Pierre-Yves Boëlle

Epidemiology and treatment of painful procedures in neonates in intensive care units.

CONTEXT Effective strategies to improve pain management in neonates require a clear understanding of the epidemiology and management of procedural pain. OBJECTIVE To report epidemiological data on neonatal pain collected from a geographically defined region, based on direct bedside observation of neonates. DESIGN, SETTING, AND PATIENTS Between September 2005 and January 2006, data on all painful and stressful procedures and corresponding analgesic therapy from the first 14 days of admission were prospectively collected within a 6-week period from 430 neonates admitted to tertiary care centers in the Paris region of France (11.3 millions inhabitants) for the Epidemiology of Procedural Pain in Neonates (EPIPPAIN) study. MAIN OUTCOME MEASURE Number of procedures considered painful or stressful by health personnel and corresponding analgesic therapy. RESULTS The mean (SD) gestational age and intensive care unit stay were 33.0 (4.6) weeks and 8.4 (4.6) calendar days, respectively. Neonates experienced 60,969 first-attempt procedures, with 42,413 (69.6%) painful and 18,556 (30.4%) stressful procedures; 11,546 supplemental attempts were performed during procedures including 10,366 (89.8%) for painful and 1180 (10.2%) for stressful procedures. Each neonate experienced a median of 115 (range, 4-613) procedures during the study period and 16 (range, 0-62) procedures per day of hospitalization. Of these, each neonate experienced a median of 75 (range, 3-364) painful procedures during the study period and 10 (range, 0-51) painful procedures per day of hospitalization. Of the 42,413 painful procedures, 2.1% were performed with pharmacological-only therapy; 18.2% with nonpharmacological-only interventions, 20.8% with pharmacological, nonpharmacological, or both types of therapy; and 79.2% without specific analgesia, and 34.2% were performed while the neonate was receiving concurrent analgesic or anesthetic infusions for other reasons. Prematurity, category of procedure, parental presence, surgery, daytime, and day of procedure after the first day of admission were associated with greater use of specific preprocedural analgesia, whereas mechanical ventilation, noninvasive ventilation and administration of nonspecific concurrent analgesia were associated with lower use of specific preprocedural analgesia. CONCLUSION During neonatal intensive care in the Paris region, large numbers of painful and stressful procedures were performed, the majority of which were not accompanied by analgesia.

Estimating the impact of school closure on influenza transmission from Sentinel data

The threat posed by the highly pathogenic H5N1 influenza virus requires public health authorities to prepare for a human pandemic. Although pre-pandemic vaccines and antiviral drugs might significantly reduce illness rates, their stockpiling is too expensive to be practical for many countries. Consequently, alternative control strategies, based on non-pharmaceutical interventions, are a potentially attractive policy option. School closure is the measure most often considered. The high social and economic costs of closing schools for months make it an expensive and therefore controversial policy, and the current absence of quantitative data on the role of schools during influenza epidemics means there is little consensus on the probable effectiveness of school closure in reducing the impact of a pandemic. Here, from the joint analysis of surveillance data and holiday timing in France, we quantify the role of schools in influenza epidemics and predict the effect of school closure during a pandemic. We show that holidays lead to a 20–29% reduction in the rate at which influenza is transmitted to children, but that they have no detectable effect on the contact patterns of adults. Holidays prevent 16–18% of seasonal influenza cases (18–21% in children). By extrapolation, we find that prolonged school closure during a pandemic might reduce the cumulative number of cases by 13–17% (18–23% in children) and peak attack rates by up to 39–45% (47–52% in children). The impact of school closure would be reduced if it proved difficult to maintain low contact rates among children for a prolonged period.

Significant Reduction of Antibiotic Use in the Community after a Nationwide Campaign in France, 2002–2007

Didier Guillemot and colleagues describe the evaluation of a nationwide programme in France aimed at decreasing unnecessary outpatient prescriptions for antibiotics. The campaign was successful, particularly in reducing prescriptions for children.

Diffusion-weighted magnetic resonance imaging for the assessment of fibrosis in chronic hepatitis C†

Liver biopsy is the gold standard for assessing fibrosis but has several limitations. We evaluated a noninvasive method, so‐called diffusion‐weighted magnetic resonance imaging (DWMRI), which measures the apparent diffusion coefficient (ADC) of water, for the diagnosis of liver fibrosis in patients with chronic hepatitis C virus (HCV). We analyzed 20 healthy volunteers and 54 patients with chronic HCV (METAVIR: F0, n = 1; F1, n = 30; F2, n = 8; F3, n = 5; and F4, n = 10) prospectively included. Patients with moderate‐to‐severe fibrosis (F2‐F3‐F4) had hepatic ADC values lower than those without or with mild fibrosis (F0‐F1; mean: 1.10 ± 0.11 versus 1.30 ± 0.12 × 10−3 mm2/s) and healthy volunteers (mean: 1.44 ± 0.02 × 10−3 mm2/s). In discriminating patients staged F3‐F4, the areas under the receiving operating characteristic curves (AUCs) were 0.92 (±0.04) for magnetic resonance imaging (MRI), 0.92 (±0.05) for elastography, 0.79 (±0.08) for FibroTest, 0.87 (±0.06) for the aspartate aminotransferase to platelets ratio index (APRI), 0.86 (±0.06) for the Forns index, and 0.87 (±0.06) for hyaluronate. In these patients, the sensitivity, specificity, positive predictive value, and negative predictive value were 87%, 87%, 72%, and 94%, respectively, with an ADC cutoff level of 1.21 × 10−3 mm2/s. In discriminating patients staged F2‐F3‐F4, the AUC values were 0.79 (±0.07) for MRI, 0.87 (±0.05) for elastography, 0.68 (±0.09) for FibroTest, 0.81 (±0.06) for APRI, 0.72 (±0.08) for the Forns index, and 0.77 (±0.06) for hyaluronate. Conclusion: This preliminary study suggests that DWMRI compares favorably with other noninvasive tests for the presence of significant liver fibrosis. (HEPATOLOGY 2007.)

Understanding the dynamics of Ebola epidemics

Ebola is a highly lethal virus, which has caused at least 14 confirmed outbreaks in Africa between 1976 and 2006. Using data from two epidemics [in Democratic Republic of Congo (DRC) in 1995 and in Uganda in 2000], we built a mathematical model for the spread of Ebola haemorrhagic fever epidemics taking into account transmission in different epidemiological settings. We estimated the basic reproduction number (R0) to be 2.7 (95% CI 1.9-2.8) for the 1995 epidemic in DRC, and 2.7 (95% CI 2.5-4.1) for the 2000 epidemic in Uganda. For each epidemic, we quantified transmission in different settings (illness in the community, hospitalization, and traditional burial) and simulated various epidemic scenarios to explore the impact of control interventions on a potential epidemic. A key parameter was the rapid institution of control measures. For both epidemic profiles identified, increasing hospitalization rate reduced the predicted epidemic size.

ABCB4 gene mutation-associated cholelithiasis in adults.

BACKGROUND & AIMS We recently put forward arguments in favor of ABCB4 gene (adenosine triphosphate-binding cassette, subfamily B, member 4) defects as a risk factor for symptomatic cholelithiasis in adults. In this study, we characterized ABCB4 gene mutations in a series of patients with symptomatic cholelithiasis to determine the genetic basis and the clinical phenotype of ABCB4 gene mutation-associated cholelithiasis. METHODS We analyzed the entire ABCB4 gene coding sequences in a first group of 32 patients who had a clinical history compatible with the syndrome previously described, in a second group of 28 patients who presented with a classic gallstone disease that justified a cholecystectomy, and in a third group of 33 patients without a history of cholelithiasis. RESULTS We identified both heterozygous and homozygous ABCB4 gene point mutations in 18 of 32 (56%) patients who presented with clinical criteria of the syndrome, whereas no mutation was detected in the 2 other groups of patients (P < 0.001). Three independent clinical features were strongly associated with point mutations: recurrence of symptoms after cholecystectomy (odds ratio, 8.5); intrahepatic hyperechoic foci, intrahepatic sludge, or microlithiasis (odds ratio, 6.1); and age <40 years at the onset of symptoms (odds ratio, 3.0). ABCB4 gene point mutations were detected exclusively in the patients who showed 2 or 3 of these clinical features. CONCLUSIONS Our results show that ABCB4 gene mutations represent a major genetic risk factor in a symptomatic and recurring form of cholelithiasis in young adults.

Stage II Colon Cancer Prognosis Prediction by Tumor Gene Expression Profiling

PURPOSE This study mainly aimed to identify and assess the performance of a microarray-based prognosis predictor (PP) for stage II colon cancer. A previously suggested 23-gene prognosis signature (PS) was also evaluated. PATIENTS AND METHODS Tumor mRNA samples from 50 patients were profiled using oligonucleotide microarrays. PPs were built and assessed by random divisions of patients into training and validation sets (TSs and VSs, respectively). For each TS/VS split, a 30-gene PP, identified on the TS by selecting the 30 most differentially expressed genes and applying diagonal linear discriminant analysis, was used to predict the prognoses of VS patients. Two schemes were considered: single-split validation, based on a single random split of patients into two groups of equal size (group 1 and group 2), and Monte Carlo cross validation (MCCV), whereby patients were repeatedly and randomly divided into TS and VS of various sizes. RESULTS The 30-gene PP, identified from group 1 patients, yielded an 80% prognosis prediction accuracy on group 2 patients. MCCV yielded the following average prognosis prediction performance measures: 76.3% accuracy, 85.1% sensitivity, and 67.5% specificity. Improvements in prognosis prediction were observed with increasing TS size. The 30-gene PS were found to be highly-variable across TS/VS splits. Assessed on the same random splits of patients, the previously suggested 23-gene PS yielded a 67.7% mean prognosis prediction accuracy. CONCLUSION Microarray gene expression profiling is able to predict the prognosis of stage II colon cancer patients. The present study also illustrates the usefulness of resampling techniques for honest performance assessment of microarray-based PPs.

Cirrhotic patients in the medical intensive care unit: Early prognosis and long-term survival*

Objectives:To reassess the prognosis of patients with cirrhosis admitted to the intensive care unit. Design:A retrospective study in a medical intensive care unit in a teaching hospital in France. Patients:All patients with cirrhosis without previous liver transplantation admitted in the period from 2005 to 2008. Interventions:None. Main Results:One hundred thirty-eight patients were studied. Survival rates in the intensive care unit, in hospital, and at 6 months were 59% (95% confidence interval, 50%–67%), 46% (95% confidence interval, 38%–54%), and 38% (95% confidence interval, 30%–47%), respectively. In-hospital survival rates for patients requiring vasopressors, mechanical ventilation, or renal replacement therapy were 20%, 33%, and 31%, respectively. On day 1, independent risk factors for inhospital mortality were age, albuminemia, international normalized ratio, and the Sequential Organ Failure Assessment score computed after discarding points for hematologic failure (modified Sequential Organ Failure Assessment score). Liver disease severity, assessed using a clinical classification, did not correlate with in-hospital mortality. In patients still alive after 3 days, the only prognostic factor was the modified Sequential Organ Failure Assessment score computed after 3 days. To predict inhospital mortality, the modified Sequential Organ Failure Assessment score on day 1 had a greater area under the receiver operating characteristic curve (0.84) than the Simplified Acute Physiology Score II (0.78), the Child-Pugh score (0.76), the model for end-stage liver disease score (0.77), or the model for end-stage liver disease–natremia score (0.75). The inhospital mortality rate with three or four nonhematologic organ failures on day 1 was not >70%, whereas it was 89% with three nonhematologic organ failures after 3 days spent in the intensive care unit. Conclusion:In-hospital survival rate of intensive care unit-admitted cirrhotic patients seemed acceptable, even in patients requiring life-sustaining treatments and/or with multiple organ failure on admission. The most important risk factor for in-hospital mortality was the severity of nonhematologic organ failure, as best assessed after 3 days. A trial of unrestricted intensive care for a few days could be proposed for select critically ill cirrhotic patients.

Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis.

Variants associated with meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10−12 at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10−9 at rs4077468) accounted for ∼5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.

Chains of transmission and control of Ebola virus disease in Conakry, Guinea, in 2014: an observational study

BACKGROUND An epidemic of Ebola virus disease of unprecedented size continues in parts of west Africa. For the first time, large urban centres such as Conakry, the capital of Guinea, are affected. We did an observational study of patients with Ebola virus disease in three regions of Guinea, including Conakry, aiming to map the routes of transmission and assess the effect of interventions. METHODS Between Feb 10, 2014, and Aug 25, 2014, we obtained data from the linelist of all confirmed and probable cases in Guinea (as of Sept 16, 2014), a laboratory database of information about patients, and interviews with patients and their families and neighbours. With this information, we mapped chains of transmission, identified which setting infections most probably originated from (community, hospitals, or funerals), and computed the context-specific and overall reproduction numbers. FINDINGS Of 193 confirmed and probable cases of Ebola virus disease reported in Conakry, Boffa, and Télimélé, 152 (79%) were positioned in chains of transmission. Health-care workers contributed little to transmission. In March, 2014, individuals with Ebola virus disease who were not health-care workers infected a mean of 2·3 people (95% CI 1·6-3·2): 1·4 (0·9-2·2) in the community, 0·4 (0·1-0·9) in hospitals, and 0·5 (0·2-1·0) at funerals. After the implementation of infection control in April, the reproduction number in hospitals and at funerals reduced to lower than 0·1. In the community, the reproduction number dropped by 50% for patients that were admitted to hospital, but remained unchanged for those that were not. In March, hospital transmissions constituted 35% (seven of 20) of all transmissions and funeral transmissions constituted 15% (three); but from April to the end of the study period, they constituted only 9% (11 of 128) and 4% (five), respectively. 82% (119 of 145) of transmission occurred in the community and 72% (105) between family members. Our simulations show that a 10% increase in hospital admissions could have reduced the length of chains by 26% (95% CI 4-45). INTERPRETATION In Conakry, interventions had the potential to stop the epidemic, but reintroductions of the disease and poor cooperation of a few families led to prolonged low-level spread, showing the challenges of Ebola virus disease control in large urban centres. Monitoring of chains of transmission is crucial to assess and optimise local control strategies for Ebola virus disease. FUNDING Labex IBEID, Reacting, PREDEMICS, NIGMS MIDAS initiative, Institut Pasteur de Dakar.