Trust in MDE Components: the DOMINO Experiment

International audienceA large number of modeling activities can be automatic or computer assisted. This automation ensures a more rapid and robust software development. However, engineers must ensure that the models have the properties required for the application. In order to tend towards this requirement, the DOMINO project (DOMaINs and methodological prOcess) proposes to use the socalled trustworthy Model-Driven Engineering (MDE) components and aims to provide a methodology for the validation and qualification of such components

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Letter to the Editor gomery-Asberg Depression Rating Scale, the Brief Psychiatric Rating Scale and the SLE Disease Activity Index (SLEDAI) During the course of the study, 5 patients were admitted with SLE and catatonia. These 5 patients, all female, met the inclusion criteria. All of them (or their families on their behalf) agreed to PE. Three of the patients were teenagers who had been hospitalized for several weeks without any improvement, receiving a treatment regimen combining psychotropic medications, corticoids and immunosuppressors. Three patients exhibited life-threatening complications: 2 were severely malnourished and the third had a pulmonary infection and skin lesions due to immobility. One patient showed a severe renal involvement. The last patient was included because of resistance after 3 weeks of treatment. The mean number of PE that patients received was 7.2 (range: 3-11). We found a significant improvement for all clinical variables. Mean CRS and SLEDAI scores before PE were 15 (range: 11-16) and 18.8 (range: 12-22), respectively. Both scores dramatically decreased after PE to a mean of 1.2 (range: 0-6) and 3.4 (range: 0-12), respectively (Wilcoxon paired test: Z = -2.032, p = 0.042). In particular, 3 patients very much improved on the Clinical Global Impression Scale after the first week of PE. The biological variables paralleled clinical improvement. At follow-up, 4 patients were still doing well; in particular, all the teenagers were able to return to school with minimal treatment for SLE. The last patient (case 4) died in her local hospital as a consequence of a septic shock 3 months after discharge. To date, only a few case studies have reported the possible use of PE in neuropsychiatric SLE The consecutive patients were recruited at Pitié-Salpêtrière Hospital from 2001 to 2004. For inclusion, the diagnosis of SLE was based on the revised criteria of the American College of Rheumatolog

Cryofibrinogen in patients with hepatitis C virus infection.

International audienceBACKGROUND: Mixed cryoglobulin is usually associated with hepatitis C virus (HCV) infection and might cause systemic vasculitis. The presence and impact of cryofibrinogen, another cryoprotein, in the serum of HCV-infected patients have not yet been evaluated. The objective was to study the prevalence and the clinical and therapeutic impacts of cryofibrinogen in HCV-infected patients. METHODS: A total of 143 consecutive HCV-infected (RNA+) patients (including 57 patients with HCV-related vasculitis) were screened for cryofibrinogen and cryoglobulin (positive if >0.05 g/L). The main characteristics and outcome were evaluated according to the cryofibrinogen/cryoglobulin status at baseline. RESULTS: At baseline, 53 of 143 patients (37%) were cryofibrinogen positive, most of whom (47/53 [89%]) were also cryoglobulin positive. Only 37 of 90 cryofibrinogen-negative patients (41%) were cryoglobulin positive (P<.001). In patients with HCV-related vasculitis, 28 of 57 (49%) were cryofibrinogen positive compared with 25 of 86 patients (29%) without vasculitis (P=.03). There was a higher rate of renal involvement in cryofibrinogen-negative/cryoglobulin-positive patients than in cryofibrinogen-positive/cryoglobulin-positive patients (10/25 [40%] vs 3/27 [11%], respectively; P=.02). After a mean follow-up of 32.6 months, among patients who were cryofibrinogen positive at baseline, 12 of 26 (46%) of those who received an HCV treatment were cryofibrinogen negative at the end of follow-up compared with 4 of 16 (25%) of those who did not receive antiviral drugs. Most patients who became cryofibrinogen negative also became cryoglobulin negative (93%). CONCLUSION: Cryoproteins, including cryoglobulin and cryofibrinogen, are frequently found in the serum of HCV-infected patients. In such patients, a positive cryofibrinogen status is closely related to the presence of cryoglobulin at baseline and after antiviral therapy

Whole blood versus serum hydroxychloroquine levels for drug monitoring of patients with systemic lupus erythematosus : prehole blood versus serum hydroxychloroquine levels for drug monitoring of patients with systemic lupus erythematosus : preliminary results of a pharmacological study.

International audienceBackground: In order to assess the pharmacokinetic/pharmacodynamic relationship of hydroxychloroquine (HCQ) in patients with systemic lupus erythematosus (SLE), HCQ levels have been measured in whole blood as well as in serum but both methods have never been compared. In addition, cut offs for non-adherence (classically 200ng/ml but also 100 ng/mL) have been established only in whole blood. Objectives: The aims of this study were (1) to compare these two pharmacological approaches, and (2) since it would be very interesting to retrospectively assess severe non-adherence in clinical trials or in large cohort of patients in which only serum samples are usually available, to determine if serum HCQ level cut offs could be established for identification of severe non-adherent patients. Methods: The HCQ and desethylchloroquine (DCQ) levels were measured in serum and whole blood from 573 SLE patients. The risk factors for active SLE (SLEDAI score >4) were identified using multiple logistic regression. HCQ serum level was also measured in 51 non-adherent patients (whole blood HCQ level <200 ng/mL). Results: The mean HCQ and DCQ levels were 916 ± 449 and 116 ± 55 ng/mL in whole blood, respectively; and 469 ± 223 and 63 ± 31 ng/mL in serum, respectively. The mean ratio of serum/whole blood level for HCQ and DCQ were 0.53 ± 0.15 and 0.57 ± 0.21, respectively. A strong positive correlation was found between serum and whole blood levels of HCQ (rho=0.837 [CI95% 0.810-0.860], p<0.0001), and DCQ (rho=0.771 [CI95% 0.736-0.802], p<0.0001). In the multivariate analysis, only corticosteroids (p=0.044), immunosuppressant (p=0.027), HCQ whole blood level (p=0.023) and hemoglobin (p=0.009) were identified as an independent risk factor of active SLE but serum HCQ level was not. Given the mean ratio of serum/whole blood level for HCQ was 0.53, we extrapolated that serum HCQ level cut offs of 106 and 53 ng/mL would correspond to the previously used cut-off of 200 and 100 ng/mL of HCQ in whole blood. Using HCQ serum level cut off of 106 ng/mL, 43 of 51 patients (84%) with blood HCQ levels <200 ng/mL would also have been considered as non-adherent. The positive and negative predictive value of HCQ serum level < 106 ng/ml to detect non-adherence were 96.6% and 63.6%, respectively. Of these 51 patients, 25 patients (49%) exhibited HCQ whole blood concentration below 100 ng/mL. Using HCQ serum level cut off of 53 ng/mL, 23 of 25 patients (92%) with HCQ whole blood level<100 ng/mL, would also have been considered as non-adherent. The positive and negative predictive value of HCQ serum level < 53 ng/ml to detect non-adherence were 82.1% and 90.9%. Conclusion: Our data support the use of whole blood rather than serum as the matrix for drug monitoring of HCQ levels in SLE patients. However, when whole blood is not available, our results support the use of HCQ serum level to assess non-adherence with a cut off of 106 ng/mL corresponding to 200 ng/ml in whole bloo

Study of anti-Müllerian hormone and its relation to the subsequent probability of pregnancy in 112 patients with systemic lupus erythematosus, exposed or not to cyclophosphamide.

International audienceCONTEXT: Cyclophosphamide is used for renal and major extrarenal involvement in systemic lupus erythematosus (SLE) and is associated with a risk of premature ovarian failure. There are no data available about the relation between anti-Müllerian hormone (AMH) serum levels and the probability of subsequent pregnancy in SLE patients. OBJECTIVE: We analyzed AMH levels and the probability of pregnancy in SLE women exposed to cyclophosphamide. DESIGN AND SETTING: We conducted a matched cohort study in referral centers for SLE. PATIENTS: Fifty-six cyclophosphamide-exposed SLE women younger than 40 years of age and 56 control SLE women matched for age within 6 months participated in the study. MAIN OUTCOME MEASURES: AMH was measured in samples from the PLUS study (ClinicalTrials.gov no. NCT00413361). All patients were interviewed in May 2012 regarding their obstetric status. RESULTS: The mean age ± SD of the 112 patients was 31.6 ± 5.8 years. The mean AMH level was low (1.21 ± 1.01 ng/mL) and was significantly lower in patients exposed to cyclophosphamide (P = .03) and in patients older than 30 years (P = .02). During a median follow-up (interval between sampling and the interview) period of 4.2 (range, 2.5-4.8) years, 38 patients sought to become pregnant, and 32 (84.2%) succeeded. In the univariate analysis, the risk of failure was associated with cumulative cyclophosphamide dose (P = .007) and older age (P = .02), but not with AMH. CONCLUSION: We confirmed that AMH levels are low in SLE patients and decrease significantly with age and cyclophosphamide exposure. Nonetheless, the risk of failure to conceive was low and was predicted by cyclophosphamide exposure and age, but not by AMH levels

Hydroxychloroquine levels in patients with systemic lupus erythematosus: whole blood is preferable but serum levels also detect non-adherence

International audienceBackground: Hydroxychloroquine (HCQ) levels can be measured in both serum and whole blood. No cut-off point for non-adherence has been established in serum nor have these methods ever been compared. The aims of this study were to compare these two approaches and determine if serum HCQ cut-off points can be established to identify non-adherent patients.Methods: HCQ levels were measured in serum and whole blood from 573 patients with systemic lupus erythematosus (SLE). The risk factors for active SLE (SLEDAI score > 4) were identified by multiple logistic regression. Serum HCQ levels were measured in 68 additional patients known to be non-adherent, i.e. with whole-blood HCQ < 200 ng/mL.Results: The mean (± SD) HCQ levels were 469 ± 223 ng/mL in serum and 916 ± 449 ng/mL in whole blood. The mean ratio of serum/whole-blood HCQ levels was 0.53 ± 0.15. In the multivariate analysis, low whole-blood HCQ levels (P = 0.023), but not serum HCQ levels, were independently associated with active SLE. From the mean serum/whole-blood level ratio, a serum HCQ level of 106 ng/mL was extrapolated as the corresponding cut-off to identify non-adherent patients with a sensitivity of 0.87 (95% CI 0.76-0.94) and specificity of 0.89 (95% CI 0.72-0.98). All serum HCQ levels of patients with whole-blood HCQ below the detectable level (< 20 ng/mL) were also undetectable (< 20 ng/mL).Conclusions: These data suggest that whole blood is better than serum for assessing the pharmacokinetic/pharmacodynamic relation of HCQ. Our results support the use of serum HCQ levels to assess non-adherence when whole blood is unavailable