[Early intervention in bipolar affective disorders: Why, when and how]. / Intervenir précocement dans les stades débutants du trouble bipolaire : pourquoi, quand et comment.

OBJECTIVES: Bipolar disorder (BD) is a chronic and severe psychiatric disease. There are often significant delays prior to diagnosis, and only 30 to 40 % of patients will experience complete remission. Since BD occurs most often at a young age, the disorder can seriously obstruct future socio-professional development and integration. Vulnerability-stress model of BD is considered to be the result of an interaction between vulnerability genes and environmental risk factors, which leads to the onset of the disorder most often in late adolescence or early adulthood. The clinical "staging" model of BD situates the subject in a clinical continuum of varying degrees of severity (at-risk status, first episode, full-blown BD). Given the demonstrated effectiveness of early intervention in the early stages of psychotic disorder, we posit that early intervention for early stages of BD (i.e. at-risk status and first episode mania or hypomania) would reduce the duration of untreated illness and optimize the chances of therapeutic response and recovery. METHODS: We conducted a narrative review of the literature to gather updated data on: (1) features of early stages: risk factors, at-risk symptoms, clinical specificities of the first manic episode; (2) early screening: targeted populations and psychometric tools; (3) early treatment: settings and therapeutic approaches for the early stages of BD. RESULTS: (1) Features of early stages: among genetic risk factors, we highlighted the diagnosis of BD in relatives and affective temperament including as cyclothymic, depressive, anxious and dysphoric. Regarding prenatal environmental risk, we identified peripartum factors such as maternal stress, smoking and viral infections, prematurity and cesarean delivery. Later in the neurodevelopmental course, stressful events and child psychiatric disorders are recognized as increasing the risk of developing BD in adolescence. At-risk symptoms could be classified as "distal" with early but aspecific expressions including anxiety, depression, sleep disturbance, decreased cognitive performance, and more specific "proximal" symptoms which correspond to subsyndromic hypomanic symptoms that increase in intensity as the first episode of BD approaches. Specific clinical expressions have been described to assess the risk of BD in individuals with depression. Irritability, mixed and psychotic features are often observed in the first manic episode. (2) Early screening: some individuals with higher risk need special attention for screening, such as children of people with BD. Indeed, it is shown that children with at least one parent with BD have around 50 % risk of developing BD during adolescence or early adulthood. Groups of individuals presenting other risk factors, experiencing an early stage of psychosis or depressive disorders should also be considered as targeted populations for BD screening. Three questionnaires have been validated to screen for the presence of at-risk symptoms of BD: the Hypomanic Personality Scale, the Child Behavior Checklist-Paediatric Bipolar Disorder, and the General Behavior Inventory. In parallel, ultra-high risk criteria for bipolar affective disorder ("bipolar at-risk") distinguishing three categories of at-risk states for BD have been developed. (3) Early treatment: clinical overlap between first psychotic and manic episode and the various trajectories of the at-risk status have led early intervention services (EIS) for psychosis to reach out for people with an early stage of BD. EIS offers complete biopsychosocial evaluations involving a psychiatric examination, semi-structured interviews, neuropsychological assessments and complementary biological and neuroimaging investigations. Key components of EIS are a youth-friendly approach, specialized and intensive care and client-centered case management model. Pharmaceutical treatments for at-risk individuals are essentially symptomatic, while guidelines recommend the use of a non-antipsychotic mood stabilizer as first-line monotherapy for the first manic or hypomanic episode. Non-pharmacological approaches including psychoeducation, psychotherapy and rehabilitation have proven efficacy and should be considered for both at-risk and first episode of BD. CONCLUSIONS: EIS for psychosis might consider developing and implementing screening and treatment approaches for individuals experiencing an early stage of BD. Several opportunities for progress on early intervention in the early stages of BD can be drawn. Training first-line practitioners to identify at-risk subjects would be relevant to optimize screening of this population. Biomarkers including functional and structural imaging measures of specific cortical regions and inflammation proteins including IL-6 rates constitute promising leads for predicting the risk of transition to full-blown BD. From a therapeutic perspective, the use of neuroprotective agents such as folic acid has shown particularly encouraging results in delaying the emergence of BD. Large-scale studies and long-term follow-up are still needed to achieve consensus in the use of screening and treatment tools. The development of specific recommendations for the early stages of BD is warranted.

The value of five blood markers in differentiating mycosis fungoides and Sézary syndrome: a validation cohort.

BACKGROUND: Clinical and histological diagnosis of Sézary syndrome (SS) and mycosis fungoides (MF) is challenging in clinical routine. OBJECTIVES: We investigated five blood markers previously described for SS (T-plastin, Twist, KIR3DL2, NKp46 and Tox) in a prospective validation cohort of patients. METHODS: We included 447 patients in this study and 107 patients were followed up for prognosis. The markers were analysed by reverse transcriptase quantitative real-time polymerase chain reaction (RT-qPCR) on peripheral blood leucocytes and CD4+ T cells in a cohort of consecutive patients with early MF, erythrodermic MF and SS and compared with patients presenting with benign inflammatory dermatoses (BID) and erythrodermic BID. The markers were assessed in parallel to gold standard values such as CD4/CD8 ratio, loss of CD7 and CD26 membrane expression and CD4 absolute values. Sensitivity and specificity were analysed by receiver operator characteristic curves. The prognostic value of selected markers was analysed on a subset of patients. This study was conducted in one centre. RESULTS: We defined cut-off values for each marker. T-plastin, Twist and KIR3DL2 had the best validity. SS may be overrepresented. The combination of T-plastin and Twist was able to differentiate between erythrodermic MF or BID and SS. The additional analysis of KIR3DL2 may be useful to predict the prognosis. CONCLUSIONS: We propose T-plastin, Twist and KIR3DL2 measured by RT-qPCR as new diagnostic markers for Sézary syndrome.

Efficacy of anti-TNF alpha in severe and refractory major vessel involvement of Behcet's disease: A multicenter observational study of 18 patients.

OBJECTIVE: To describe the outcome and tolerance in patients treated with anti-TNFα in severe and refractory major vessel disease in Behçet's disease (BD). METHODS: A multicenter study evaluating 18 refractory BD patients with major vessel involvement [pulmonary artery (n = 4), aorta (n = 4) or peripheral artery aneurysm (n = 1) and/or pulmonary artery (n = 7), inferior vena cava (n = 5), or intra-cardiac (n = 3) thrombosis or Budd Chiari Syndrome (n = 2)] treated with anti-TNFα agents. RESULTS: Vascular remission was achieved in 16 (89%) patients. The 9 months risk of relapse was significantly higher with conventional immunosuppressants used prior anti-TNFα agents as compared to anti-TNFα therapy [OR = 8.7 (1.42-62.6), p = 0.03]. The median daily dose of corticosteroids significantly decreased at 12 months. Side effects included infection (n = 4) and pulmonary edema (n = 1). CONCLUSION: TNFα-antagonists are safe and might be associated with a decreased risk of relapse at 9 months compared to conventional immunosuppressants in BD patients with major vessels disease.

Tumor metabolism assessed by FDG-PET/CT and tumor proliferation assessed by genomic grade index to predict response to neoadjuvant chemotherapy in triple negative breast cancer.

PURPOSE: Survival is increased when pathological complete response (pCR) is reached after neoadjuvant chemotherapy (NAC), especially in triple-negative breast cancer (TNBC) patients. Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG) and the genomic grade index (GGI), each separately, showed good potential to predict pCR. Our study was designed to evaluate the predictive value for the therapeutic response of a combination of parameters based on FDG-PET, histoclinical features and molecular markers of proliferation. METHODS: Molecular parameters were measured on pre-treatment biopsy. Tumor metabolic activity was measured using two PET/CT scans, one before and one after 2 cycles of NAC. The pCR was determined on specimen after NAC. Event-free survival (EFS) was estimated using the Kaplan Meier method. RESULTS: Of 55 TNBC patients, 19 (35%) reached pCR after NAC. Tumor grade and Ki67 were not associated with pCR whereas GGI (P = 0.04) and its component KPNA2 (P = 0.04) showed a predictive value. The change of FDG uptake between PET1 and PET2 (ΔSUVmax) was highly associated with pCR (P = 0.0001) but the absolute value of baseline SUVmax was not (P = 0.11). However, the AUC of pCR prediction increased from 0.63 to 0.76 when baseline SUVmax was combined with the GGI (P = 0.016). The only two parameters associated with EFS were ΔSUVmax (P = 0.048) and pathological response (P = 0.014). CONCLUSIONS: The early tumor metabolic change during NAC is a powerful parameter to predict pCR and outcome in TNBC patients. The GGI, determined on pretreatment biopsy, is also predictive of pCR and the combination GGI and baseline SUVmax improves the prediction.

Investigating covariate-by-centre interaction in survival data.

In survival analysis, assessing the existence of potential centre effects on the baseline hazard or on the effect of fixed covariates on the baseline hazard, such as treatment-by-centre interaction, is a frequent clinical concern in multicentre studies. Survival models with random effects on the baseline hazard and/or on the effect of the covariates of interest have been largely applied, for instance, to investigate potential centre effects. We aimed to develop a procedure to routinely test for multiple random effects in survival analyses. We propose a statistic and a permutation approach to test whether all or a subset of components of the variance-covariance matrix of random effects are non-zero in a mixed-effects Cox model framework. Performances of the proposed permutation tests are examined under different null hypotheses corresponding to the different components of the variance-covariance matrix, i.e ., to the different random effects considered on the baseline hazard and/or on the covariates effects. Several alternative hypotheses are evaluated using simulations. The results indicate that the permutation tests have valid type I error rates under the null and achieve satisfactory power under all alternatives. The procedure is applied to two European cohorts of haematological stem cell transplants in acute leukaemia to investigate the heterogeneity across centres in leukaemia-free survival and the potential heterogeneity in prognostic factors effects across centres.

Usefulness of daily surveillance blood cultures in allogeneic hematopoietic stem cell transplant recipients on steroids: a 1-year prospective study.

BACKGROUND: Bloodstream infections (BSI) are frequent and potentially severe complications in allogeneic hematopoietic stem cell transplant (AHSCT) recipients. In patients on steroids, surveillance blood cultures (SBCs) are routinely performed to detect asymptomatic BSI but their usefulness remains controversial. METHODS: We performed a 1-year, observational, prospective, single-center study to assess the utility of daily SBCs in AHSCT recipients on steroids and a case-control study to identify risk factors associated with positive SBCs. All blood cultures (BCs) obtained from adults hospitalized in the HSCT unit were prospectively studied throughout 1 year. Characteristics, treatments, and outcome of patients were retrieved from medical charts. RESULTS: A total of 3594 BCs were obtained in 177 patients, including 1450 SBCs in 82 AHSCT recipients on steroids. In 33 patients, 103 SBCs (7%) were positive. Low-virulence bacteria were identified in 74% of episodes. When analyzing first episode of positive SBCs (28 patients), 6 (21%) true BSI were identified. CONCLUSIONS: Patients with positive SBCs were receiving antibiotic treatment less frequently at the time of SBCs (P < 0.001) and had more frequently BCs obtained through central venous access (P < 0.04) when compared to patients with negative SBCs. Daily SBCs in AHSCT recipients on steroids only rarely identify BSI and clear benefit for patients could not be demonstrated.

[Teledermatology in a prison setting: A retrospective study of 500 expert opinions]. / Télédermatologie en milieu carcéral : étude rétrospective de 500 télé-expertises.

BACKGROUND: Fresnes prison is one of the largest penitentiary centres in France (around 2300 inmates). Since dermatological consultations are not possible on site, a teledermatology agreement was signed in 2008 between the Kremlin-Bicêtre hospital, used by the Fresnes consultation unit and outpatient care (UCSA) and the Saint-Louis hospital for remote dermatological expertise. We report the results of the last 3 years of teledermatology activity in this prison. PATIENTS AND METHODS: All teledermatology consultations from September 2010 to September 2013 were analysed. The teledermatological consultations requested by UCSA doctors included photos of lesions, patient history and disease history. Applications were sent by e-mail via the secure AP-HP (Paris Hospitals) intranet. In all instances, patients had consented to being photographed and these photos were transmitted for remote expertise. The answers were given in a maximum period of 5 working days. The following data were studied: sex, age, phototype, medical history, diagnoses, assessments requested and treatment received. RESULTS: Five hundred teledermatological consultations were analysed. Among the patients, 94.1% were male with a mean age of 34 years. Phototypes IV and VI constituted the majority, with respective percentages of 30.6% and 28.6%. The dermatoses diagnosed were for the most part mild and varied: cutaneous infections (20.2%), monitoring of nevi (11.5%), genital warts (10%), eczema (8.5%), acne (8.1%) and psoriasis (4.2%). Two cases (basal cell carcinoma and lupus) required ablation. Systemic treatments such as methotrexate and isotretinoin were initiated and monitored remotely. DISCUSSION: The most frequently observed diagnoses were not significantly different from those observed in the general population with comparable characteristics. The high phototype of patients requires extensive experience of the dermatology of black skin. Teledermatology is also important in monitoring nevi among prisoners. The low incidence of scabies is due to its systematic detection in prisoners on initial entry into prison. Furthermore, teledermatology is actively used in the teaching of prison doctors requiring training, and whose requests are becoming more and more relevant with time. CONCLUSION: This study provides greater knowledge of dermatological diseases in prison and shows teledermatology to be a tool suited to the specific constraints of this universe, while providing inmates with medical care as close as possible to that of the general population, and it thus helps ensure that their fundamental human rights are upheld.

Response to antiviral therapy in haematopoietic stem cell transplant recipients with cytomegalovirus (CMV) reactivation according to the donor CMV serological status.

Pre-emptive antiviral treatment efficiently prevents occurrence of cytomegalovirus (CMV) disease in allogeneic stem cell transplant recipients. However, successive treatment courses can be necessary. The current study was aimed at determining factors that could influence the response to antiviral treatment, in particular the donor CMV serostatus. A total of 147 consecutive CMV-seropositive recipients (R+) were included and prospectively monitored for 6 months after transplantation. Reactivation of CMV occurred in 111 patients, 61 of 78 with a CMV-positive donor (D+) and in 50 of 69 with a CMV-negative donor (D-) (p 0.45). Baseline viral loads and initial viral doubling times did not differ between D+/R+ and D-/R+. Fifteen D+/R+ and four D-/R+ had self-resolving CMV infections. A total of 92 patients received antiviral treatment and 81 (88%) had a significant decrease in CMV load under therapy. Repeated CMV episodes were observed in 67% of those and were significantly more frequent in D-/R+ than in D+/R+ (p <0001). Half-life of CMV under treatment was significantly longer in D-/R+ than in D+/R+. Treatment failure observed in eight recipients was associated with low leucocyte count at reactivation onset, and was significantly more frequent in D-/R+ (six patients) than in D+/R+ (two patients) (p <0.0001). CMV strains resistant to antivirals were found in two D-/R+. Donor CMV serostatus influenced neither CMV reactivation occurrence nor the kinetics of CMV DNA load in the early phase of CMV replication but had a significant impact on response to antiviral therapy. Virological drug-resistance remained rare.

Propensity score estimators for the average treatment effect and the average treatment effect on the treated may yield very different estimates.

OBJECTIVE: Propensity score matching is typically used to estimate the average treatment effect for the treated while inverse probability of treatment weighting aims at estimating the population average treatment effect. We illustrate how different estimands can result in very different conclusions. STUDY DESIGN: We applied the two propensity score methods to assess the effect of continuous positive airway pressure on mortality in patients hospitalized for acute heart failure. We used Monte Carlo simulations to investigate the important differences in the two estimates. RESULTS: Continuous positive airway pressure application increased hospital mortality overall, but no continuous positive airway pressure effect was found on the treated. Potential reasons were (1) violation of the positivity assumption; (2) treatment effect was not uniform across the distribution of the propensity score. From simulations, we concluded that positivity bias was of limited magnitude and did not explain the large differences in the point estimates. However, when treatment effect varies according to the propensity score (E[Y(1)-Y(0)|g(X)] is not constant, Y being the outcome and g(X) the propensity score), propensity score matching ATT estimate could strongly differ from the inverse probability of treatment weighting-average treatment effect estimate. We show that this empirical result is supported by theory. CONCLUSION: Although both approaches are recommended as valid methods for causal inference, propensity score-matching for ATT and inverse probability of treatment weighting for average treatment effect yield substantially different estimates of treatment effect. The choice of the estimand should drive the choice of the method.

Angle of fetal head progression measured using transperineal ultrasound as a predictive factor of vacuum extraction failure.

OBJECTIVE: To evaluate the predictive value of angle of progression (AoP) of the fetal head for a failed vacuum delivery. METHODS: This was a prospective observational study that included women with a singleton pregnancy of ≥ 37 weeks' gestation, in cephalic presentation requiring vacuum extraction. Transperineal ultrasound was performed immediately before vacuum extraction, although AoP was measured on stored images after delivery. Vacuum extraction was defined as failed when the duration of extraction exceeded 20 min or the vacuum cup detached more than three times. We compared the demographic and ultrasound data of failed vacuum deliveries with those that were successful. The predictive value of AoP for failure of vacuum delivery was calculated. RESULTS: AoP was measured in 235 women. Vacuum extractions failed in 30 (12.8%) women (29/184 nulliparous and 1/51 parous) and resulted in 28 vaginal deliveries by forceps and two Cesarean deliveries. Median AoP was significantly lower in the vacuum failure group compared with those with successful vacuum delivery (136.6° (interquartile range (IQR), 129.8-144.1°) vs 145.9° (IQR, 135.0-158.4°); P < 0.01). As all but one failed vacuum extraction occurred among nulliparous women, the predictive value of AoP was calculated in this subgroup of women. The area under the receiver-operating characteristics curve for prediction of vacuum extraction failure was 0.67 (95% CI, 0.57-0.77) and the optimal AoP cut-off was 145.5°. Above this value, the rate of vacuum extraction failure fell below 5%. CONCLUSION: AoP is a predictive factor of failed vacuum extraction, especially among nulliparous women whose risk of failure is high. AoP measurement may help in choosing between forceps and vacuum extraction. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Takayasu Arteritis and Pregnancy.

OBJECTIVE: To assess the relationship between Takayasu arteritis (TAK) and pregnancy outcome. METHODS: This study included 240 pregnancies in 96 patients fulfilling the American College of Rheumatology 1990 criteria for the classification of TAK and/or the 1994 Chapel Hill Consensus Conference nomenclature/criteria for vasculitis. We analyzed obstetric and maternal outcomes in women who were pregnant before and/or at the same time as or after TAK diagnosis. We assessed factors associated with complicated pregnancy. RESULTS: One hundred forty-two pregnancies occurred in 52 patients before TAK diagnosis (median age at pregnancy 26 years [interquartile range 23-30 years]), and 98 pregnancies occurred in 52 patients concomitant with or after TAK diagnosis (median age at pregnancy 28 years [interquartile range 26-31 years]). Pregnancies concomitant with or after TAK diagnosis had a 13-fold higher rate of obstetric complications compared to pregnancies before TAK diagnosis (odds ratio 13 [95% confidence interval 5-33], P < 0.0001). TAK was associated with a 40% frequency of obstetric complications, including preeclampsia/eclampsia (24 pregnancies [24%]), premature delivery (8 pregnancies [8%]), and intrauterine fetal growth restriction or death (5 pregnancies [5%]). Maternal complications of TAK occurred during 39% of pregnancies and included mainly new-onset or worsening hypertension (26 pregnancies [27%]). In multivariate analysis, smoking (odds ratio 6.15 [95% confidence interval 1.31-28.8]) and disease activity of TAK (a National Institutes of Health score of >1) (odds ratio 28.7 [95% confidence interval 7.89-104.7]) were independently associated with obstetric and maternal complications. CONCLUSION: TAK negatively affects pregnancy outcomes. Disease activity increases the risk of obstetric and maternal complications, mainly due to arterial hypertension.

Efficacy of anti-TNF alpha in severe and/or refractory Behçet's disease: Multicenter study of 124 patients.

OBJECTIVE: To report the efficacy and safety of anti-TNF agents in patients with severe and/or refractory manifestations of Behçet's disease (BD). METHODS: We performed a multicenter study of main characteristics and outcomes of anti-TNF alpha treatments [mainly infliximab (62%), and adalimumab (30%)] in 124 BD patients [48% of men; median age of 33.5 (28-40) years]. RESULTS: Overall response (i.e. complete and partial) rate was 90.4%. Clinical responses were observed in 96.3%, 88%, 70%, 77.8%, 92.3% and 66.7% of patients with severe and/or refractory ocular, mucocutaneous, joint, gastro-intestinal manifestations, central nervous system manifestations and cardiovascular manifestations, respectively. No significant difference was found with respect to the efficacy of anti-TNF used as monotherapy or in association with an immunosuppressive agent. The incidence of BD flares/patient/year was significantly lower during anti-TNF treatment (0.2 ± 0.5 vs 1.7 ± 2.4 before the use of anti-TNF, p < 0.0001). The prednisone dose was significantly reduced at 6 and 12 months (p < 0.0001). In multivariate analysis, retinal vasculitis was negatively associated with complete response to anti-TNF (OR = 0.33 [0.12-0.89]; p = 0.03). The efficacy and relapse free survival were similar regardless of the type of anti-TNF agent used. After a median follow-up of 21 [7-36] months, side effects were reported in 28% of patients, including infections (16.3%) and hypersensitivity reactions (4.1%). Serious adverse events were reported in 13% of cases. CONCLUSION: Anti-TNF alpha therapy is efficient in all severe and refractory BD manifestations. Efficacy appears to be similar regardless of the anti-TNF agent used (infliximab or adalimumab).

Prognosis of neutropenic patients admitted to the intensive care unit.

PURPOSE: The prognosis of critically ill cancer patients has improved recently. Controversies remain as regard to the specific prognosis impact of neutropenia in critically ill cancer patients. The primary objective of this study was to assess hospital outcome of critically ill neutropenic cancer patients admitted into the ICU. The secondary objective was to assess risk factors for unfavorable outcome in this population of patients and specific impact of neutropenia. METHODS: We performed a post hoc analysis of a prospectively collected database. The study was carried out in 17 university or university-affiliated centers in France and Belgium. Neutropenia was defined as a neutrophil count lower than 500/mm(3). RESULTS: Among the 1,011 patients admitted into the ICU during the study period 289 were neutropenic at the time of admission. Overall, 131 patients died during their hospital stay (hospital mortality 45.3 %). Four variables were associated with a poor outcome, namely allogeneic transplantation (OR 3.83; 95 % CI 1.75-8.35), need for mechanical ventilation (MV) (OR 6.57; 95 % CI 3.51-12.32), microbiological documentation (OR 2.33; CI 1.27-4.26), and need for renal replacement therapy (OR 2.77; 95 % CI 1.34-5.74). Two variables were associated with hospital survival, namely age younger than 70 (OR 0.22; 95 % CI 0.1-0.52) and neutropenic enterocolitis (OR 0.37; 95 % CI 0.15-0.9). A case-control analysis was also performed with patients of the initial database; after adjustment, neutropenia was not associated with hospital mortality (OR 1.27; 95 % CI 0.86-1.89). CONCLUSION: Hospital survival was closely associated with younger age and neutropenic enterocolitis. Conversely, need for conventional MV, for renal replacement therapy, and allogeneic hematopoietic stem cell transplantation (HSCT) were associated with poor outcome.

Molecular determinants of the recognition of ulipristal acetate by oxo-steroid receptors.

The human progesterone receptor (PR) plays a key role in reproductive function in women. PR antagonists have numerous applications in female health care including regular and emergency contraception, and treatment of hormone-related pathological conditions such as breast cancer, endometriosis, and leiomyoma. The main factor limiting their long-term administration is the fact that they cross-bind to other oxo-steroid receptors. Ulipristal acetate (UPA), a highly potent PR antagonist, has recently come onto the market and is much more selective for PR than the other oxo-steroid receptors (androgen, AR, glucocorticoid, GR, and mineralocorticoid, MR receptors) and, remarkably, it displays lower GR-inactivating potency than RU486. We adopted a structural approach to characterizing the binding of UPA to the oxo-steroid receptors at the molecular level. We solved the X-ray crystal structure of the ligand-binding domain (LBD) of the human PR complexed with UPA and a peptide from the transcriptional corepressor SMRT. We used the X-ray crystal structure of the GR in its antagonist conformation to dock UPA within its ligand-binding cavity. Finally, we generated three-dimensional models of the LBD of androgen and mineralocorticoid receptors (AR and MR) in an antagonist conformation and docked UPA within them. Comparing the structures revealed that the network of stabilizing contacts between the UPA C11 aryl group and the LBD is responsible for its high PR antagonist potency. It also showed that it is the inability of UPA to contact Gln642 in GR that explains why it has lower potency in inactivating GR than RU486. Finally, we found that the binding pockets of AR and MR are too small to accommodate UPA, and allowed us to propose that the extremely low sensitivity of MR to UPA is due to inappropriate interactions with the C11 substituent. All these findings open new avenues for designing new PR antagonist compounds displaying greater selectivity.

Trends in death attributed to myocardial infarction, heart failure and pulmonary embolism in Europe and Canada over the last decade.

BACKGROUND: Worldwide, cardiovascular diseases and cancer account for ∼40% of deaths. Certain reports have shown a progressive decrease in mortality. Our main objective was to assess mortality trends related to myocardial infarction (MI), heart failure (HF) and pulmonary embolism (PE). METHODS: MI, HF and PE were studied as cause of death based on the analysis of death certificates in Canada (C), England and Wales (E), France (F) and Sweden (S). We also used a multiple cause approach. Age-standardized death rates (SDR) were calculated. RESULTS: The SDR for MI, HF or PE as the underlying cause of death, all decreased during the last decade. The decrease in SDR secondary to MI exceeded that for HF or PE. Concerning multiple cause of death, a greater decrease was also found for MI, compared with HF or PE. CONCLUSIONS: We confirm the beneficial trends in SDR with MI, HF or PE both as underlying or multiple causes in the studied countries. For HF and PE, multiple cause approach seems more accurate to describe the burden of these two pathologies. Our study also suggests that more efforts should be dedicated to HF and PE in order to achieve similar trends than in MI.

Diagnostic accuracy of urinary dipstick to exclude catheter-associated urinary tract infection in ICU patients: a reappraisal.

OBJECTIVES: We wanted to assess the diagnostic accuracy of urinary dipstick testing in excluding catheter-associated urinary tract infection (CAUTI) in intensive care unit (ICU) patients with fever or hypothermia. METHODS: This was a prospective observational cohort study in a medical-surgical ICU. Patients with new-onset fever >38.3 °C or hypothermia <36 °C at least 48 h after urinary catheter insertion were included over a 2-year period. At each episode, a urinary dipstick test and a urine culture were performed as the criterion standard. Extensive microbiological investigations for extra-urinary infections were performed also. The performances of various urinary dipstick result combinations in ruling out CAUTI were compared based on the likelihood ratios (LR+ and LR-). RESULTS: Symptomatic CAUTI was diagnosed in 31 (24.4 %) of the 127 included patients (195 episodes of fever or hypothermia). LR+ was best for combined leukocyte esterase-positive and nitrite-positive dipstick results (overall population: 14.91; 95 % confidence interval [95 % CI], 5.53-40.19; patients without urinary symptoms: 15.63; 95 % CI, 5.76-42.39). LR- was best for either leukocyte esterase-positive or nitrite-positive dipstick results (overall population: 0.41; 95 % CI, 0.57-0.65; patients without urinary symptoms, 0.36; 95 % CI, 0.21-0.60). CONCLUSIONS: Urinary dipstick testing at the bedside does not help to rule out symptomatic CAUTI in medical or surgical ICU patients with fever or hypothermia.

Permutation tests for centre effect on survival endpoints with application in an acute myeloid leukaemia multicentre study.

When analysing multicentre data, it may be of interest to test whether the distribution of the endpoint varies among centres. In a mixed-effect model, testing for such a centre effect consists in testing to zero a random centre effect variance component. It has been shown that the usual asymptotic χ(2) distribution of the likelihood ratio and score statistics under the null does not necessarily hold. In the case of censored data, mixed-effects Cox models have been used to account for random effects, but few works have concentrated on testing to zero the variance component of the random effects. We propose a permutation test, using random permutation of the cluster indices, to test for a centre effect in multilevel censored data. Results from a simulation study indicate that the permutation tests have correct type I error rates, contrary to standard likelihood ratio tests, and are more powerful. The proposed tests are illustrated using data of a multicentre clinical trial of induction therapy in acute myeloid leukaemia patients.

Peg-IFNα/ribavirin/protease inhibitor combination in hepatitis C virus associated mixed cryoglobulinemia vasculitis: results at week 24.

BACKGROUND: The standard-of-care treatment of patients with hepatitis C virus (HCV)-mixed cryoglobulinemia (MC) vasculitis includes pegylated interferon α (PegIFN)-α plus ribavirin and/or rituximab. About 30-40% of patients are non-responders or relapsers to such combination. OBJECTIVE: To analyse the safety and efficacy of Peg-IFNα/ribavirin/protease inhibitor combination in HCV-MC vasculitis. PATIENTS AND METHODS: Open-label, prospective, cohort study including 23 patients with HCV-MC vasculitis. Peg-IFNα/ribavirin was associated to telaprevir (375 mg three times daily, for 12 weeks, (n=15)) or boceprevir (800 mg three times daily, for 44 weeks, (n=8)) for 48 weeks. RESULTS: The median age was 59 (52.5-66) years, with 48.8% women. Thirteen patients (56.5%) were complete clinical responders, and 10 (43.5%) were partial responders at week 24. The virological response (ie, HCV RNA negativation) was of 69.6% at week 24 (p=0.005). The cryoglobulin level decreased from 0.44 to 0.06 g/l (p=0.0006) and the C4 level increased from 0.09 to 0.15 g/l (p=0.045). Grades 3 and 4 adverse events (mainly anaemia, neutropenia and thrombocytopenia) were observed in 10 cases (43.5%). Twenty patients (87%) received erythropoietin, 9 (39.1%) had red cell transfusion, and 2 (8.7%) had granulocyte stimulating agents. Antiviral therapy discontinuation was required in 8 (34.7%) patients for virological non-response (n=5), virological relapse (n=2) and depression (n=1). CONCLUSIONS: Peg-IFNα/ribavirin/protease inhibitor combination seems highly effective in HCV-MC. Such therapeutic regimen should be administered cautiously considering the high rate of side effects.