005), while outcomes were comparable between all groups for patients transplanted beyond CR1. In multivariate analysis, 9/10 versus 10/10 URD was associated with higher non-relapse mortality (HR 1.34, p = 0.001), similar risk of relapse and chronic GVHD and inferior LFS (HR 1.25, p = 0.0001), and OS (HR 1.27, p = 0.0001). There was no difference in adjusted transplant outcomes between 9/10 and 8/10 mM-URD., Conclusions: Reduced intensity conditioned allo-SCT with a 10/10 M-URD remains the preferable option for AML patients above the age of 50 years. The use of a 9/10 or an 8/10 mM-URD in patients not having a fully matched donor represents an alternative therapeutic option that should be compared to other alternative donor transplant strategies.

N-terminal acetylation is a common protein modification in eukaryotes associated with numerous cellular processes. Inherited mutations in NAA10, encoding the catalytic subunit of the major N-terminal acetylation complex NatA have been associated with diverse, syndromic X-linked recessive disorders, whereas de novo missense mutations have been reported in one male and one female individual with severe intellectual disability but otherwise unspecific phenotypes. Thus, the full genetic and clinical spectrum of NAA10 deficiency is yet to be delineated. We identified three different novel and one known missense mutation in NAA10, de novo in 11 females, and due to maternal germ line mosaicism in another girl and her more severely affected and deceased brother. In vitro enzymatic assays for the novel, recurrent mutations p.(Arg83Cys) and p.(Phe128Leu) revealed reduced catalytic activity. X-inactivation was random in five females. The core phenotype of X-linked NAA10-related N-terminal-acetyltransferase deficiency in both males and females includes developmental delay, severe intellectual disability, postnatal growth failure with severe microcephaly, and skeletal or cardiac anomalies. Genotype-phenotype correlations within and between both genders are complex and may include various factors such as location and nature of mutations, enzymatic stability and activity, and X-inactivation in females., (© 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc.)

Introduction: The present study was developed to investigate the effects of norepinephrine alone on hemodynamics and intrinsic cardiac function in a pig model of cardiogenic shock mimicking the clinical setting., Methods: Cardiogenic shock was induced by 1-h ligation of the left anterior descending (LAD) artery followed by reperfusion. Pigs were monitored with a Swan-Ganz catheter, a transpulmonary thermodilution catheter, and a conductance catheter placed in the left ventricle for pressure-loop measurements. Measurements were performed before LAD occlusion, 1 h after LAD occlusion, and 4 h after myocardial reperfusion., Results: Myocardial infarction and reperfusion was followed by cardiogenic shock characterized by a significant increase in heart rate and significant decreases in mean arterial pressure (MAP), mixed venous oxygen saturation (SVO2), left ventricular end-diastolic pressure (LVEDP), prerecruitable stroke work (PRSW), and cardiac power index (CPI). Lactate levels were significantly increased. The systemic vascular resistance index (SVRI) and global end-diastolic volume index (GEDVI) remained unchanged. When compared with the control group (n = 6), norepinephrine infusion (n = 6) was associated with no changes in heart rate, a significant increase in MAP, SVO2, left ventricular ejection fraction, pressure development during isovolumic contraction, SVRI, and CPI and a decrease in lactate level. Cardiac index tended to increase (P = 0.059), whereas PRSW did not change in the norepinephrine group. LVEDP and GEDVI remained unchanged., Conclusions: Norepinephrine alone is able to improve hemodynamics, cardiac function, and tissue oxygenation in a pig model of ischemic cardiogenic shock.

Objectives: The undeniable asset of the antagonist protocols in in vitro fertilization is the decrease of the risks of ovarian hyperstimulation syndrome, by the use of a release by GnRH agonist. Nevertheless, questioning persist concerning the rates of clinical pregnancies, the oocyte quantity and the empty follicle syndrome. We thus studied these parameters in our center., Methods: A retrospective study was realized from January 1st, 2013 till July 31st, 2015. The main objective was the evaluation of the rate of clinical pregnancies in antagonist protocol. A first group of 775 cycles have benefited from a release of the ovulation by HCG, while a second group of 204 cycles, by GnRH agonist. The secondary objectives were the oocyte quantity, the rate of ovarian hyperstimulation syndrome, and the rate of empty follicle syndrome., Results: No statistically significant difference was found between both groups concerning the rates of clinical pregnancies, oocytes quantity, and the rate of empty follicle syndrome, whatever is the type of used release, in fresh embryo transfer. A syndrome of premature ovarian hyperstimulation syndrome was found at 7.9 % of the patients in the group 2 versus 2.3 % in the group 1, with a statistically significant difference (P<0.05). At these patients, a strategy of frozen embryo transfer ("freeze all") was proposed. The accumulated rates by pregnancy in both groups were not statistically different., Conclusion: The release by GnRH agonist does not show inferiority in terms of clinical pregnancy, in comparison to HCG., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Renal medullary carcinoma (RMC) is a rare and highly aggressive neoplasm that most often occurs in the setting of sickle cell trait or sickle cell disease (SCD). Most patients present with metastatic disease resistant to conventional chemotherapy, and therefore there is an urgent need for molecular insight to propose new therapies., Objective: To determine the molecular alterations and oncogenic pathways that drive RMC development., Design, Setting, and Participants: A series of five frozen samples of patients with RMC was investigated by means of gene expression profiling, array comparative genomic hybridization, and RNA and whole exome sequencing (WES)., Outcome Measurements and Statistical Analysis: RNA and DNA sequencing read data were analyzed to detect gene fusions and somatic mutations. Gene fusions mutations were validated by real-time polymerase chain reaction and fluorescence in situ hybridization. Gene expression profiling was analyzed by unsupervised hierarchical clustering and Gene Set Enrichment Analysis (Broad Institute, Cambridge, MA, USA)., Results and Limitations: We observed inactivation of the tumor suppressor gene SMARCB1 in all tumors. In all four cases developed in patients with SCD, we identified an original mechanism of interchromosomal balanced translocations that disrupt the SMARCB1 sequence and thus contribute to its inactivation. Gene expression profiling revealed that RMC shares common oncogenic pathways with pediatric malignant rhabdoid tumors, another tumor subtype characterized by SMARCB1 deficiency., Conclusions: RMCs are characterized by an original mechanism of interchromosomal balanced translocations that disrupt the SMARCB1 sequence. WES reveals that RMCs show no other recurrent genetic alteration and an overall stable genome, underscoring the oncogenic potency of SMARCB1 inactivation., Patient Summary: Our comprehensive molecular study supports a pivotal role of the tumor suppressor gene SMARCB1 in the development of renal medullary carcinoma. The use of therapeutic strategies based on the biologic effects of its inactivation should now open new perspectives for this typically lethal malignancy., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The prevalence of childhood psoriasis is estimated at between 0.4% and 0.7%. Clinical aspects of the diseases depend on age. The aim of this study was to investigate the clinical aspects of psoriasis according to age and sex., Patients and Methods: A cross-sectional, multicentre study of children with psoriasis was performed by investigators belonging to the Research Group of the French Society of Paediatric Dermatology. The study was conducted from April 2012 to March 2013. Inclusion criteria were age less than 18 years and clinical diagnosis of psoriasis. The children were classified into 3 groups by age: infants: <2 years; children: ≥2 years and <13 years; adolescents≥13 years. The information collected included demographic data, clinical, epidemiological, and therapeutic aspects of the psoriasis, as well as analysis of comorbidities., Results: Three hundred and thirteen children were included: 27 (8.6%) infants, 207 (66.1%) children, and 79 (25.2%) adolescents. Plaque psoriasis was the most frequent clinical type of psoriasis seen in children and adolescents (>41%), but it accounted for only 25.9% of psoriasis of infants (P<0.0001). Napkin psoriasis (37.0%) and inverse psoriasis (22.2%) were the most common forms of psoriasis seen in infants and were described significantly more frequently in this group than in the two other groups (P<0.003). Nail involvement was more common in adolescents (37.2%, P=0.03) and children (32.9%) than in infants (14.8%) and affected boys more than girls (43.6% vs 22.0%, P<0.0001). Girls presented scalp psoriasis more frequently (17.7% vs 8.7%, P=0.02). Local vitamin-D treatment and systemic therapies were used more frequently in children and adolescents than in infants. There was no significant difference for treatment use, including for acitretin, according to gender., Discussion: Plaque psoriasis was the most common clinical type of psoriasis in children but affected less than 50% of the children. Age had a significant impact on extra-cutaneous skin disorders and on treatment used, while sex had little incidence. The frequency of comorbidities was not affected by age., Conclusion: Childhood psoriasis thus presents specific characteristics dependent on the age of the child. The results of studies exclusively dealing with adults cannot be extrapolated to children., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Purpose: To describe the multidetector row computed tomography (MDCT) imaging features of HCC that develops in patients who are free from underlying liver cirrhosis and to determine if the MDCT presentation of this specific tumor differs from that of the more common HCC that develops in patients with liver cirrhosis using a retrospective case-control study., Patients and Methods: The MDCT examinations of 38 patients with HCC in non-cirrhotic liver (group 1) were quantitatively and qualitatively analyzed and compared to those obtained in 38 patients with HCC in cirrhotic liver (group 2) matched for age and gender. Quantitative and qualitative characteristics of HCC of both groups were compared using univariate analysis., Results: HCCs were significantly larger in group 1 (81.5mm±55.5) than in group 2 (44.5mm±39.1 SD; P=0.0015). In group 1, HCCs were more frequently single tumors (87%) than in group 2 (37%) (P<0.0001), encapsulated (92% vs. 47% respectively; P<0.0001), had more frequently fatty component (24% vs. 8%, respectively; P=0.0279) and internal hemorrhage (29% vs. 3%, respectively; P=0.0033). No significant differences were found between the two groups for location, hyperenhancement of HCC during the arterial phase, washout during the portal phase, endoluminal portal involvement by HCC, endoportal cruoric thrombus, invasion of adjacent organs and underlying liver steatosis., Conclusion: HCC in non-cirrhotic liver are larger than those observed in cirrhotic liver and more frequently present as a single encapsulated tumor. They have the same patterns of enhancement than HCC that develops in cirrhotic liver., (Copyright © 2015 Éditions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Background: HIV-infected patients with TB need simplified, effective and well-tolerated antiretroviral regimens., Methods: The French ANRS 129 BKVIR open trial evaluated the once-daily tenofovir DF/emtricitabine and efavirenz combination, started within 12 weeks after TB treatment initiation, in antiretroviral-naive HIV-1-infected patients. Success was defined as an HIV-1 RNA <50 copies/mL and TB cure at 48 weeks., Results: TB was confirmed microbiologically (90%) or histologically (10%) in 69 patients (71% male; median age 43 years; 54% born in Africa). The median time between TB treatment initiation and antiretroviral therapy was 8 weeks (range 1-22 weeks). At baseline, median HIV-1 RNA was 5.4 log10 copies/mL and median CD4 cell count 74 cells/mm(3). In the ITT analysis, combined success at week 48 was achieved in 57/69 patients (83%, 95% CI 74-92). Twelve patients did not achieve virological success, and TB was not cured in one of them. Among the 47 patients who fully adhered to the strategy, the success rate was 96% (95% CI 90-100) and was not affected by low rifampicin and isoniazid serum concentrations. Forty-nine serious adverse events were reported in 31 patients (45%), and 11 led to antiretroviral drug interruption. All adverse events resolved. The immune reconstitution inflammatory syndrome occurred in 23 patients (33%, 95% CI 22-44), and was associated with a low baseline BMI (P = 0.03) and a low haemoglobin level (P = 0.02)., Conclusion: These results support the use of tenofovir DF/emtricitabine and efavirenz combination therapy for HIV infection in patients with TB., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Deep vein thrombosis (DVT) is a frequent and multifactor disease, with two major complications, post thrombotic syndrome and pulmonary embolism. Both transient (surgery, plaster immobilization, bed rest/hospitalization) and chronic/persistent (age, cancer, clinical or biological thrombophilia…) risk factors modulate treatment duration. Diagnostic management relies on clinical evaluations, probability followed by laboratory tests or imaging. So far, compression ultrasound is the diagnostic test of choice to make a positive diagnosis of DVT. Anticoagulants at therapeutic dose for at least 3 months constitute the cornerstones of proximal (i.e. involving popliteal or more proximal veins) DVT therapeutic management. The arrival of new oral anticoagulants should optimize ambulatory management of DVT., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 ×), NKX2-5 (6 ×), ZIC3 (3 ×), MLPA (2 ×) and ELN (4 ×). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era.

Background: Interferon- and ribavirin (RBV)-free regimens can improve patient-reported outcomes (PROs) during treatment., Aim: To compare PROs during treatment with ledipasvir and sofosbuvir (LDV/SOF) to placebo and to LDV/SOF + RBV., Methods: Treatment-experienced CH-C genotype 1 patients with compensated cirrhosis (N = 154) were randomized to receive 24 weeks of LDV/SOF or 12 weeks of placebo followed by 12 weeks of LDV/SOF + RBV (the SIRIUS clinical trial). While blinded to their HCV RNA level and study treatment, patients completed PRO questionnaires (SF-36, FACIT-F, CLDQ-HCV, WPAI:SHP) at baseline, during and post-treatment., Results: Baseline PRO scores were similar between the two study arms. Patients receiving LDV/SOF showed improvement in a number of PROs (predominantly related to mental health) starting as early as 4 weeks after treatment initiation; no PRO decrement from baseline were noted, and no PRO scores were inferior to placebo (all P > 0.05). In the second 12 weeks, patients who were receiving LDV/SOF continued to improve PROs (up to +9.2% from a 100% maximum possible score, P < 0.05), while patients receiving LDV/SOF + RBV had less gains or no improvement in their PRO scores. However, regardless of the regimen, patients who successfully cleared the virus (N = 149) had significant improvement in all aspects of PROs (up to +12.2% by post-treatment week 12, up to +16.9% by week 24)., Conclusions: Treatment-experienced cirrhotic patients experience a notable improvement of their PROs during treatment with LDV/SOF. Furthermore, achieving SVR-12 is associated with significant PRO improvement, which further improves at post-treatment week 24 in this difficult to treat group of patients with chronic hepatitis C., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Data are sparse regarding the effects of prolonged prone positioning (PP) during VV-ECMO. Previous studies, using short sessions (<12 h), failed to find any effects on respiratory system compliance. In the present analysis, the effects of prolonged PP sessions (24 h) were retrospectively studied with regard to safety data, oxygenation and respiratory system compliance., Methods: Retrospective review of 17 consecutive patients who required both VV-ECMO and prone positioning. PP under VV-ECMO was considered when the patient presented at least one unsuccessful ECMO weaning attempt after day 7 or refractory hypoxemia combined or not with persistent high plateau pressure. PP sessions had a duration of 24 h with fixed ECMO and respiratory settings. PP was not performed in patients under vasopressor treatment and in cases of recent open chest cardiac surgery., Results: Despite optimized protective mechanical ventilation and other adjuvant treatment (i.e. PP, inhaled nitric oxide, recruitment maneuvers), 44 patients received VV-ECMO during the study period for refractory acute respiratory distress syndrome. Global survival rate was 66 %. Among the latter, 17 patients underwent PP during VV-ECMO for a total of 27 sessions. After 24 h in prone position, PaO2/FiO2 ratio significantly increased from 111 (84-128) to 173 (120-203) mmHg (p < 0.0001) while respiratory system compliance increased from 18 (12-36) to 32 (15-36) ml/cmH2O (p < 0.0001). Twenty-four hours after the return to supine position, tidal volume was increased from 3.0 (2.2-4.0) to 3.7 (2.8-5.0) ml/kg (p < 0.005). PaO2/FiO2 ratio increased by over 20 % in 14/14 sessions for late sessions (≥7 days) and in 7/13 sessions for early sessions (<7 days) (p = 0.01). Quantitative CT scan revealed a high percentage of non-aerated or poorly-aerated lung parenchyma [52 % (41-62)] in all patients. No correlation was found between CT scan data and respiratory parameter changes. Hemodynamics did not vary and side effects were rare (one membrane thrombosis and one drop in ECMO blood flow)., Conclusion: When used in combination with VV-ECMO, 24 h of prone positioning improves both oxygenation and respiratory system compliance. Moreover, our study confirms the absence of serious adverse events.

Background: Transcatheter aortic-valve implantation (TAVI) is a new therapeutic choice for treating aortic stenosis in patients considered high risk for surgery. This blooming therapeutic technique still requires evaluation of medium and long term outcome., Method: We hereby report our results of the first 150 consecutive patients to receive TAVI implants in our population recruited from July 2009 to March 2013 in a retrospective and monocentric study. We analyzed long term morbidity and mortality criteria. We compared the apical and femoral approach results and researched predictors of cardiac mortality., Results: The mean monitoring period was 387.62 days, mean Euroscore was 21.8, and mean Society of Thoracic Surgeons (STS) risk score was 9.2. The success rate for the procedure was 94.6 %. A total of 39 patients died. The mortality rates at the immediate perioperative point, 30 days, 1 year, and 2 years, were 4 %, 11.3 %, 22.7 %, and 26 %, respectively. As regards complications, there were 10 hemodynamic complications (6.6 %) and 20 vascular (13.3 %), 11 cardiac tamponades (7.4 %), eight mechanical (5.3 %), ten major hemorrhagic (6.7 %), 14 pulmonary (9.3 %), and 18 infectious complications (12 %). When comparing the rates of reported complications in terms of different approaches, we observed significantly more hemodynamic complications in the apical group (p = 0.049). Pulmonary complications were also significantly more common in cases of apical approach (p = 0.029). The majority of the patients reported clear functional improvement throughout their follow-up., Conclusion: The results of the first 150 patients to receive the implant at the Nancy University Teaching Hospital (CHU Nancy) were consistent with findings in the literature. TAVI proved a credible and effective alternative to surgical valve replacement for patients at high risk during surgery.

Purpose: The objectives of this study were to determine the frequency with which intraductal papillary mucinous pancreatic neoplasms (IPMNs) show fistulization to adjacent organs and to describe the multidetector row computed tomography (MDCT) and magnetic resonance imaging (MRI) findings for this specific complication., Methods: A retrospective analysis of the clinical and imaging files of all patients with IPMNs who were followed over 8 years by our department was performed to identify those with fistula formation. Two radiologists determined the type of IPMN, the number and size of visible fistulas, the involved adjacent organs, the pancreatic location and the presence of imaging findings suggestive of malignant transformation of the IPMN. Histological correlation was also performed., Results: A total of 423 patients were included. Fistula formation was present in 8 patients (1.9%). The corresponding IPMNs were of the main duct type (n=4; 50%), the branch duct type (n=1; 13%) or the mixed type (n=3; 38%). In half of the cases, these tumors were discovered incidentally. A total of 26 fistulas (1-7 per patient) were identified. These fistulas involved the duodenum (65.4%), stomach (19.2%), common bile duct (11.5%) and colon (3.8%). All patients had fistulas to the duodenum. All fistulas appeared to develop from a malignant IPMN based on the imaging studies, but two of the five available samples did not exhibit atypia (a quarter of all fistulas). In 50% of cases, the IPMN was of the intestinal form., Conclusions: Fistulas are uncommon complications of IPMNs, regardless of malignant transformation of the IPMNs. Fistulas appear to predominate among malignant main-duct IPMNs, are generally multiple and affect several organs, and their preferential target is the duodenum. However, fistulas do not adhere to a strict criterion of malignancy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Previous studies have demonstrated that ICU (intensive care unit) survivors have decreased long-term survival rates compared to the general population. However, knowledge about how to identify ICU survivors with higher risk of death and the adjustable factors associated with mortality is still lacking., Methods and Design: The FROG-ICU (the French and European Outcome Registry in Intensive Care Units) study is a prospective, observational, multicenter cohort study where ICU survivors are followed up to one year after ICU discharge. Beside one year survival, the study is designed to assess incidence and identifying risk factors for mortality over the year following discharge from the ICU. All consecutive patients admitted in ICU to the 28 participating centers during the study period will be included. Every subject will undergo an evaluation at admission, throughout the ICU stay and at ICU discharge. The global, especially cardiovascular, assessment of each subject will be performed through a complete clinical exam, instrumental tests (electrocardiogram, echocardiogram) and biological parameters. Blood and urine samples will be collected at admission and at discharge with the primary goal to assess effectiveness of routine and novel cardiovascular, inflammatory and renal biomarkers, with potential interest in risk stratification for patients who survive an ICU stay. The follow up will include a careful tracking of patients through telephone calls and questionnaires at 3, 6 and 12 months after ICU discharge. FROG-ICU aims to identify the clinical and biological phenotype of patients with different levels of probability of death in the year after ICU discharge., Discussion: FROG-ICU has been designed to better understand long term outcome after ICU discharge as well as risk factors for all-cause and cardiovascular morbidity and associated mortality. It is a large prospective multicenter cohort with a biological (on plasma and urine) collection and one-year follow-up of ICU patients. FROG ICU will allow performing a risk stratification of ICU survivors as to recognize the subset of patients who may benefit from an early intervention to allow decreased cardiovascular morbidity and related mortality., Trial Registration: ClinicalTrials.gov NCT01367093 .

Microvascular obstruction (MVO) and transmural infarct size are prognostic factors after acute myocardial infarction (AMI). We assessed the value of myocardial deformation patterns using 3D speckle tracking imaging (3DSTI) in detecting myocardial and microvascular damage after AMI. One hundred patients with first ST-segment elevation MI from the REMI Study were prospectively included. Transthoracic echocardiography with 3DSTI and CMR were performed within 72 h after revascularization therapy. Global (3DG) and segmental (3DS) values of LV longitudinal (LS), circumferential and radial area strain were obtained. Late gadolinium enhancement (LGE) and MVO was quantified as transmural (>50%) or non-transmural (<50%). Predictive performance was assessed by area under the receiver operating curve characteristic (AUC). Mean LVEFCMR was 45.8 ± 9.2 % with 22.2 ± 12.7% transmural LGE. MVO was present in 55 patients (MVO transmural extent 11.4 ± 11.8%). In global analysis, all 3DG strain values were correlated with LVEFCMR and infarct size, with the best correlation obtained for 3DGAS (r = -0.678; p < 0.0001). All 3DG strain values, with the exception of LS, were significantly different between patients with and without MVO. In segmental analysis, all 3DS strain values were significantly lower in transmurally infarcted segments than in non-infarcted segments, and all 3DS values except 3DSRS were significantly lower in non-transmural infarcted segments than in non-infarcted segments. The best 3DS strain for detecting non-viable segments with MVO (MVO > 75%) was 3DSAS [AUC 0.867 (0.849-0.884), 78.0% sensitivity and 81.1% specificity for 3DSAS = -16.1%]. Importantly, 3DSRS and 3DSAS were associated with an increase in diagnostic accuracy of both transmural LGE and MVO over 3DSLS (all increase in AUC > 0.04, all p < 0.01). The newly developed 3DSTI, especially 3DSAS, is a sensitive and reproducible tool to predict and quantify the transmural extent of scar. This new early imaging strategy improve the prediction of MVO while enabling to assess the success of reperfusion and the risk of late systolic remodeling in STEMI.

The early management of pediatric hand burns includes surgical treatment, medical follow up and prevention of abnormal scarring by splits and/or pressure garment therapy. The aim of this review was to find the best available evidence in the literature on the surgical part of this management. This review started with a search in the PubMed database for the keywords, hand AND/OR child AND/OR burn. Only the articles published between January 1(st), 2005 and January 1(st), 2011 were selected. The data were compared to French and American textbooks. Contradictory findings were reported on the timing of the excision and graft, with only two comparative studies reported, with a lot of biases. The state of the art on the initial management of hand burns in children is not totally conclusive due to the lack of statistic power in these studies, but many expert opinions help to define options for good therapeutic paradigms. It is important to include these patients in prospective protocols with both early and long-term follow-up in order to increase the amount of evidence at our disposal.

Objective: The risk of cardiovascular morbidity and mortality is significantly increased in patients with diabetes; thus, it is important to determine whether glucose-lowering therapy affects this risk over time. Changes in cardiovascular risk markers were examined in patients with type 2 diabetes treated with exenatide twice daily (a glucagon-like peptide-1 receptor agonist) or glimepiride (a sulfonylurea) added to metformin in the EURopean EXenAtide (EUREXA) study., Research Design and Methods: Patients with type 2 diabetes failing metformin were randomized to add-on exenatide twice daily (n = 515) or glimepiride (n = 514) until treatment failure defined by hemoglobin A1C. Anthropomorphic measures, blood pressure (BP), heart rate, lipids, and high-sensitivity C-reactive protein (hsCRP) over time were evaluated., Results: Over 36 months, twice-daily exenatide was associated with improved body weight (-3.9 kg), waist circumference (-3.6 cm), systolic/diastolic BP (-2.5/-2.6 mmHg), high-density lipoprotein (HDL)-cholesterol (0.05 mmol/L), triglycerides (-0.2 mmol/L), and hsCRP (-1.7 mg/L). Heart rate did not increase (-0.3 beats/minute), and low-density lipoprotein-cholesterol (0.2 mmol/L) and total cholesterol (0.1 mmol/L) increased slightly. Between-group differences were significantly in favor of exenatide for body weight (P < 0.0001), waist circumference (P < 0.001), systolic BP (P < 0.001), diastolic BP (P = 0.023), HDL-cholesterol (P = 0.001), and hsCRP (P = 0.004). Fewer patients randomized to exenatide twice daily versus glimepiride required the addition of at least one antihypertensive (20.4 vs 26.4%; P = 0.026) or lipid-lowering medication (8.4 vs 12.8%; P = 0.025)., Conclusions: Add-on exenatide twice daily was associated with significant, sustained improvement in several cardiovascular risk markers in patients with type 2 diabetes versus glimepiride., Clinical Trial Registration: NCT00359762, http://www.ClinicalTrials.gov.

Unlabelled: Various critical events, liver related or not, occur in patients with compensated cirrhosis, but their respective burden remains to be prospectively assessed. The aim of this prospective cohort study involving 35 French centers was to capture the whole spectrum of complications occurring in compensated viral cirrhosis (VC) using competing risks analyses. Inclusion criteria were: histologically proven cirrhosis resulting from hepatitis C virus (HCV) or hepatitis B virus (HBV); Child-Pugh A; and no previous hepatic complications. The cohort was considered as a multistate disease model, cumulative incidences (CumIs) of events were estimated in a competing risks framework. A total of 1,654 patients were enrolled from 2006 to 2012 (HCV, 1,308; HBV, 315; HCV-HBV, 31). During a median follow-up of 34 months, at least one liver nodule was detected in 271 patients, confirmed as hepatocellular carcinoma (HCC) in 128 (4-year cumI: 10.5%) and cholangiocarcinoma in 3. HCC incidence was higher in HCV (4-year cumI: 11.4% vs. 7.4%; P = 0.05). HCC fulfilled Milan criteria in 79.3%, leading to curative treatment in 70.4%. Liver decompensation occurred more frequently in HCV patients (4-year cumI: 10.8% vs. 3.6%; P = 0.0004). Virological eradication/control was achieved in 34.1% of HCV and 88.6% of HBV patients and was associated with a marked decrease in HCC, decompensation, and bacterial infection incidences. Survival was shorter in HCV patients (4-year cumI: 91.6% vs. 97.2%; P = 0.0002). Death (n = 102; missing data: 6) was attributed to liver disease in 48 (47%; liver cancer: n = 18; miscellaneous, n = 30) and extrahepatic causes in 48 (47%; bacterial infection: n = 13; extrahepatic cancers: n = 10; cardiovascular events: n = 5; miscellaneous, n = 20)., Conclusion: After 3 years of follow-up, extrahepatic events still explained half of deaths in patients with compensated VC. A strong decrease in complications was linked to virological eradication/control., (© 2015 by the American Association for the Study of Liver Diseases.)

Objective: Preliminary experimental data suggest that selective β1-blockers may improve ex vivo cardiac function in animal sepsis. Currently, the effects of esmolol on in vivo cardiac function and on vascular function are unknown. The present study was designed to examine the effects of the β1-selective blocker esmolol on myocardial and vascular function in peritonitis-induced septic rats and to explore the inflammatory pathways involved in this process., Design: Randomized animal study., Setting: University research laboratory., Subjects: Male Wistar rats., Interventions: Four hours after cecal ligation and puncture, Wistar rats were randomly allocated to the following groups: control, esmolol, norepinephrine (started at 18 hr after the surgery), and esmolol (started at 4 hr after the surgery) + norepinephrine (started at 18 hr after the surgery). Assessment at 18 hours after surgery was focused on cardiac contractility and vascular ex vivo function. Cardiac and vascular protein expressions of nuclear factor κB and endothelial nitric oxide synthase/Akt/inducible nitric oxide synthase pathways were assessed by Western blotting., Measurements and Main Results: When compared with sham-operated animals, cecal ligation and puncture animals developed hypotension, cardiac depression, and vascular hyporesponsiveness to vasopressor treatment. Esmolol infusion increased cardiac contractility and restored mesenteric vasoreactivity. This effect was associated with a decrease in nuclear factor κB activation, an increase in Akt and endothelial nitric oxide synthase phosphorylation, and a decrease in inducible nitric oxide synthase expression both at the cardiac and vessel level. Esmolol infusion was also associated with an up-regulation in α1-vascular adrenoreceptors., Conclusion: Adjunction of selective β1-blockade to standard septic shock management enhances intrinsic cardiac contractility and vascular responsiveness to catecholamines. These protective cardiovascular effects are likely predominantly attributed to the anti-inflammatory effect of esmolol.

Background: Molluscum contagiosum (MC) is caused by a DNA virus of the poxvirus group. It is common in children, and is also found in sexually active adults and HIV-seropositive patients. Cellular immunity is essential to controlling MC virus infection. We report the first observation of a patient with stage IV Sezary syndrome, who presented multiple molluscum contagiosum, spread and surrounded by a pale halo., Case Report: A woman aged 70 presented with aggravation of Sezary syndrome diagnosed in 2009 and treated with topical corticosteroids. The examination showed a generalized pruritic exanthem and multiple flesh-coloured papules from 1 to 3 mm, spread over the entire skin surface and surrounded by a white halo. Histological examination of a lesion showed the presence of infected cells with intracytoplasmic inclusions infected in an acanthotic epidermis, surrounded by a melaninopenic hypomelanosis with a normal melanocyte density. There was no inflammatory character. The diagnosis of multiple molluscum contagiosum was given, the application of clobetasol propionate was suspended and treatment with chlorambucil 4 mg/day and prednisone 0.5 mg/kg/day was started. The evolution of the rash and pruritus was rapidly favourable. After 3 months, the rash and pruritus had regressed. There was no molluscum contagiosum or clear halo., Conclusion: We report the original observation of a patient with stage IV Sezary syndrome, who presented multiple molluscum contagiosum, spread and surrounded by a pale halo, without inflammation, eczema or disappearance of melanocytes. This halo could be due to the secretion of a protein by molluscum contagiosum inhibiting inflammation around this MC. To our knowledge, this phenomenon reported in a patient with severe atopic dermatitis associated with Sezary syndrome has not previously been described., (© 2014 European Academy of Dermatology and Venereology.)