Cost of complex abdominal wall reconstruction with biological prostheses in a French public hospital.

GOAL: Retrospective analysis of bioprosthetic abdominal wall reconstruction in our center with regard to expenses and reimbursement. PATIENTS AND METHODS: This study included all patients undergoing bioprosthetic abdominal wall reconstruction between 2009 and 2015. All costs were considered in determining the hospital expenditures. Next we compared the incoming revenue for each hospital stay based on disease-related groups (DRG) and additional daily hospital fees. RESULTS: Seventy-six patients underwent abdominal wall reconstruction, 67 of whom had economical data that were exploitable. On the average, our center lost €15,233 for every hospital stay associated with bioprosthetic abdominal wall reconstruction. The existing DRG system is not well adapted to provide adequate reimbursement for costs related to complex abdominal wall repairs, especially when post-operative morbidity leads to prolonged hospital stay and increased expenses. CONCLUSION: Abdominal wall repairs with bioprostheses are expensive and are poorly reimbursed in the French Health care system, mainly because they are often associated with complications that increase the costs considerably. In our opinion, it seems necessary that either reimbursement of this type of prosthesis should be higher than the current DRG allows, or that the DRG classification be redefined, or even, that a specific DRG be created for complex abdominal wall reconstruction.

Combined therapy in children and adolescents with classical Hodgkin's lymphoma: A report from the SFCE on MDH-03 national guidelines.

Hodgkin's lymphoma (HL) in children and adolescents is highly curable, but children are at risk of long-term toxicity. The MDH-03 guidelines were established in order to decrease the burden of treatment in good-responder patients, and this report should be considered a step toward further optimization of treatment within large collaborative trials. We report the therapy and long-term outcomes of 417 children and adolescents treated according to the national guidelines, which were applied between 2003 and 2007 in France. The patients were stratified into three groups according to disease extension. Chemotherapy consisted of four cycles of VBVP (vinblastine, bleomycin, VP16, prednisone) in localized stages (G1/95 pts/23%), four cycles of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone, adriamycin, bleomycin, vinblastine) cycles in intermediate stages (G2/184 pts/44%) and three cycles of OPPA (vincristine, procarbazine, prednisone, adriamycin) plus three cycles of COPP in advanced stages (G3/138 pts/33%). Radiation therapy of the involved field was given to 97% of the patients, with the dose limited to 20 Gy in good responders (88%). With a median follow-up of 6.6 years, the 5-year event-free survival (EFS) and overall survival (OS) were 86.7% (83.1-89.7%) and 97% (94.5-98.1%), respectively. EFS and OS for G1, G2, and G3 were 98% and 100%, 81% and 97%, and 87% and 95%, respectively. Low-risk patients treated without alkylating agents and anthracycline had excellent outcomes and a low expected incidence of late effects. Intensification with a third OPPA cycle in high-risk group patients, including stage IV patients, allowed for very good outcomes, without increased toxicity.

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis.

There is currently a major concern regarding the optimal immunosuppression therapy to be administered after hematopoietic stem cell transplantation (HSCT) to reduce both the toxicity of GvHD and the rate of relapse. We report the outcome of high-risk leukemia children transplanted with a new way of managing cyclosporine (CsA)-based GvHD prophylaxis. A total of 110 HSCT in 109 ALL or AML children who received CsA without mycophenolate or methotrexate in matched related as well as in matched or mismatched unrelated stem cell transplantation were included. CsA dosage regimens were individualized to obtain specific trough blood concentrations values. The incidences of grade I-II and III-IV acute GvHD were 69.1% and 1.8%, respectively, and 8.4% for chronic GvHD. GvHD was neither more frequent nor severe in unrelated than in related HSCT. GvHD occurred in 87% of patients with a mean CsA trough concentration ⩽120 ng/mL versus 43% with concentration >120 ng/mL (P<0.0001). Five-year disease-free survival (DFS) and overall survival were 78% and 83.6%, respectively. DFS was 76.9% for ALL and 80.4% for AML patients. There was no difference in DFS between matched siblings and matched unrelated or mismatched unrelated HSCT. DFS in patients with minimal residual disease (MRD) ⩾10(-3) and in those with MRD <10(-3) before SCT was comparable. Our results indicate that a GvHD prophylaxis regimen based on CsA without mycophenolate or methotrexate is safe and effective whatever the donor compatibility is. These results suggest that GvL effect may be enhanced by this strategy of GvHD prophylaxis.

High methotrexate exposure and toxicity in children with t(9;22) positive acute lymphoblastic leukaemia treated with imatinib.

WHAT IS KNOWN AND OBJECTIVE: Although there is one report on the possible reduced clearance of methotrexate in an adult patient when given concomitantly with imatinib, there is little information on the possible pharmacokinetic interaction. We report on three cases of delayed elimination of methotrexate in children with chromosome Philadelphia-positive acute lymphoblastic leukaemia treated concomitantly with imatinib. CASE SUMMARY: Three patients, aged 9-17 years, presented with high methotrexate blood levels following co-administration of imatinib and high-dose methotrexate. Two patients presented with clinical symptoms (nausea, epigastric pain and mucositis, acute renal failure, liver cytolysis). One patient required extra supplementary folinic acid doses than used in the standard protocol and one child required the use of carboxypeptidase-G2. WHAT IS NEW AND CONCLUSION: There is an apparent pharmacokinetic interaction between imatinib and methotrexate in children. Several mechanisms could explain this interaction, including competition for BCRP or ABCB transporters. Temporary withdrawal of imatinib may be necessary for preventing severe methotrexate-related adverse events.

[Lacidipine efficacy and safety for high blood pressure treatment in pediatric oncohematology]. / Efficacité et tolérance de la lacidipine dans le traitement de l'hypertension artérielle en onco-hématologie pédiatrique.

In adults, lacidipine seems to have no CYP3A4-inhibiting action. This particular characteristic makes it advantageous when combined with drugs metabolized by CYP3A4, such as cyclosporine. Until now, no data on the efficacy or safety of this calcium antagonist have been available in children. Thirty-nine hypertensive children (age: 0.13-14 years) receiving lacidipine in oncohematology for a mean of 75 days were included in this retrospective study. The causes of high blood pressure were renal tumor (n=7), catecholamine-secreting tumor (n=4), corticoid treatment (n=5), and cyclosporine treatment (n=23). An initial dosage of 0.05 mg/kg/day was sufficient for 41% of the patients. The remaining patients needed to increase the dosage, by steps of 0.03 mg/kg/day, until reaching an average effective dosage of 0.1 mg/kg/day. Lacidipine significantly decreased blood pressure by 30 (±14) mmHg for systolic blood pressure and by 26 (±13) mmHg for diastolic blood pressure. A medication plan with twice-daily administration was not significantly more effective than a single administration per day. Lacidipine was well tolerated, and no toxicity-related withdrawal of treatment occurred. For 22 patients treated with both cyclosporine and lacidipine, renal function was not disturbed over time, suggesting its preservation by lacidipine. No significant increase in cyclosporine blood concentration was detected. Lacidipine seems to be an effective calcium antagonist in pediatric oncohematology, is well tolerated, has a kidney-protector effect and no drug interaction when combined with cyclosporine.

Nearest-neighbor based wavelet entropy rate measures for intrapartum fetal heart rate variability.

The interpretation and analysis of intrapartum fetal heart rate (FHR), enabling early detection of fetal acidosis, remains a challenging signal processing task. The ability of entropy rate measures, amongst other tools, to characterize temporal dynamics of FHR variability and to discriminate non-healthy fetuses has already been massively investigated. The present contribution aims first at illustrating that a k-nearest neighbor procedure yields estimates for entropy rates that are robust and well-suited to FHR variability (compared to the more commonly used correlation-integral algorithm). Second, it investigates how entropy rates measured on multiresolution wavelet and approximation coefficients permit to improve classification performance. To that end, a supervised learning procedure is used, that selects the time scales at which entropy rates contribute to discrimination. Significant conclusions are obtained from a high quality scalp electrode database of nearly two thousands subjects collected in a French public university hospital.

The novel arsenical Darinaparsin circumvents BRG1-dependent, HO-1-mediated cytoprotection in leukemic cells.

Darinaparsin (Dar) is a more potent cytotoxic arsenical than arsenic trioxide (ATO). We hypothesized that the increased cytotoxicity of Dar may be because of a decreased cytoprotective response. We observed that, unlike ATO, Dar does not induce heme oxygenase-1 (HO-1), even though it induces expression of other nuclear factor (erythroid-derived 2)-like 2 (NRF2)-dependent detoxifying enzymes to a greater extent than ATO, in both cancer cell lines and patient-derived leukemic cells. This strengthens the emerging evidence, showing that response to reactive oxygen species (ROS) is stimuli specific. Dar treatment prevents recruitment of the transcriptional coregulator Brahma-related gene 1 (BRG1) to the HMOX1 promoter, which is required for HMOX1 expression. The inability of Dar to induce HO-1 correlates with arrest in G2/M cell cycle phase and BRG1 phosphorylation. Inhibition of HO-1 increases the toxicity of ATO, but has no effect on Dar-induced apoptosis. Accordingly, the lack of HO-1 induction is involved in Dar's enhanced antileukemic properties. Our data highlight cytoprotective responses mediated by HO-1 and BRG1 as a novel target for enhancing the therapeutic range of arsenicals.

[Impact of the angles and the age of the thrombus on efficacity of thromboaspiration device. A bench study]. / Impact du diamètre et de l'âge du thrombus sur la thromboaspiration. Étude expérimentale.

INTRODUCTION: Coronary thrombectomy is usually used to treat acute coronary syndrome. Many studies evaluated its benefit in this context however, it is still unknown if coronary characteristics are predictive of success or failure. The aim of our laboratory bench study was to evaluate the impact of angiographic characteristics on the thromboaspiration efficiency. METHODS: Glass tubes of 150 mm in the length were used, with five diameters: 2; 2.6; 3; 3.6 and 4 mm; and for each diameter, three angulations: no angulation; 90° and 120°. Blood sample were taken from healthy subject and thrombi of 3 and 6 hours old were performed, with a constant volume for each test. Thromboaspirations were performed with an Export(®) catheter (Medtronic). The primary endpoint was total thrombectomy. A total of 240 thromboaspirations were performed. RESULTS: A total thrombectomy was obtained for 71.2% of the tests. It was achieved more frequently with the smaller diameter, respectively: 100% for 2 mm, 81.3% for 2.6 mm, 89.6% for 3 mm vs 54.2% for 3.6 mm and 31.3% for 4 mm (P<0.001). No differences were observed between the 2 thrombi ages (73.3% for the 3 hours old thrombi and 69.2% for the 6 hours old thrombi, P = 0.476), nor between the three tube's angulations (77.5% for no angle, 66.3% for 90° and 70.0% for 120°, P = 0.278). RESULTS AND CONCLUSION: This study shows an impact of the coronary diameters on the rate of thromboaspiration success with an Export(®) catheter. Beyond 3 mm of diameter, the rate of success is divided by 2: for diameters less or equal to 3 mm, 90.3% of success vs 42.7% for diameters greater than 3 mm (P<0.001). There is no difference of efficiency between the 3 and 6 hours old thrombi, neither between the tube's angulations. However, this is a preliminary and further works are needed to clarify how to optimize the aspiration and the impact of other catheters.

The euHCVdb suite of in silico tools for investigating the structural impact of mutations in hepatitis C virus proteins.

Hepatitis C is a viral infection of the liver that results in acute hepatitis and chronic liver disease, including cirrhosis and liver cancer. An estimated 170 million persons are chronically infected worldwide. The Hepatitis C virus is the pathogen agent responsible for hepatitis C. HCV is an enveloped RNA-positive virus of the flaviviridae family. The HCV genome shows remarkable sequence variability. This variability leads to the classification of HCV into 6 genotypes, numerous subtypes and HCV exists in each infected patient as quasi-species. The genotype may be linked to the severity of the disease and to the efficiency of the combination treatment with interferon and ribavirin. To date, no vaccine to prevent or cure HCV exists. Numerous HCV specific inhibitors have been designed and some are currently under clinical trials. However, resistances of HCV against these inhibitors have been identified. We developed the European Hepatitis C Virus Database (euHCVdb, http://euhcvdb.ibcp.fr/), a collection of functionally and structurally (3D-models) annotated HCV sequences integrated with sequence and structure analysis tools. We show below how the euHCVdb database is a useful in silico tool that can help drug design, combating resistance to drug treatment and understand structural biology of the HCV.

Experimental evidence of non-Gaussian fluctuations near a critical point.

The orientation fluctuations of the director of a liquid crystal are measured, by a sensitive polarization interferometer, close to the Fréedericksz transition, which is a second-order transition driven by an electric field. We show that, near the critical value of the field, the spatially averaged order parameter has a generalized Gumbel distribution instead of a Gaussian one. The latter is recovered away from the critical point. The relevance of slow modes is pointed out. The parameter of the generalized Gumbel distribution is related to the effective number of degrees of freedom.

Ligand-escape pathways from the ligand-binding domain of PPARgamma receptor as probed by molecular dynamics simulations.

Conformational rearrangements of peroxysome proliferator activated receptor (PPARgamma) ligand-binding domain (LBD) that accompany the release and binding of ligands are not well understood. To determine the major events associated with the escape of the partial agonist GW0072, molecular dynamic (MD) simulations were performed using two different methods: reversed targeted molecular dynamics (TMD(-1)) and time-dependent distance restraints (TDR) using as restraints either the root mean square deviation from a reference structure (TMD(-1)) or the distance between the geometrical centers of the binding pocket and of the ligand (TDR). Both methods do not assume any a priori route for ligand extraction. To avoid artifacts, different initial simulation conditions were used and particular attention was paid for giving time to the protein to relax during the extraction process by running 10-12 ns simulations within explicit water. Two distinct exit gates A and B were found, independently of initial conditions and method. During the exit process no interaction between GW0072 and the transactivation AF-2 helix was observed. Our results suggest that the ligand uses the intrinsic flexibility of the protein to move within the receptor. Paths A and B are very similar to those found for other nuclear receptors, suggesting that these routes are a common characteristics of nuclear receptors that are used by different kinds of ligands. Finally, the knowledge of entry/exit pathways of a receptor should be very useful in discriminating between different ligands that could have been favorably docked in the binding pocket by introducing docking along these pathways into computational drug design protocols.

Entropy production and time asymmetry in nonequilibrium fluctuations.

The time-reversal symmetry of nonequilibrium fluctuations is experimentally investigated in two out-of-equilibrium systems: namely, a Brownian particle in a trap moving at constant speed and an electric circuit with an imposed mean current. The dynamical randomness of their nonequilibrium fluctuations is characterized in terms of the standard and time-reversed entropies per unit time of dynamical systems theory. We present experimental results showing that their difference equals the thermodynamic entropy production in units of Boltzmann's constant.

Work fluctuation theorems for harmonic oscillators.

The work fluctuations of an oscillator in contact with a thermostat and driven out of equilibrium by an external force are studied experimentally and theoretically within the context of fluctuation theorems. The oscillator dynamics is modeled by a second order Langevin equation. Both the transient and stationary state fluctuation theorems hold and the finite time corrections are very different from those of a first order Langevin equation. The periodic forcing of the oscillator is also studied; it presents new and unexpected short time convergences. Analytical expressions are given in all cases.

MAGOS: multiple alignment and modelling server.

UNLABELLED: MAGOS is a web server allowing automated protein modelling coupled to the creation of a hierarchical and annotated multiple alignment of complete sequences. MAGOS is designed for an interactive approach of structural information within the framework of the evolutionary relevance of mined and predicted sequence information. AVAILABILITY: The web server is freely available at http://pig-pbil.ibcp.fr/magos.

[Disposable vs reusable laryngeal mask airway: a cost-minimization analysis]. / Masques laryngés à usage unique vs réutilisable : une étude de minimisation de coûts.

JUSTIFICATION: According to French regulations concerning the risk of Creutzfeldt-Jakob disease transmission, traceability procedures of all sterile medical devices which need to be reused are mandatory. Despite sterilization processes, the reusable laryngeal mask airway (LMA) prion disease transmission remains possible. As a result, the disposable LMA has been introduced. OBJECTIVE: Assuming clinical equivalence was achieved, the cost of disposable vs reusable LMA was studied in a university hospital. STUDY DESIGN: A Cost-minimization analysis of disposable vs reusable laryngeal mask airway was realised. METHODS: Disposable LMA cost was calculated as the sum of product cost and elimination cost. Reusable LMA were autoclaved after hospital purchasing in two separate sterilizing processing units of the same hospital. Reusable LMA cost was determined combining materiel and labor costs. RESULTS: The reusable LMA cost depended on the sterilizing processing unit concerned and varied between 9.59 Euros and 9.69 vs 8.38 Euros for the single-use LMA. CONCLUSION: With the cost savings made possible by use of disposable LMA in both labor and consumables, this practice should be considered.

Nonequilibrium fluctuations in a resistor.

In small systems where relevant energies are comparable to thermal agitation, fluctuations are of the order of average values. In systems in thermodynamical equilibrium, the variance of these fluctuations can be related to the dissipation constant in the system, exploiting the fluctuation-dissipation theorem. In nonequilibrium steady systems, fluctuations theorems (FT) additionally describe symmetry properties of the probability density functions (PDFs) of the fluctuations of injected and dissipated energies. We experimentally probe a model system: an electrical dipole driven out of equilibrium by a small constant current I, and show that FT are experimentally accessible and valid. Furthermore, we stress that FT can be used to measure the dissipated power P = R I2 in the system by just studying the PDFs' symmetries.

Nonlinear Transition to a Global Mode for Traveling-Wave Instability in a Finite box.

Using hydrothermal waves in a long narrow channel as an ideal supercritical nonlinear wave system, we study the critical behavior at onset for a finite cell with poorly reflecting boundaries. We observe a spatially nonuniform global eigenmode localized near the end of the cell and associated with a wave front invading the cell. The onset of this mode-corresponding to the absolute instability transition-is shifted above the value corresponding to convective instability, measured in an annular channel with periodic boundary conditions. Experimental critical exponents are discussed in the framework of existing theoretical descriptions and quantitative comparison with the complex Ginzburg-Landau model is attempted.