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2.  Glucocorticoid receptor gene polymorphisms associated with progression of lung disease in young patients with cystic fibrosis 
Respiratory Research  2007;8(1):88.
The variability in the inflammatory burden of the lung in cystic fibrosis (CF) patients together with the variable effect of glucocorticoid treatment led us to hypothesize that glucocorticoid receptor (GR) gene polymorphisms may affect glucocorticoid sensitivity in CF and, consequently, may contribute to variations in the inflammatory response.
We evaluated the association between four GR gene polymorphisms, TthIII, ER22/23EK, N363S and BclI, and disease progression in a cohort of 255 young patients with CF. Genotypes were tested for association with changes in lung function tests, infection with Pseudomonas aeruginosa and nutritional status by multivariable analysis.
A significant non-corrected for multiple tests association was found between BclI genotypes and decline in lung function measured as the forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC). Deterioration in FEV1 and FVC was more pronounced in patients with the BclI GG genotype compared to the group of patients with BclI CG and CC genotypes (p = 0.02 and p = 0.04 respectively for the entire cohort and p = 0.01 and p = 0.02 respectively for F508del homozygous patients).
The BclI polymorphism may modulate the inflammatory burden in the CF lung and in this way influence progression of lung function.
PMCID: PMC2217522  PMID: 18047640
3.  Impaired cortical processing of inspiratory loads in children with chronic respiratory defects 
Respiratory Research  2007;8(1):61.
Inspiratory occlusion evoked cortical potentials (the respiratory related-evoked potentials, RREPs) bear witness of the processing of changes in respiratory mechanics by the brain. Their impairment in children having suffered near-fatal asthma supports the hypothesis that relates asthma severity with the ability of the patients to perceive respiratory changes. It is not known whether or not chronic respiratory defects are associated with an alteration in brain processing of inspiratory loads. The aim of the present study was to compare the presence, the latencies and the amplitudes of the P1, N1, P2, and N2 components of the RREPs in children with chronic lung or neuromuscular disease.
RREPs were recorded in patients with stable asthma (n = 21), cystic fibrosis (n = 32), and neuromuscular disease (n = 16) and in healthy controls (n = 11).
The 4 RREP components were significantly less frequently observed in the 3 groups of patients than in the controls. Within the patient groups, the N1 and the P2 components were significantly less frequently observed in the patients with asthma (16/21 for both components) and cystic fibrosis (20/32 and 14/32) than in the patients with neuromuscular disease (15/16 and 16/16). When present, the latencies and amplitudes of the 4 components were similar in the patients and controls.
Chronic ventilatory defects in children are associated with an impaired cortical processing of afferent respiratory signals.
PMCID: PMC2020473  PMID: 17822538
4.  Comparison of superior vena cava and femoroiliac vein pressure according to intra-abdominal pressure 
Previous studies have shown a good agreement between central venous pressure (CVP) measurements from catheters placed in superior vena cava and catheters placed in the abdominal cava/common iliac vein. However, the influence of intra-abdominal pressure on such measurements remains unknown.
We conducted a prospective, observational study in a tertiary teaching hospital. We enrolled patients who had indwelling catheters in both superior vena cava (double lumen catheter) and femoroiliac veins (dialysis catheter) and into the bladder. Pressures were measured from all the sites, CVP, femoroiliac venous pressure (FIVP), and intra-abdominal pressure.
A total of 30 patients were enrolled (age 62 ± 14 years; SAPS II 62 (52–76)). Fifty complete sets of measurements were performed. All of the studied patients were mechanically ventilated (PEP 3 cmH20 (2–5)). We observed that the concordance between CVP and FIVP decreased when intra-abdominal pressure increased. We identified 14 mmHg as the best intra-abdominal pressure cutoff, and we found that CVP and FIVP were significantly more in agreement below this threshold than above (94% versus 50%, P = 0.002).
We reported that intra-abdominal pressure affected agreement between CVP measurements from catheter placed in superior vena cava and catheters placed in the femoroiliac vein. Agreement was excellent when intra-abdominal pressure was below 14 mmHg.
PMCID: PMC3424143  PMID: 22742667
Intensive unit care; Central venous pressure; Superior vena cava; Femoroiliac vena; Intra-abdominal pressure
5.  Accuracy of ICD-10 Codes for Surveillance of Clostridium difficile Infections, France 
Emerging Infectious Diseases  2012;18(6):979-981.
The sensitivity and specificity of surveillance for Clostridium difficile infections according to International Classification of Diseases, 10th revision, codes were compared with laboratory results as standard. Sensitivity was 35.6%; specificity was 99.9%. Concordance between the 2 methods was moderate. Surveillance based on ICD-10 codes underestimated the rate based on laboratory results.
PMCID: PMC3358151  PMID: 22607707
Clostridium difficile; International Classification of Diseases; ICD-10 codes; surveillance; epidemiology; bacteria; France
6.  Pulmonary acceleration time to optimize the timing of lung transplant in cystic fibrosis 
Pulmonary Circulation  2012;2(1):75-83.
Pulmonary hypertension (PH) may affect survival in cystic fibrosis (CF) and can be assessed on echocardiographic measurement of the pulmonary acceleration time (PAT). The study aimed at evaluating PAT as a tool to optimize timing of lung transplant in CF patients. Prospective multicenter longitudinal study of patients with forced expiratory volume in 1 second (FEV1) ≤60% predicted. Echocardiography, spirometry and nocturnal oximetry were obtained as part of the routine evaluation. We included 67 patients (mean FEV1 42±12% predicted), among whom 8 underwent lung transplantation during the mean follow-up of 19±6 months. No patients died. PAT was determined in all patients and correlated negatively with systolic pulmonary artery pressure (sPAP, r=–0.36, P=0.01). Patients in the lowest PAT tertile (<101 ms) had lower FEV1 and worse nocturnal oxygen saturation, and they were more often on the lung transplant waiting list compared to patients in the other tertiles. Kaplan–Meier curves showed a shorter time to lung transplantation in the lowest PAT tertile (P<0.001) but not in patients with sPAP>35 mmHg. By multivariate analysis, FEV1and nocturnal desaturation were the main determinants of reduced PAT. A PAT<101 ms reduction is a promising tool for timing of lung transplantation in CF.
PMCID: PMC3342752  PMID: 22558523
cystic fibrosis; echocardiography; pulmonary acceleration time; pulmonary hypertension; pulmonary transplantation
7.  The Chikungunya Epidemic on La Réunion Island in 2005–2006: A Cost-of-Illness Study 
This study was conducted to assess the impact of chikungunya on health costs during the epidemic that occurred on La Réunion in 2005–2006.
Methodology/Principal Findings
From data collected from health agencies, the additional costs incurred by chikungunya in terms of consultations, drug consumption and absence from work were determined by a comparison with the expected costs outside the epidemic period. The cost of hospitalization was estimated from data provided by the national hospitalization database for short-term care by considering all hospital stays in which the ICD-10 code A92.0 appeared. A cost-of-illness study was conducted from the perspective of the third-party payer. Direct medical costs per outpatient and inpatient case were evaluated. The costs were estimated in Euros at 2006 values. Additional reimbursements for consultations with general practitioners and drugs were estimated as €12.4 million (range: €7.7 million–€17.1 million) and €5 million (€1.9 million–€8.1 million), respectively, while the cost of hospitalization for chikungunya was estimated to be €8.5 million (€5.8 million–€8.7 million). Productivity costs were estimated as €17.4 million (€6 million–€28.9 million). The medical cost of the chikungunya epidemic was estimated as €43.9 million, 60% due to direct medical costs and 40% to indirect costs (€26.5 million and €17.4 million, respectively). The direct medical cost was assessed as €90 for each outpatient and €2,000 for each inpatient.
The medical management of chikungunya during the epidemic on La Réunion Island was associated with an important economic burden. The estimated cost of the reported disease can be used to evaluate the cost/efficacy and cost/benefit ratios for prevention and control programmes of emerging arboviruses.
Author Summary
For a long time, studies of chikungunya virus infection have been neglected, but since its resurgence in the south-western Indian Ocean and on La Réunion Island, this disease has been paid greater amounts of attention. The economic and social impacts of chikungunya epidemics are poorly documented, including in developed countries. This study estimated the cost-of-illness associated with the 2005–2006 chikungunya epidemics on La Réunion Island, a French overseas department with an economy and health care system of a developed country. “Cost-of-illness” studies measure the amount that would have been saved in the absence of a disease. We found that the epidemic incurred substantial medical expenses estimated at €43.9 million, of which 60% were attributable to direct medical costs related, in particular, to expenditure on medical consultations (47%), hospitalization (32%) and drugs (19%). The costs related to care in ambulatory and hospitalized cases were €90 and €2000 per case, respectively. This study provides the basic inputs for conducting cost-effectiveness and cost-benefit evaluations of chikungunya prevention strategies.
PMCID: PMC3114750  PMID: 21695162
8.  Preliminary estimation of risk factors for admission to intensive care units and for death in patients infected with A(H1N1)2009 influenza virus, France, 2009-2010 
PLoS Currents  2010;2:RRN1150.
To estimate the magnitude of the risks associated with age, obesity, pregnancy and diabetes, we compared the prevalence of these conditions reported in hospitalized severe cases to that in the general population, during the 2009-2010 A(H1N1) pandemic flu in France. Pregnancy, obesity, heart failure and diabetes were risk factors for admission into an intensive care unit (OR=5.2 [95%CI 4.0-6.9], 3.8 [3.0-4.9], 3.3 [2.6-4.1] and 2.8 [2.3-3.4], respectively). Only heart failure, obesity, and diabetes were significantly associated with death (OR=6.9 [4.9-9.8], 3.6 [1.9-6.2], and 3.5 [2.5-5.1], respectively). Elderly adults were at lower risk of being admitted into an ICU, but at higher risk of death.
PMCID: PMC2836028  PMID: 20228857
9.  Relationship between HIV protease inhibitors and QTc interval duration in HIV-infected patients: a cross-sectional study 
QTc interval prolongation and torsades de pointes have been reported in HIV-infected patients. Protease inhibitors (PIs) are suspected to contribute to this adverse reaction. However, many factors can prolong QTc interval. We examined factors influencing QTc duration in HIV-infected patients.
Unselected HIV-infected patients (n = 978) were enrolled in this prospective, single-centre cross-sectional study. Variables related to infection and treatments were collected. A digital electrocardiographic record was recorded in each patient and QT interval duration was measured and corrected using both Bazett's (QTcB) and Fridericia's (QTcF) formula. Results were analysed with a multivariable linear model.
After excluding arrhythmias and complete bundle branch blocks, QT interval was measured in 956 patients. The mean (SD) QTcB was 418 ms (23) and QTcF was 405 ms (20). QTc was found prolonged (>450 ms in women and >440 ms in men) in 129 [13.5%; 95% confidence interval (CI) 11.5, 15.8] and 38 (4%; 95% CI 2.9, 5.4) patients using Bazett and Fridericia corrections, respectively. On multivariable analysis, incomplete bundle branch block, ventricular hypertrophy, signs of ischaemic cardiopathy, female gender, White ethnic origin and age were significantly associated with QTc prolongation. The only HIV variable independently associated with QTc prolongation was the duration of infection (P = 0.023). After adjustment, anti-HIV treatment, in particular PI (P = 0.99), was not associated with QTc prolongation.
Although PIs block in vitro hERG current, they are not independently associated with QTc interval prolongation. Prolonged QTc interval in HIV-infected patients is primarily associated with factors commonly known to prolong QT and with the duration of HIV infection.
PMCID: PMC2668087  PMID: 19076152
electrocardiography; HIV infection; HIV protease inhibitors; long QT syndrome
10.  Comparison of the antiviral activity of adefovir and tenofovir on hepatitis B virus in HIV-HBV-coinfected patients 
Antiviral Therapy  2008;13(5):705-713.
Characteristics and factors influencing viral decay under TDF and ADV need to be determined in HIV-HBV co-infected patients.
Patients and methods
This non-randomized, open label study compared the HBV DNA decay in 85 HIV-HBV co-infected patients initiating a combined antiretroviral regimen either including TDF or associated with ADV. The first 6 month-change in viral load was analyzed using mixed-linear models. The adjusted hazards rate ratio, comparing the rates of undetectable HBV-DNA between treatments, was calculated using Cox proportional hazard model.
The HBV-DNA decay, adjusted for baseline HBV viral load, was more pronounced in patients treated with TDF than with ADV (−66% versus −53% at 12 months, p=0.0001). Patients in the TDF group presented a steeper slope of decline, estimated at 1.1 (95% CI: 0.9, 1.3) compared to 0.8 (95% CI: 0.6, 1.0) in the ADV group (p=0.036). The mean time to HBV-DNA undetectability was 19.3 months (95% CI: 16.7 – 22.0) with TDF and 25.9 months (95% CI: 21.1 – 30.7) with ADV. When adjusted for HBe Ag, HBV-DNA and ALT levels at baseline, the influence of treatment on time to HBV-DNA undetectability remained in favor of TDF versus ADV (HR = 2.79; 95 % CI: 1.05–7.40, p=0.039)
The early-phase HBV-DNA decay is more strongly influenced by TDF than by ADV. This is associated with a sustained antiviral activity in the TDF group, in which patients reach the threshold of HBV undetectability at a faster rate and at a larger proportion than those taking ADV.
PMCID: PMC2665195  PMID: 18771054
Adenine; analogs & derivatives; pharmacology; therapeutic use; Adult; Antiviral Agents; pharmacology; therapeutic use; DNA, Viral; blood; Drug Therapy, Combination; Female; HIV Infections; complications; drug therapy; virology; Hepatitis B; complications; drug therapy; virology; Hepatitis B virus; drug effects; genetics; Humans; Male; Middle Aged; Phosphonic Acids; pharmacology; therapeutic use; Proportional Hazards Models; Treatment Outcome; Viral Load; chronic hepatitis B, HIV infection, modelling, tenofovir, adefovir
11.  Impact of Capsular Switch on Invasive Pneumococcal Disease Incidence in a Vaccinated Population 
PLoS ONE  2008;3(9):e3244.
Despite the dramatic decline in the incidence of invasive pneumococcal disease (IPD) observed since the introduction of conjugate vaccination, it is feared that several factors may undermine the future effectiveness of the vaccines. In particular, pathogenic pneumococci may switch their capsular types and evade vaccine-conferred immunity.
Methodology/Principal Findings
Here, we first review the literature and summarize the available epidemiological data on capsular switch for S. pneumoniae. We estimate the weekly probability that a persistently carried strain may switch its capsule from four studies, totalling 516 children and 6 years of follow-up, at 1.5×10−3/week [4.6×10−5–4.8×10−3/week]. There is not enough power to assess an increase in this frequency in vaccinated individuals. Then, we use a mathematical model of pneumococcal transmission to quantify the impact of capsular switch on the incidence of IPD in a vaccinated population. In this model, we investigate a wide range of values for the frequency of vaccine-selected capsular switch. Predictions show that, with vaccine-independent switching only, IPD incidence in children should be down by 48% 5 years after the introduction of the vaccine with high coverage. Introducing vaccine-selected capsular switch at a frequency up to 0.01/week shows little effect on this decrease; yearly, at most 3 excess cases of IPD per 106 children might occur due to switched pneumococcal strains.
Based on all available data and model predictions, the existence of capsular switch by itself should not impact significantly the efficacy of pneumococcal conjugate vaccination on IPD incidence. This optimistic result should be tempered by the fact that the selective pressure induced by the vaccine is currently increasing along with vaccine coverage worldwide; continued surveillance of pneumococcal populations remains of the utmost importance, in particular during clinical trials of the new conjugate vaccines.
PMCID: PMC2531230  PMID: 18802466
12.  Risk Assessment of Transmission of Sporadic Creutzfeldt-Jakob Disease in Endodontic Practice in Absence of Adequate Prion Inactivation 
PLoS ONE  2007;2(12):e1330.
Experimental results evidenced the infectious potential of the dental pulp of animals infected with transmissible spongiform encephalopathies (TSE). This route of iatrogenic transmission of sporadic Creutzfeldt-Jakob disease (sCJD) may exist in humans via reused endodontic instruments if inadequate prion decontamination procedures are used.
Methodology/Principal Findings
To assess this risk, 10 critical parameters in the transmission process were identified, starting with contamination of an endodontic file during treatment of an infectious sCJD patient and ending with possible infection of a subsequent susceptible patient. It was assumed that a dose-risk response existed, with no-risk below threshold values. Plausible ranges of those parameters were obtained through literature search and expert opinions, and a sensitivity analysis was conducted. Without effective prion-deactivation procedures, the risk of being infected during endodontic treatment ranged between 3.4 and 13 per million procedures. The probability that more than one case was infected secondary to endodontic treatment of an infected sCJD patient ranged from 47% to 77% depending on the assumed quantity of infective material necessary for disease transmission. If current official recommendations on endodontic instrument decontamination were strictly followed, the risk of secondary infection would become quasi-null.
The risk of sCJD transmission through endodontic procedure compares with other health care risks of current concern such as death after liver biopsy or during general anaesthesia. These results show that single instrument use or adequate prion-decontamination procedures like those recently implemented in dental practice must be rigorously enforced.
PMCID: PMC2129113  PMID: 18159228
13.  ISHAPE: new rapid and accurate software for haplotyping 
BMC Bioinformatics  2007;8:205.
We have developed a new haplotyping program based on the combination of an iterative multiallelic EM algorithm (IEM), bootstrap resampling and a pseudo Gibbs sampler. The use of the IEM-bootstrap procedure considerably reduces the space of possible haplotype configurations to be explored, greatly reducing computation time, while the adaptation of the Gibbs sampler with a recombination model on this restricted space maintains high accuracy. On large SNP datasets (>30 SNPs), we used a segmented approach based on a specific partition-ligation strategy. We compared this software, Ishape (Iterative Segmented HAPlotyping by Em), with reference programs such as Phase, Fastphase, and PL-EM. Analogously with Phase, there are 2 versions of Ishape: Ishape1 which uses a simple coalescence model for the pseudo Gibbs sampler step, and Ishape2 which uses a recombination model instead.
We tested the program on 2 types of real SNP datasets derived from Hapmap: adjacent SNPs (high LD) and SNPs spaced by 5 Kb (lower level of LD). In both cases, we tested 100 replicates for each size: 10, 20, 30, 40, 50, 60, and 80 SNPs. For adjacent SNPs Ishape2 is superior to the other software both in terms of speed and accuracy. For SNPs spaced by 5 Kb, Ishape2 yields similar results to Phase2.1 in terms of accuracy, and both outperform the other software.
In terms of speed, Ishape2 runs about 4 times faster than Phase2.1 with 10 SNPs, and about 10 times faster with 80 SNPs. For the case of 5kb-spaced SNPs, Fastphase may run faster with more than 100 SNPs.
These results show that the Ishape heuristic approach for haplotyping is very competitive in terms of accuracy and speed and deserves to be evaluated extensively for possible future widespread use.
PMCID: PMC1919397  PMID: 17573965

Results 1-13 (13)