Could CT scan avoid unnecessary flexible bronchoscopy in children with active pulmonary tuberculosis? A retrospective study.

BACKGROUND: Systematic flexible bronchoscopy is advocated in the initial management of childhood pulmonary tuberculosis. METHODS: Our aim was to describe and to compare the systematic flexible bronchoscopy findings of 53 children (6.5 + or - 4.4 years; 52.8% boys) with active pulmonary tuberculosis to their initial clinical and radiological (chest x-ray, n=53; CT, n=45) features in an 11-year retrospective study. RESULTS: Flexible bronchoscopy was normal in 51% of cases. A severe tracheobronchial involvement (extrinsic compression >50% or obstructive endoluminal mass >25% of the lumen) was found in 10 patients. Flexible bronchoscopy guided therapy in 13 cases (steroids n=12, bronchoscopic extraction of a granuloma n=1) and permitted isolation of Mycobacterium tuberculosis in three patients (5.7%). No useful information was obtained by flexible bronchoscopy in 73.5% of cases. No correlation was found between flexible bronchoscopy findings and clinical features or x-ray findings. Conversely, a strong correlation was found between severe bronchoscopic involvement and tracheobronchial luminal narrowing on CT. The CT negative predictive value was 100% (95% CI 91% to 100%). Based on CT results, flexible bronchoscopy could have been avoided in about 60% of our patients. CONCLUSIONS: Flexible bronchoscopy remains a very relevant tool in the diagnostic and therapeutic management of childhood pulmonary tuberculosis but resulted in treatment modification or microbiological proof in a minority of our patients. We propose that flexible bronchoscopy in children with pulmonary tuberculosis be limited to those who show tracheobronchial luminal narrowing on an initial CT scan.

Drug reimbursement and GPs' prescribing decisions: a randomized case-vignette study about the pharmacotherapy of obesity associated with type 2 diabetes: how GPs react to drug reimbursement.

This study sought to identify the effect of drug reimbursability--a decision made in France by the National Authority for Health--on physicians' prescribing practices for a diet drug such as rimonabant, approved for obese or overweight patients with type-2 diabetes. A cross-sectional survey of French general practitioners (GPs) presented a case-vignette about a patient for whom this drug is indicated in two alternative versions, differing only in its reimbursability, to two separate randomized subsamples of GPs in early 2007, before any decision was made about reimbursement. The results indicate that (i) more than 20% of GPs in private practice would be willing to prescribe a non-reimbursed diet drug for patients with obesity complicated by type 2 diabetes; (ii) the number of GPs willing to prescribe it would increase by 47.6% if the drug were reimbursed, and (iii) such a drug would be adopted at a higher rate by GPs who have regular contacts with pharmaceutical sales representatives. In France, unlike most other countries, drug reimbursement status is a signal of quality. However, our results suggest that a significant proportion of GPs would spontaneously adopt anti-obesity drugs even if they were not reimbursed. Decisions about reimbursement of pharmaceutical products should be made taking into account that reimbursement is likely to intensify prescription.

[Access to medicines in France]. / Accès aux médicaments en France.

In France the total cost of medicinal products reimbursed by health insurers in 2007 was over 25 thousand million euros, and access to new drugs is neither restricted nor rationed, despite the unfavorable economic situation. In 2007 and 2008 the Transparency Commission (TC) of the French National Authority for Health (Haute Autorité de Santé) approved the reimbursement of 97% of new drugs and new indications for existing products, within 90 days on average. The 3% of medicinal products that were not approved did not represent therapeutic advances and could be considered to be of dubious utility. If evaluation of new drugs is to be an independent process, then HAS must not only be independent of the decision-maker, funding bodies and commercial firms, but must also be a purely medical and technical organization. This implies removing all financial consideration from the picture, including the size of the target population that may qualify for a new treatment. This system could be further improved by creating special procedures to promote funding for innovations outside the marketing authorization system, thereby providing patients with faster access to the drugs they need; these procedures would include temporary authorisation, temporary treatment protocols, and a special-case function for treatment of chronic and rare conditions. Currently, new treatments produced by the pharmaceutical industry are paid for by national funding bodies and, from this point of view, it is difficult to argue that drug innovation is under-supported in France. On the other hand, it is well known that France has long been the largest consumer of medicinal drugs, both in Europe and worldwide. Two behavioral patterns partially explain this situation: one is a tendency to believe that drugs are the answer to all health concerns, and the other is a preference for new, more expensive drugs, even though "never" is not necessarily "better".

Intrapleural administration of pemetrexed: a pharmacokinetic study in an animal model.

BACKGROUND: Pemetrexed is a key drug for the treatment of malignant pleural mesothelioma. The intrapleural administration of pemetrexed might increase its efficacy and decrease its toxicity in comparison with intravenous administration. The aim of this study was to assess in an animal model the pharmacokinetics of pemetrexed administered intrapleurally compared with intravenously. METHODS: Thirty Wistar rats were randomly assigned to four groups defined by route (intravenous or intrapleural) and dose (10 or 100 mg/kg) of pemetrexed. After pemetrexed administration, serial plasma pemetrexed concentrations were analyzed by high performance liquid chromatography to determine the maximum plasma concentration (C(max)), the area under the plasma concentration-time curve (AUC), and the total body clearance (CL). RESULTS: The C(max) was significantly lower after intrapleural versus intravenous administration of 10 mg/kg pemetrexed (14.36 microg/ml versus 29.83 microg/ml; p = 0.008) or 100 mg/kg pemetrexed (70.64 microg/ml versus 218.64 microg/ml; p = 0.001). At either dose, the AUC and the CL did not significantly differ according to the route of administration. CONCLUSIONS: While intravenous and intrapleural administration of pemetrexed yielded similar AUC and CL, the intrapleural route yielded a significantly lower C(max). As Cmax is a determinant of pemetrexed toxicity, intrapleural administration might offer a means of widening the effective therapeutic index of the drug by improving tolerability. Future studies are needed to confirm this hypothesis in malignant pleural mesothelioma patients.

Analysis of the DYSF mutational spectrum in a large cohort of patients.

Dysferlinopathies belong to the heterogeneous group of autosomal recessive muscular dystrophies. Mutations in the gene encoding dysferlin (DYSF) lead to distinct phenotypes, mainly Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). Here, we analysed the mutational data from the largest cohort described to date, a cohort of 134 patients, included based on clinical suspicion of primary dysferlinopathy and/or dysferlin protein deficiency identified on muscle biopsy samples. Data were compiled from 38 patients previously screened for mutations in our laboratory (Nguyen, et al., 2005; Nguyen, et al., 2007), and 96 supplementary patients screened for DYSF mutations using genomic DHPLC analysis, and subsequent sequencing of detected variants, in a routine diagnostic setting. In 89 (66%) out of 134 patients, molecular analysis identified two disease causing mutations, confirming the diagnosis of primary Dysferlinopathy on a genetic basis. Furthermore, one mutation was identified in 30 patients, without identification of a second deleterious allele. We are currently developing complementary analysis for patients in whom only one or no disease-causing allele could be identified using the genomic screening procedure. Altogether, 64 novel mutations have been identified in this cohort, which corresponds to approximately 25% of all DYSF mutations reported to date. The mutational spectrum of this cohort significantly shows a higher proportion of nonsense mutations, but a lower proportion of deleterious missense changes as compared to previous series. (c) 2008 Wiley-Liss, Inc.

Influence of -308 A/G polymorphism in the tumor necrosis factor alpha gene on etanercept treatment in rheumatoid arthritis.

OBJECTIVE: To determine whether the -308 A/G tumor necrosis factor alpha (TNFalpha) gene polymorphism can predict the outcome of etanercept therapy in 86 patients with rheumatoid arthritis (RA), as already observed in patients treated with infliximab. METHODS: Eighty-six RA patients treated with etanercept were genotyped for -308 A/G TNFalpha gene polymorphism by polymerase chain reaction and melting curve analysis, using specific gene primers and probes. Patients were subdivided into group A (G/A genotype) and group G (G/G genotype). We compared clinical responses to etanercept between groups A and G after 6 months, using the Disease Activity Score in 28 joints (DAS28). After 12-month treatment, 48 of 86 patients were evaluated again. RESULTS: Of 86 patients, 18 (21%) belonged in group A and 68 (79%) belonged in group G. After 6-month treatment, 55.6% of patients in group A and 82.4% of patients in group G had DAS28 improvement >1.2 (P = 0.027 by chi-square). The mean +/- SD DAS28 improvement was 1.69 +/- 1.31 in group A and 2.23 +/- 1.19 in group G (P = 0.098 by t-test). After 1-year treatment 48 patients were tested again: 10 (21%) belonged in group A and 38 (79%) belonged in group G. Forty percent of patients in group A and 87% in group G had DAS28 improvement >1.2 (P = 0.005 by chi-square). The mean +/- SD DAS28 improvement was 1.334 +/- 1.37 in group A and 2.29 +/- 1.47 in group G (Mann-Whitney U test = 115, P = 0.0057). CONCLUSION: RA patients with a -308 G/G TNFalpha genotype respond to etanercept better than patients with a -308 A/G genotype.

Impact of intensive care on renal function before graft harvest: results of a monocentric study.

BACKGROUND: The aim of life-support measures in brain-dead donors is to preserve the functional value of their organs. In renal transplantation, serum creatinine level is one of the criteria for graft harvest. The aim of this study was to assess the impact of intensive care on donor renal function through two criteria: preharvesting serum creatinine level above 120 micromol/L and the elevation of serum creatinine level above 20% between intensive care unit (ICU) admission and graft harvest. METHODS: Between 1 January 1999 and 31 December 2005, we performed an observational study on 143 brain-dead donors. ICU chronology, hemodynamic, hematosis, and treatment data were collected for each patient from ICU admission to kidney removal. RESULTS: Twenty-two percent of the 143 patients had a serum creatinine level above 120 micromol/L before graft harvest. The independent factors revealed by multivariate analysis were the administration of epinephrine (odds ratio [OR]: 4.36, 95% confidence interval [CI]: 1.33 to 14.32; p = 0.015), oliguria (OR: 3.73, 95% CI: 1.22 to 11.36; p = 0.021), acidosis (OR: 3.26, 95% CI: 1.07 to 9.95; p = 0.038), the occurrence of disseminated intravascular coagulation (OR: 3.97, 95% CI: 1.05 to 15.02; p = 0.042), female gender (OR: 0.13, 95% CI: 0.03 to 0.50; p = 0.003), and the administration of desmopressin (OR: 0.12, 95% CI: 0.03 to 0.44; p = 0.002). The incidence of elevated serum creatinine level above 20% between admission and graft harvest was 41%. The independent risk factors were the duration of brain death greater than 24 hours (OR: 2.64, 95% CI: 1.25 to 5.59; p = 0.011) and the volume of mannitol (OR: 2.08, 95% CI: 1.03 to 4.21; p = 0.041). CONCLUSION: This study shows that the resuscitation of brain-dead donors impacts on their renal function. The uses of epinephrine and mannitol are associated with impairment of kidney function. It seems that graft harvest should be performed less than 24 hours after brain death diagnosis.

Ventilator-associated pneumonia: breaking the vicious circle of antibiotic overuse.

OBJECTIVE: To assess the rate of appropriateness of empirical antimicrobial therapy for ventilator-associated pneumonia, to evaluate de-escalation in patients with ventilator-associated pneumonia treated according to local pathway, and to identify the bacteria responsible for recurrence of ventilator-associated pneumonia. DESIGN: Prospective observational study during a 36-month period. SETTING: Medical-surgical intensive care unit of a university hospital. PATIENTS: One hundred and fifteen patients hospitalized in an intensive care unit developing ventilator-associated pneumonia with positive cultures. The patients with ventilator-associated pneumonia were treated with limited-spectrum antibiotics (i.e., without activity against Pseudomonas aeruginosa) if they had no prior hospitalization (within 21 days) or prior administration of antibiotics (within 10 days). Quantitative cultures obtained by bronchoscopy or tracheal aspiration were used to reassess empirical therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A limited-spectrum therapy was used in 79 patients (69%). Empirical antimicrobial therapy was appropriate in 100 patients (85%). The mortality rate was significantly higher in the patients in whom empirical therapy was inappropriate than in those in whom treatment was appropriate (47 vs. 20%, p=.04). De-escalation was done in respectively 26% and 72% of patients with early- and late-onset ventilator-associated pneumonia, whereas treatment was escalated in 27 patients (23%). Ventilator-associated pneumonia episodes were recurrent in 22 cases, including eight episodes due to high-risk bacteria. CONCLUSIONS: A rational empirical antimicrobial therapy for ventilator-associated pneumonia using limited-spectrum antibiotics is possible if local ecology and patient medical history and clinical status are considered. In addition, de-escalation is feasible in 42% of patients. This integrative approach may reduce the emergence of resistant bacteria, which in turns reduces the need for broad-spectrum antibiotics, breaking the vicious circle of antibiotic overuse.

[The worrying rise in the frequency of cesarean section]. / L'inquiétante augmentation du nombre de césariennes.

The rise in the incidence of Cesarean section over the last thirty years is due to several factors. In particular, maternal age is increasing, parity is declining, and situations potentially requiring Cesarean section are more frequently encountered than before (prematurity, medically assisted procreation, antenatal diagnosis, previous Cesarean section, etc.). Medicolegal pressure is also increasing, and the precautionary principle is leading more and more physicians to propose Cesarean section rather than trial labor. However, although the risks of this form of delivery have decreased, they are still higher than those of vaginal delivery, except in the emergency setting. Moreover, various pathophysiologic studies have demonstrated marked changes in the elevator muscles, nerves and pelvic support after vaginal delivery. The maternal morbidity and mortality of elective caesarean delivery at term, before the onset of labor, appear to be similar to those associated with vaginal birth. However, the maternal risks (particularly placenta praevia, placenta accreta, and uterine rupture) during subsequent pregnancies following Cesarean delivery require careful evaluation. After Cesarean section, the risk of placenta praevia during the next pregnancy is between 1% and 4%. There is subsequently a linear increase, with the risk of placenta praevia reaching nearly 10% after four Cesarean deliveries. The risks and benefits of each form of delivery are extremely difficult to weigh up, and predictors of safe vaginal delivery are lacking.

Textual guidelines versus computable guidelines: a comparative study in the framework of the PRESGUID project in order to appreciate the impact of guideline format on physician compliance.

BACKGROUND: The compliance of physicians with the clinical practice guidelines (CPG) is insufficient and needs to be improved. OBJECTIVE: To determine whether standalone computerized CPG within the PRESGUID project could improve compliance with the recommendations than the use of CPG in textual format. METHOD: Comparative analyses of the responses made by two groups of resident physicians to a set of clinical cases. One group of residents had access to the CPG exclusively in textual format (paper document) while the second group had access to the CPG exclusively in computerized format within the PRESGUID software applications. RESULTS: The computable CPG are more efficient than the paper-based CPG regarding responses in compliance with the recommendations especially those judged to be relevant by an expert. CONCLUSION: These results should encourage the bodies responsible for diffusing CPG to promote the computable format and to facilitate the computerization process.

[Generic drugs in the medical-economic context of drug prescriptions]. / Le générique dans le cadre médico-économique de la prescription de médicament.

REIMBURSABLE DRUGS: The reimbursement, or coverage of pharmaceutical costs by the sickness benefits is governed in the French system by two conditions: the drugs must have been prescribed, and must be listed in the reimbursable drug list. Inscription in the reimbursable drugs list requires approval by the transparency commission, sole commission capable of assessing the medical service rendered (MSR) by the drugs and to propose a reimbursement rate of 65 or 35%. Exceptional drugs and those prescribed in the context of long-term treatments have a specific reimbursement status. ESTABLISHING THE PRICE: The coverage of drugs by the health insurance does not permit free pricing. The costs of drugs are established by the economic committee of health products (Comité Economique des Produits de Santé--CEPS), following approval by the transparency commission, who assesses the improvement in medical services rendered (IMSR) by new products, compared with existing products. THE ECONOMIC ADVANTAGES OF GENERICS: Physicians must be as economical as possible in terms of quality, safety and efficacy of the care they provide. Moreover, to be reimbursed by the social services, a generic must provide improved medical services or lead to savings in the cost of treatment. In such conditions one can conceive that the price of a generic (which does not provide any improvement in medical services compared with the original drug) is legitimately cheaper than the original product, and source of economy for better allocation of available funds. TWO MOTIVATING MEASURES: However, the French generic market is one of the least developed among industrialized countries. Presently, the volume of generics only represents 5% of the French drug market. Its further development is foreseen within the framework of all the plans for medicalized control of health costs. Other than the classical motives that encourage prescription of generics, i.e., citizens' awareness, labelling and the control by the French medicines agency, new determinating measures in our right for health are: the pharmacists' right to substitute and the physicians' authorization and incitement then to prescribe a product under its international non-proprietary name.