Valenciennes, France
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Annane D.,University of Versailles | Timsit J.-F.,Grenoble University Hospital Center | Megarbane B.,Service de Reanimation Medicale et Toxicologique | Martin C.,Service dAnesthesie Reanimation | And 18 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Rationale: A decade after drotrecogin alfa (activated) (DAA) was released on the market worldwide, its benefit-to-risk ratio remains a matter of debate. Objectives: The current investigator-led trial was designed to evaluate the efficacy and safety of DAA, in combination with low-dose steroids, in adults with persistent septic shock. Methods: This was a multicenter (24 intensive care units), placebo-controlled, double-blind, 2 x 2 factorial design trial in which adults with persistent septic shock and no contraindication to DAA were randomly assigned to DAA alone (24 mg/kg/h for 96 h), hydrocortisone and fludrocortisone alone, their respective combinations, or their respective placebos. Primary outcome was mortality rate on Day 90. Measurements and Main Results: On October 25, 2011, the trial was suspended after the withdrawal from the market of DAA. The Scientific Committee decided to continue the trial according to a two parallel group design comparing low-dose steroids with their placebos and to analyze the effects of DAA on patients included before trial suspension. At the time trial was suspended, 411 patients had been recruited, 208 had received DAA, and 203 had received its placebo. There was no significant interaction between DAA and low-dose steroids (P = 0.47). On Day 90, there were 99 deaths (47.6%) among the 208 patients receiving DAA and 94 deaths (46.3%) among the 203 patients receiving placebo (P = 0.79). There was no evidence of a difference between DAA and its placebo for any secondary outcomes or serious adverse events. Conclusions: In adults with established and severe septic shock, DAA showed no evidence of benefit or harm. Copyright © 2013 by the American Thoracic Society.

Lemaire A.,Center Hospitalier Of Valenciennes | Plancon M.,Center Hospitalier Of Valenciennes | Bubrovszky M.,Service de Psychiatrie Adulte
Psycho-Oncologie | Year: 2014

Ketamine, a molecule mainly used as an analgesic in supportive oncology in particular in palliative care, turns out to be an excellent fast-acting antidepressant. By acting as an NMDA receptor antagonist, its mechanism of action is complementary to classical and long-acting antidepressants like selective serotonin reuptake inhibitors. These properties offer new perspectives in fast-controlling depression within the development of early palliative care in oncology. © 2014 Springer-Verlag.

Guillevin L.,University of Paris Descartes | Pagnoux C.,University of Paris Descartes | Pagnoux C.,Mount Sinai Hospital | Karras A.,University of Paris Descartes | And 22 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: The combination of cyclophosphamide and glucocorticoids leads to remission in most patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitides. However, even when patients receive maintenance treatment with azathioprine or methotrexate, the relapse rate remains high. Rituximab may help to maintain remission. METHODS: Patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide-glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. The primary end point at month 28 was the rate of major relapse (the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score >0, and involvement of one or more major organs, disease-related life-threatening events, or both). RESULTS: The 115 enrolled patients (87 with granulomatosis with polyangiitis, 23 with microscopic polyangiitis, and 5 with renal-limited ANCA-associated vasculitis) received azathioprine (58 patients) or rituximab (57 patients). At month 28, major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%) (hazard ratio for relapse, 6.61; 95% confidence interval, 1.56 to 27.96; P = 0.002). The frequencies of severe adverse events were similar in the two groups. Twenty-five patients in each group (P = 0.92) had severe adverse events; there were 44 events in the azathioprine group and 45 in the rituximab group. Eight patients in the azathioprine group and 11 in the rituximab group had severe infections, and cancer developed in 2 patients in the azathioprine group and 1 in the rituximab group. Two patients in the azathioprine group died (1 from sepsis and 1 from pancreatic cancer). CONCLUSIONS: More patients with ANCA-associated vasculitides had sustained remission at month 28 with rituximab than with azathioprine. Copyright © 2014 Massachusetts Medical Society.

PubMed | Center Hospitalier Of Valenciennes, IFR114, French Institute of Health and Medical Research and French Institute for Research in Computer Science and Automation
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

Whole-genome sequencing has revealed MYD88 L265P and CXCR4 mutations (CXCR4(mut)) as the most prevalent somatic mutations in Waldenstrm macroglobulinemia. CXCR4 mutation has proved to be of critical importance in Waldenstrm macroglobulinemia, in part due to its role as a mechanism of resistance to several agents. We have therefore sought to unravel the different aspects of CXCR4 mutations in Waldenstrm macroglobulinemia.We have scanned the two coding exons of CXCR4 in Waldenstrm macroglobulinemia using deep next-generation sequencing and Sanger sequencing in 98 patients with Waldenstrm macroglobulinemia and correlated with SNP array landscape and mutational spectrum of eight candidate genes involved in TLR, RAS, and BCR pathway in an integrative study.We found all mutations to be heterozygous, somatic, and located in the C-terminal domain of CXCR4 in 25% of the Waldenstrm macroglobulinemia. CXCR4 mutations led to a truncated receptor protein associated with a higher expression of CXCR4. CXCR4 mutations pertain to the same clone as to MYD88 L265P mutations but were mutually exclusive to CD79A/CD79B mutations (BCR pathway). We identified a genomic signature in CXCR4(mut) Waldenstrm macroglobulinemia traducing a more complex genome. CXCR4 mutations were also associated with gain of chromosome 4, gain of Xq, and deletion 6q.Our study panned out new CXCR4 mutations in Waldenstrm macroglobulinemia and identified a specific signature associated to CXCR4(mut), characterized with complex genomic aberrations among MYD88L265P Waldenstrm macroglobulinemia. Our results suggest the existence of various genomic subgroups in Waldenstrm macroglobulinemia.

Metzler K.D.,Max Planck Institute for Infection Biology | Fuchs T.A.,Max Planck Institute for Infection Biology | Fuchs T.A.,Harvard University | Nauseef W.M.,University of Iowa | And 6 more authors.
Blood | Year: 2011

The granule enzyme myeloperoxidase (MPO) plays an important role in neutrophil antimicrobial responses. However, the severity of immunodeficiency in patients carrying mutations in MPO is variable. Serious microbial infections, especially with Candida species, have been observed in a subset of completely MPOdeficient patients. Here we show that neutrophils from donors who are completely deficient in MPO fail to form neutrophil extracellular traps (NETs), indicating that MPO is required for NET formation. In contrast, neutrophils from partially MPOdeficient donors make NETs, and pharmacological inhibition of MPO only delays and reduces NET formation. Extracellular products of MPO do not rescue NET formation, suggesting that MPO acts cellautonomously. Finally, NET-dependent inhibition of Candida albicans growth is compromised in MPO-deficient neutrophils. The inability to form NETs may contribute in part to the host defense defects observed in completely MPO-deficient individuals. © 2011 by The American Society of Hematology.

Ribi C.,University of Geneva | Cohen P.,University of Paris Descartes | Pagnoux C.,University of Paris Descartes | Mahr A.,University of Paris Descartes | And 8 more authors.
Arthritis and Rheumatism | Year: 2010

Objective.To assess the efficacy of systemic corticosteroids alone as first-line treatment of polyarteritis nodosa (PAN) and microscopic polyangiitis (MPA) without poor-prognosis factors as defined by the Five-Factors Score (FFS), and to compare the efficacy and safety of azathioprine versus pulse cyclophosphamide as adjunctive immunosuppressive therapy for patients experiencing treatment failure or relapse. Methods. This prospective, multicenter, therapeutic trial included 124 patients with newly diagnosed PAN or MPA (FFS of 0) treated with corticosteroids alone. At the time of treatment failure or disease relapse, patients were randomized to receive 6 months of therapy with oral azathioprine or 6 pulses of cyclophosphamide. Analyses was performed according to an intent-to-treat strategy. Results. The mean ± SD followup period was 62 ± 33 months. Treatment with corticosteroids alone induced remission in 98 patients; 50 (40%) of these patients had sustained disease remission, 46 (37%) experienced a relapse, and 2 became corticosteroid dependent (daily prednisone dose ≥20 mg). In 26 patients (21%), treatment with corticosteroids alone failed, and 49 patients (40%) required additional immunosuppression. Among the 39 patients randomized, 13 of 19 achieved remission with cyclophosphamide pulses, and 14 of 20 achieved remission with azathioprine. Among all patients, the 1-year and 5-year survival rates were 99% and 92%, respectively. Six deaths occurred in the cyclophosphamide-treated group compared with 2 deaths in the azathioprine-treated group. Disease-free survival was significantly lower for patients with MPA than for those with PAN (P = 0.046). Conclusion. For patients with PAN or MPA with an FFS of 0, overall 5-year survival was good, but first-line corticosteroid treatment was able to achieve and maintain remission in only about half of the patients, and 40% of the patients required additional immunosuppressive therapy. Azathioprine or pulse cyclophosphamide was fairly effective for treating corticosteroid- resistant disease or major relapses. © 2010, American College of Rheumatology.

Berlin I.,French Institute of Health and Medical Research | Jacob N.,Hopital Pitie Salpetriere | Coudert M.,Unite de Recherche Clinique | Perriot J.,Dispensaire Emile Roux | And 2 more authors.
Addiction | Year: 2011

Aims To assess the efficacy of nicotine replacement therapies (NRT) when the daily dose was adapted according to saliva cotinine concentrations. Design Randomized, multi-centre, single-blind, controlled trial. Setting Twenty-one smoking cessation clinics in France. Participants A total of 310 smokers with medical comorbidities, motivated to quit, smoking ≥10 cigarettes/day, for whom smoking cessation was mandatory. NRT was administered for 3 months. The standard care group received nicotine patches with monthly dose decreases; buccal absorption NRT could be co-administered at the discretion of the investigator. In the dose adaptation group, the aim was a 100±5% nicotine substitution with respect to smoking state based on the determination of saliva cotinine concentrations. NRT daily doses were prescribed according to the previous week's saliva cotinine concentrations in the dose adaptation group; saliva cotinine concentrations were not provided in the standard care group. Measurements Prolonged abstinence rate (weeks 9-12, main outcome measure), point-prevalence and continuous abstinence rate, saliva cotinine concentration, NRT daily dose, craving for cigarettes. Findings The median daily prescribed NRT dose was 30 and 31mg/day in the first study week and 17.25 and 35.5mg/day during weeks 9-12 in the standard care group and dose adaptation group, respectively. Saliva cotinine remained stable in the dose adaptation group and decreased in the standard care group (P<0.01) by weeks 9-12. The cotinine substitution rate was significantly lower in the standard care group than in the dose adaptation group. Despite differences in NRT doses and cotinine substitution rates, prolonged (standard care group: 26.4%, dose adaptation group: 30.3%), continuous (standard care group: 8%, dose adaptation group: 12%) and point-prevalence abstinence rates were similar. Conclusions In smokers with medical comorbidities and highly motivated to quit, adaptation of the nicotine replacement therapy daily dose according to saliva cotinine does not appear to be substantially superior to standard nicotine replacement therapy use. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.

Nahon S.,Center Hospitalier Intercommunal le Raincy Montfermeil | Hagege H.,Center Hospitalier Intercommunal Of Creteil | Latrive J.P.,Center Hospitalier Of Compiegne | Rosa I.,Center Hospitalier Intercommunal Of Creteil | And 9 more authors.
Endoscopy | Year: 2012

Background and study aims: The mortality rate from upper gastrointestinal bleeding (UGIB) remains high, at 5%-10%. The aim of the current study was to describe the epidemiological characteristics, prognostic factors, and actual practice in a cohort of patients with UGIB admitted to French general hospitals. Methods: From March 2005 to February 2006, a prospective multicenter study was conducted at 53 French hospitals. A total of 3298 patients admitted for UGIB were enrolled consecutively. Patient data were collected up to the date of discharge from hospital. Results: Data were available for 2130 men and 1073 women (mean age 63 ± 18 years), one-third of whom were taking drugs that would increase the risk of UGIB. The two main causes of bleeding were peptic ulcers (38%) and esophagogastric varices (EGV) or portal hypertensive gastropathy (24.5%). Mean Rockall score was 5.0 ± 2.3.Endoscopy was performed on 96% of patients (within 24 hours in 79%), and 66% of those with ulcers and 62.5% of the EGV patients underwent hemostatic therapy when indicated. Rebleeding occurred in 9.9% of the patients, and 8.3% died. Independent predictors of rebleeding were: need for transfusion (odds ratio [OR] 19.1; 95% confidence interval [95%CI] 10.1-35.9); hemoglobin<10g/dL (OR: 1.7; 95%CI 1.1-3.3); Rockall score (OR: 1.4 for each 1 point score increase; 95%CI 1.0-1.9), systolic blood pressure <100mmHg (OR: 1.9; 95%CI 1.4-2.5), and signs of recent bleeding (OR: 2.4; 95%CI 1.7-3.5). Independent predictors of mortality were: Rockall score (OR: 2.8; 95%CI 2.0-4.0), co-morbidities (OR: 3.6 for each additional co-morbidity; 95%CI 2.0-6.3), and systolic blood pressure <100mmHg (OR: 2.1; 95%CI 1.8-2.8). Rockall score, blood pressure and co-morbidities were taken as continuous variables meaning that the OR was 1.4 for every point increase, it was the same for blood pressure. Conclusion: UGIB still occurs mainly as a result of peptic ulcers and portal hypertension in France, and causes significant rates of mortality. There is scope for improvement via better prevention (better use of UGIB-facilitating drugs), endoscopic therapy, and management of co-morbidities. © Georg Thieme Verlag KG Stuttgart · New York.

Guery B.,Lille 2 University of Health and Law | Poissy J.,Lille 2 University of Health and Law | El Mansouf L.,Center Hospitalier Of Douai | Sejourne C.,Center Hospitalier Of Douai | And 20 more authors.
The Lancet | Year: 2013

Background Human infection with a novel coronavirus named Middle East Respiratory Syndrome coronavirus (MERS-CoV) was first identified in Saudi Arabia and the Middle East in September, 2012, with 44 laboratory-confirmed cases as of May 23, 2013. We report detailed clinical and virological data for two related cases of MERS-CoV disease, after nosocomial transmission of the virus from one patient to another in a French hospital. Methods Patient 1 visited Dubai in April, 2013; patient 2 lives in France and did not travel abroad. Both patients had underlying immunosuppressive disorders. We tested specimens from the upper (nasopharyngeal swabs) or the lower (bronchoalveolar lavage, sputum) respiratory tract and whole blood, plasma, and serum specimens for MERS-CoV by real-time RT-PCR targeting the upE and Orf1A genes of MERS-CoV. Findings Initial clinical presentation included fever, chills, and myalgia in both patients, and for patient 1, diarrhoea. Respiratory symptoms rapidly became predominant with acute respiratory failure leading to mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Both patients developed acute renal failure. MERS-CoV was detected in lower respiratory tract specimens with high viral load (eg, cycle threshold [Ct] values of 22•9 for upE and 24 for Orf1a for a bronchoalveolar lavage sample from patient 1; Ct values of 22•5 for upE and 23•9 for Orf1a for an induced sputum sample from patient 2), whereas nasopharyngeal specimens were weakly positive or inconclusive. The two patients shared the same room for 3 days. The incubation period was estimated at 9-12 days for the second case. No secondary transmission was documented in hospital staff despite the absence of specific protective measures before the diagnosis of MERS-CoV was suspected. Patient 1 died on May 28, due to refractory multiple organ failure.

Antimicrobial resistance is an increasing problem in the intensive care unit (ICU), and the persistence of colonization with multidrug-resistant bacteria (MRB) may play an important role in the spreading of these bacteria. The duration of colonization with MRB is not well defined, especially after ICU discharge. The knowledge of MRB persistence in hospitalized and readmitted patients may influence prevention measures. The duration of colonization, and its characterization, may depend on several factors: type of MRB, antibiotic treatment, repeated hospitalizations, sensitivity of the microbiological tests used (cultures, polymerase chain reaction [PCR]). Most of the studies were performed in hospitalized patients colonized with MBR and readmitted to the ICU. These studies show the complexity of factors influencing the duration of colonization and show that median time until MRB clearance may increase to several months. Long-term carriages are reported in several studies for different MRB: MRSA (1–4 years), ESBL-producing enterobacteria (3 years), vancomycin-resistant enterococcal (50 weeks), carbapenem-resistant enterobacteria (1 year), multidrug-resistant Acinetobacter baumannii (42 months). Antibiotics play a major role in the emergence of MRB, and are a risk factor for persistent carriage. © 2015, Société de réanimation de langue française (SRLF) and Springer-Verlag France.

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