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Background: Respiratory syncytial virus (RSV) is the leading cause of lower-respiratory-tract infection in children. Nirsevimab, a monoclonal antibody against RSV, was implemented in a few countries in September 2023. However, its post-license effectiveness in ambulatory care settings is unknown. We aimed to assess the effectiveness of nirsevimab against RSV-bronchiolitis in outpatients aged <12 months., Methods: We conducted a test-negative case-control study based on a national ambulatory surveillance system. We included all infants aged <12 months who had bronchiolitis and results of an RSV rapid antigen test performed, visiting a network of 107 ambulatory paediatricians from September 15, 2023, to February 1, 2024. Case patients were infants with bronchiolitis and a rapid antigen test positive for RSV. Control patients were infants with bronchiolitis and a rapid antigen test negative for RSV. Effectiveness was assessed by a logistic regression model adjusted for potential confounders. A range of sensitivity analyses were conducted to assess the robustness of the findings., Findings: We included 883 outpatients who had bronchiolitis and results of an RSV rapid antigen test (453 were case patients, and 430 were control patients). Overall, 62/453 (13.7%) case patients and 177/430 (41.2%) control patients had been previously immunised for nirsevimab. The adjusted effectiveness of nirsevimab against RSV-bronchiolitis was 79.7% (95% CI 67.7-87.3). Sensitivity analyses gave similar results., Interpretation: This post-license study indicates that nirsevimab was effective in preventing RSV-bronchiolitis in ambulatory care settings., Funding: The study was supported by Association Clinique et Thérapeutique Infantile du Val de Marne (ACTIV), French Pediatrician Ambulatory Association (AFPA) and unrestricted grants from GSK, MSD, Pfizer and Sanofi., Competing Interests: YL has no conflicts of interest to disclose. RB declares receiving fees from Sanofi and MSD for medical conferences or scientific meetings. CL declares receiving travel grants from MSD, Pfizer and fees from MSD and Pfizer for scientific meetings and expert board participation. AW declares receiving fees from Sanofi, GSK and MSD for medical conferences or scientific meetings. FCS declares receiving fees from Sanofi for expert board participation. CB declares receiving fees from Sanofi, GSK and MSD for medical conferences or scientific meetings. RC reports personal fees and non-financial support from Pfizer and personal fees from GSK, Merck, Pfizer, Sanofi, Viatris outside the submitted work. NO declares receiving travel grants from MSD, Pfizer, Sanofi, and GSK., (© 2024 The Authors.)

Introduction: Fever treatment is commonly applied in patients with sepsis but its impact on survival remains undetermined. Patients with respiratory and haemodynamic failure are at the highest risk for not tolerating the metabolic cost of fever. However, fever can help to control infection. Treating fever with paracetamol has been shown to be less effective than cooling. In the SEPSISCOOL pilot study, active fever control by external cooling improved organ failure recovery and early survival. The main objective of this confirmatory trial is to assess whether fever control at normothermia can improve the evolution of organ failure and mortality at day 60 of febrile patients with septic shock. This study will compare two strategies within the first 48 hours of septic shock: treatment of fever with cooling or no treatment of fever., Methods and Analysis: SEPSISCOOL II is a pragmatic, investigator-initiated, adaptive, multicentre, open-label, randomised controlled, superiority trial in patients admitted to the intensive care unit with febrile septic shock. After stratification based on the acute respiratory distress syndrome status, patients will be randomised between two arms: (1) cooling and (2) no cooling. The primary endpoint is mortality at day 60 after randomisation. The secondary endpoints include the evolution of organ failure, early mortality and tolerance. The target sample size is 820 patients., Ethics and Dissemination: The study is funded by the French health ministry and was approved by the ethics committee CPP Nord Ouest II (Amiens, France). The results will be submitted for publication in peer-reviewed journals., Trial Registration Number: NCT04494074., Competing Interests: Competing interests: FS is a member of the executive committee of the French Intensive Care Society (SRLF). All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Haemophilus influenzae (Hi) is one of the leading bacteria implicated in childhood acute otitis media (AOM). Recent concerns have been raised about the emergence of Hi-resistant strains. We aimed to analyze the evolution of β-lactam resistance to Hi among strains isolated from nasopharyngeal carriage in children with AOM and in mild ear fluid (MEF) after the spontaneous perforation of the tympanic membrane (SPTM) in France. In this national ambulatory-based cohort study over 16 years, we analyzed the rate of Hi nasopharyngeal carriage and the proportion of β-lactam-resistant Hi strains over time using a segmented linear regression model. Among the 13,865 children (median [IQR] age, 12.7 [9.3-17.3] months; 7400 [53.4%] male) with AOM included from November 2006 to July 2022, Hi was isolated in 7311 (52.7%) children by nasopharyngeal sampling. The proportion of β-lactamase-producing and β-lactamase-negative, ampicillin-resistant (BLNAR) Hi strains in nasopharyngeal carriage remained stable during the study period. Among the 783 children (median [IQR] age, 20 [12.3-37.8] months; 409 [52.2%] male) with SPTM included from October 2015 to July 2022, Hi was isolated in 177 (22.6%) cases by MEF sampling. The proportions of β-lactamase-producing and BLNAR Hi strains did not significantly differ between nasopharyngeal (17.6% and 8.8%, respectively) and MEF (12.6% and 7.4%) samples. Accordingly, amoxicillin remains a valid recommendation as the first-line drug for AOM in France.

Objectives: We report the first case series focusing on clinical and biological characteristics of meningitis caused by ESBL-producing Escherichia coli in infants., Methods: Between 2001 and 2020, data on all cases of E. coli meningitis were prospectively collected from a network of 259 paediatric wards and 168 microbiology laboratories in France. We analysed the clinical and biological characteristics, short-term complications and long-term sequelae of ESBL-producing E. coli meningitis cases in patients <6 months old., Results: In total, 548 cases of E. coli paediatric meningitis were reported. ESBL-producing E. coli represented 12 (2.2%) cases. We included 10 patients aged <6 months old. Eight (80%) patients presented at least one sign of clinical severity: six needed mechanical ventilation, three presented signs of shock and one was in a coma. The overall short-term prognosis was good, with only one meningitis-attributed death in the first hours of care. All surviving children received carbapenems for a median of 21 days (range 9-28). Two relapses occurred, including one in a patient who received only 14 days of imipenem. We reported no long-term sequelae at a median follow-up of 20 months., Conclusions: Meropenem seems to be the treatment of choice for ESBL-producing E. coli meningitis in children and needs to be given as early as possible (<48 h) and for at least 21 days. Maternal colonization or infection with ESBL-producing Enterobacteriaceae needs to be reported to the neonatal or paediatric ICU team, in order to adapt the empirical antibiotic therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Many studies implicate microglia in the pathogenesis of Alzheimer's disease (AD) but precisely how these cells make their impact has not been determined to date. One contributory factor is likely to be the enhanced production of inflammatory mediators and it is now known that microglia with this secretory phenotype exhibit other adaptations including in their morphology, function, and metabolism. AD, like many neurological disorders, demonstrates a sex bias and recent evidence indicates that the sexual dimorphism in microglial function, which has been recognized for many years in early development, persists into adulthood and aging. Here, we demonstrate sex-related differences in microglia from post mortem tissue of male and female AD patients and a marked increase in the number of dystrophic and rod-shaped microglia in tissue from female AD patients compared with males. Furthermore, there was an increase in iron-laden microglia in tissue from female AD patients and this has been reported to reflect mitochondrial changes. To address this further, we assessed changes in microglia from male and female APP/PS1 mice and demonstrate that iron accumulation in microglia is increased to a greater extent in tissue prepared from females compared with males. This was associated with altered expression of genes coding for proteins that modulate mitochondrial function. The findings suggest that sex-related differences in the severity and perhaps incidence of AD may, at least in part, arise from sexual dimorphism in microglia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 O’Neill, Mela, Gaban, Bechet, McGrath, Walsh, McIntosh and Lynch.)

Therapeutic strategies for Alzheimer's disease (AD) have largely focused on the regulation of amyloid pathology while those targeting tau pathology, and inflammatory mechanisms are less explored. In this regard, drugs with multimodal and concurrent targeting of Aβ, tau, and inflammatory processes may offer advantages. Here, we investigate one such candidate drug in the triple transgenic 3xTg-AD mouse model of AD, namely the disease-modifying oral neuroimmunomodulatory therapeutic used in patients with multiple sclerosis, called fingolimod. In this study, administration of fingolimod was initiated after behavioral symptoms are known to emerge, at 6 months of age. Treatment continued to 12 months when behavioral tests were performed and thereafter histological and biochemical analysis was conducted on postmortem tissue. The results demonstrate that fingolimod reverses deficits in spatial working memory at 8 and 12 months of age as measured by novel object location and Morris water maze tests. Inflammation in the brain is alleviated as demonstrated by reduced Iba1-positive and CD3-positive cell number, less ramified microglial morphology, and improved cytokine profile. Finally, treatment with fingolimod was shown to reduce phosphorylated tau and APP levels in the hippocampus and cortex. These results highlight the potential of fingolimod as a multimodal therapeutic for the treatment of AD., (© 2022. The Author(s).)

There is a striking sex-related difference in the prevalence of many neurodegenerative diseases, highlighting the need to consider whether treatments may exert sex-specific effects. A change in microglial activation state is a common feature of several neurodegenerative diseases and is considered to be a key factor in driving the inflammation that characterizes these conditions. Among the changes that have been described is a switch in microglial metabolism towards glycolysis which is associated with production of inflammatory mediators and reduced function. Marked sex-related differences in microglial number, phenotype and function have been described in late embryonic and early postnatal life in rodents and some reports suggest that sexual dimorphism extends into adulthood and age and, in models of Alzheimer's disease, the changes are more profound in microglia from female, compared with male, mice. Dimethyl fumarate (DMF) is a fumaric acid ester used in the treatment of psoriasis and relapsing remitting multiple sclerosis and, while its mechanism of action is unclear, it possesses anti-inflammatory and anti-oxidant properties and also impacts on cell metabolism. Here we treated 16-18-month-old female and male mice with DMF for 1 month and assessed its effect on microglia. The evidence indicates that it exerted sex-specific effects on microglial morphology and metabolism, reducing glycolysis only in microglia from female mice. The data suggest that this may result from its ability to inactivate glyceraldehyde-3-phosphate dehydrogenase (GAPDH).

Objectives: Oral treatment of febrile urinary tract infections (FUTIs) can be impaired by MDR Enterobacterales often combining ESBL and inhibitor-resistant genes. We studied the impact of β-lactamases and Enterobacterales' genotypes on the cefixime, cefpodoxime and mecillinam ± amoxicillin/clavulanate MICs., Materials and Methods: In this multicentric study, we included 251 previously whole-genome-sequenced ESBL-producing Enterobacterales, isolated in French children with FUTIs. The MICs of cefixime, cefpodoxime, mecillinam alone and combined with amoxicillin/clavulanate were determined and analysed with respect to genomic data. We focused especially on the isolates' ST and their type of β-lactamases. Clinical outcomes of patients who received cefixime + amoxicillin/clavulanate were also analysed., Results: All isolates were cefixime and cefpodoxime resistant. Disparities depending on blaCTX-M variants were observed for cefixime. The addition of amoxicillin/clavulanate restored susceptibility for cefixime and cefpodoxime in 97.2% (MIC50/90 of 0.38/0.75 mg/L) and 55.4% (MIC50/90 of 1/2 mg/L) of isolates, respectively, whatever the ST, the blaCTX-M variants or the association with inhibitor-resistant β-lactamases (34.2%). All isolates were susceptible to mecillinam + amoxicillin/clavulanate with MIC50/90 of 0.19/0.25 mg/L, respectively. Neither therapeutic failure nor any subsequent positive control urine culture were reported for patients who received cefixime + amoxicillin/clavulanate as an oral relay therapy (n = 54)., Conclusions: Despite the frequent association of ESBL genes with inhibitor-resistant β-lactamases, the cefixime + amoxicillin/clavulanate MICs remain low. The in vivo efficacy of this combination was satisfying even when first-line treatment was ineffective. Considering the MIC distributions and pharmacokinetic parameters, mecillinam + amoxicillin/clavulanate should also be an alternative to consider when treating FUTIs in children., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Sleeve gastrectomy is the most common bariatric procedure worldwide. Several studies report good short- and midterm results. However, recent studies report alarming long-term outcomes, in particular about the revision rate., Objectives: The aim of this study is the assessment of the revisional rate after sleeve gastrectomy and the analysis of most common reasons for surgical conversion and early complications., Setting: This study is based on a national claims database comprehensive of all bariatric procedures performed in a 10-year period., Methods: The French Programme De Médicalisation des Systèmes d'Information database was used to identify all patients who underwent sleeve gastrectomy between 2008 and 2018. Codes for diagnoses and procedures were used to describe the reason for and the morbidity of revision surgeries. Multivariate Cox proportional hazard regression analysis was performed to compare the risk of having a revision procedure., Results: During the analyzed period, a total of 224,718 sleeve gastrectomies were performed. The rate of revision surgery after sleeve gastrectomy was 4.7%, 7.5%, and 12.2%, at 5, 7, and 10 years post procedure, respectively. A history of gastric banding was associated with a higher risk of revision (hazard ratio, 2.81; 95% CI, 2.66-2.95; P < .001). The most common revision procedure was gastric bypass (75.2%), followed by resleeve (18.7%). The main reasons for revision surgery were persistence of obesity (87.0%) and gastroesophageal reflux disease (5.2%). After revision surgery, we observed the following complications: 5.1% gastric leak, 18% bleeding, and reoperation rate of 6.4%., Conclusions: This study suggests that a large number of patients who initially underwent a sleeve gastrectomy will undergo a revisional surgery. This information should be considered in the initial choice of the bariatric procedure, and patients should be informed of the mid- and long-term risks., (Copyright © 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The population structure of extraintestinal pathogenic Escherichia coli evolves over time, notably due to the emergence of antibiotic-resistant clones such as ESBL-producing Enterobacteriaceae (ESBL-E)., Objectives: To analyse by WGS the genetic diversity of a large number of ESBL-E isolated from urinary tract infections in children from paediatric centres across France between 2014 and 2017 and collected by the National Observatory of febrile urinary tract infection (FUTI) caused by ESBL-E., Methods: A total of 40 905 Enterobacteriaceae-positive urine cultures were identified. ESBL-E were found in 1983 samples (4.85%). WGS was performed on 251 ESBL-E causing FUTI. STs, core genome MLST (cgMLST), serotype, fimH allele, ESBL genes and presence of papGII key virulence factor were determined., Results: E. coli and Klebsiella pneumoniae were found in 86.9% (218/251) and 11.2% (28/251) of cases, respectively. Several STs predominate among E. coli such as ST131, ST38, ST69, ST73, ST95, ST405, ST12 and ST1193, while no ST emerged in K. pneumoniae. E. coli ST131, ST38 and ST1193 increased during the study period, with a heterogeneity in papGII prevalence (64.5%, 35% and 20% respectively). Most isolates harboured the CTX-M type (97%) with a predominance of blaCTX-M-15. blaCTX-M-27, an emerging variant in E. coli, is found in various STs. cgMLST enabled discrimination of clusters within the main STs., Conclusions: The predominance of ST131, and the emergence of other STs such as ST38 and ST1193 combined with ESBL genes deserves close epidemiological surveillance considering their high threat in infectious disease. cgMLST could be a discriminant complementary tool for the analyses., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Over the past 3 decades, the pediatric department of the university Intercommunal Créteil hospital, a referral center for sickle cell disease (SCD), has prospectively evaluated immunoglobulin (Ig) levels in a cohort of 888 children with SCD, including 731 with severe sickle genotypes (HbSS and HbSβ 0 thalassemia) and 157 with milder genotypes (HbSC and HbSβ + thalassemia). We found consistent sickle genotype differences in levels of IgG and IgA, with increased levels of IgA and IgG in the severe versus milder genotype, from early childhood to late adolescence. Additionally, our results revealed a low serum IgM level, irrespective of sickle genotype. Finally, we found that IgA and IgG levels were significantly increased after therapeutic intensification with hydroxyurea but were stabilized in children receiving a transfusion program. The mechanisms contributing to these changes in Ig levels are unclear as is their clinical significance. We believe they should be further investigated.

Background: Pneumococcal conjugate vaccine (PCV) implementations led to major changes in serotype distribution and antibiotic resistance in carriage, accompanied by changes in antibiotic consumption., Objectives: To assess the dynamic patterns of antimicrobial non-susceptibility across non-PCV13 serotypes following PCV implementations., Methods: We conducted a quasi-experimental interrupted time series analysis based on a 17 year French nationwide prospective cohort. From 2001 to 2018, 121 paediatricians obtained nasopharyngeal swabs from children with acute otitis media who were aged 6 months to 2 years. The main outcome was the rate of penicillin-non-susceptible pneumococci (PNSP), analysed by segmented regression., Results: We enrolled 10 204 children. After PCV13 implementation, the PNSP rate decreased (-0.5% per month; 95% CI -0.9 to -0.1), then, after 2014, the rate slightly increased (+0.7% per month; 95% CI +0.2 to +1.2). Global antibiotic use within the previous 3 months decreased over the study period (-22.2%; 95% CI -33.0 to -11.3), but aminopenicillin use remained high. Among the main non-PCV13 serotypes, four dynamic patterns of penicillin susceptibility evolution were observed, including unexpected patterns of serotypes emerging while remaining or even becoming penicillin susceptible. In contrast to PNSP strains, for these latter patterns, the rate of co-colonization with Haemophilus influenzae increased concomitant with their emergence., Conclusions: In a context of continuing high antibiotic selective pressure, a progressive increase in PNSP rate was observed after 2014. However, we highlighted an unexpected variability in dynamic patterns of penicillin susceptibility among emerging non-PCV13 serotypes. Antibiotic resistance may not be the only adaptive mechanism to antimicrobial selective pressure, and co-colonization with H. influenzae may be involved., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The recent emergence and diffusion in the community of Escherichia coli isolates belonging to the multidrug-resistant and CTX-M-27-producing sequence type 131 (ST131) C1-M27 cluster makes this cluster potentially as epidemic as the worldwide E. coli ST131 subclade C2 composed of multidrug-resistant isolates producing CTX-M-15. Thirty-five extended-spectrum beta-lactamase (ESBL)-producing ST131 isolates were identified in a cohort of 1,885 French children over a 5-year period. They were sequenced to characterize the ST131 E. coli isolates producing CTX-M-27 recently emerging in France. ST131 isolates producing CTX-M-27 ( n = 17), and particularly those belonging to the C1-M27 cluster ( n = 14), carried many resistance-encoding genes and predominantly an F1:A2:B20 plasmid type. In multivariate analysis, having been hospitalized since birth (odds ratio [OR], 10.9; 95% confidence interval [CI], 2.4 to 48.8; P = 0.002) and being cared for in a day care center (OR, 9.4; 95% CI, 1.5 to 59.0; P  = 0.017) were independent risk factors for ST131 CTX-M-27 fecal carriage compared with ESBL-producing non-ST131 isolates. No independent risk factor was found when comparing CTX-M-15 ( n = 11)- and CTX-M-1/14 ( n = 7)-producing ST131 isolates with ESBL-producing non-ST131 isolates or with non-ESBL-producing isolates. Several factors may contribute to the increase in fecal carriage of CTX-M-27-producing E. coli isolates, namely, resistance to multiple antibiotics, capacity of the CTX-M-27 enzyme to hydrolyze both cefotaxime and ceftazidime, carriage of a peculiar F-type plasmid, and/or capacity to colonize children who have been hospitalized since birth or who attend day care centers., (Copyright © 2019 American Society for Microbiology.)

Background: Biofilm production by Haemophilus influenzae and Streptococcus pneumoniae has been implicated in the pathogenesis of otitis media, mainly in chronic and recurrent cases. We studied the "in vitro" biofilm production by these 2 species isolated alone or together from the nasopharynx of children with acute otitis media., Methods: The studied strains were from 3 pneumococcal conjugate vaccine (PCV) periods: pre-PCV7, post-PCV7/pre-PCV13 and post-PCV13. A modified microtiter plate assay with crystal violet stain was used to study the biofilm production of 182 H. influenzae and 191 S. pneumoniae strains., Results: Overall, 117/181 (64.6%) H. influenzae and 128/191 (66.8%) S. pneumoniae strains produced biofilm. The proportion of biofilm-producing H. influenzae strains was greater with than without the isolation of S. pneumoniae in the same sample (75.5% vs 52.3%, p = 0.001). Conversely, the proportion of biofilm-producing S. pneumoniae strains was not affected by the presence or not of H. influenzae (66.3% vs 67.4%). S. pneumoniae serotypes 6B, 15B/C, 19A, 35F and 35B were the better biofilm producers (80%). Serotypes 11A, 14, 15A, 19F and 19A were more associated with H. influenzae biofilm-producing strains. Overall, 89/94 (94.6%) of cases with combined isolation showed biofilm production by S. pneumoniae or H. influenzae., Conclusion: This study emphasizes the high proportion of biofilm production by H. influenzae and S. pneumoniae strains isolated from the nasopharynx of children with acute otitis media, which reinforces the results of studies suggesting the importance of biofilm in the pathogenesis of acute otitis media.

Background. Objectives: Behavioral changes in a febrile child are usually considered to stem from the fever. We studied sickness behavior (SB) in terms of its clinical components and its relation to fever., Methods: This observational, multicenter study included children aged 6 months to 3 years who were either febrile (fever ≥12 hours, ≥ 39°C and ≥38°C at inclusion) or non-febrile and well. The child had to have been awake for the 2 hours preceding the consultation and cared for by the parent who brought him/her to the doctor. SB was evaluated according to 6 parameters over this 2-hour period: time spent playing, distance covered, time spent seeking comfort, time spent whining or crying, time spent in a state of irritation or of anger, most distorted facial expression. Two parameters were assessed for the 24-hour period preceding the consultation: time spent sleeping and appetite. The parent reported the degree of change in these parameters compared with the usual situation, using rating scales., Results: 200 febrile children (most with nonspecific upper respiratory infections) and 200 non-febrile children were included. The mean values of the 8 parameters differed significantly (p<0.001) between the 2 groups and were independent of the height of fever at inclusion in the febrile children. In the study conditions, paracetamol failed to improve SB when the child was still feverish., Conclusion: The 8 parameters suggested that SB and fever are two independent manifestations that are activated simultaneously during an infection. This independence is in harmony with recommendations to treat the discomfort of SB and not the fever.

Background: In December 2013, the French public health authorities recommended the use of Bexsero® (meningococcus B vaccine) in areas with endemic risk and for patients at risk for invasive meningococcal B disease. In this context, InfoVac-France performed a national survey a few months after the implementation of the vaccine to evaluate physicians' perceptions and experiences with this new vaccine., Methods: This survey was proposed by email in April 2014 to the InfoVac network. An initial email explained the purpose of this study and proposed an online questionnaire., Results: Between April 29 and May 16, 2014, 1502 physicians answered online: 502 GPs (33%), 939 pediatricians (63%), and 61 other specialists (4%). In response, 91% of physicians would like to use this vaccine and 87% of pediatricians versus 50% of GPs knew that the vaccine was marketed. Physicians had been informed of the vaccine mostly via the InfoVac network (61%). The immunization schedules for all ages were slightly known by physicians (9% for GPs and 43% of pediatricians). This vaccination was still rarely proposed (18%) more often because it was not reimbursed to patients (62%). Although 39% of physicians were planning to propose the vaccine to their patients, 54% remained undecided. A total of 9% of pediatricians and 2% of GPs had already used this vaccination., Conclusion: This InfoVac-France survey shows that physicians would support the implementation of this vaccine, but questions persist as to its effectiveness, impact on carriage, and duration of protection., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: Non-immune travelers are at risk of acquiring hepatitis B (HB) in high prevalence countries., Method: At the Institut Pasteur Vaccination Center in a retrospective study we retrieved hepatitis B serological data from the vaccination database between 2008 and 2012. Serology (HBsAg, HBsAb and HBcAb) is proposed to travelers who have no information about their previous HB vaccination status if they travel to countries of high or intermediate prevalence of HB, for long or frequent trips., Results: Of 1093 people 53.1% were men, mean age was 39.6 ± 13.0 years. Prevalence of chronic HBV infection was 5.86% (64 subjects). Their mean age was 36.2 ± 7.3 years, 65.6% were men. Seroprevalence of people of sub-Saharan African origin was 9.2%, higher than the other geographic groups. Past, resolved HB infection was found in 320 subjects, 29.3% of the population; 90.3% were of sub-Saharan African origin. A subgroup of the "Past, resolved HB infection": 73 people (6.7% of the population) had isolated HB core antibodies. Vaccine induced immunity was found in 286 subjects (26.17% of the total population), 40% of people born in France. All three markers of HB were negative at 38.7% of our total population (423 people), and 54% of people of French origin., Conclusions: HB seroprevalence was higher than in general French and European population, due to our large number of individuals with immigrant background. Pre-travel counseling allows screening and vaccination of non-immune travelers and detection of chronic HB infection cases., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Non-typable Haemophilus influenzae (NT-Hi) infection is frequently associated with acute otitis media (AOM) treatment failure, recurrence or chronic otitis media. Persistence of otopathogens in a biofilm-structured community was implicated in these situations. Here, we compared biofilm production by H. influenzae strains obtained by culture of middle ear fluid (MEF) from children with AOM treatment failure and by strains isolated from nasopharyngeal (NP) samples from healthy children or those with AOM (first episode or recurrence). We aimed to evaluate an association of clinical signs and in vitro biofilm formation and establish risk factors of carrying a biofilm-producing strain., Methods: We used a modification of the microtiter plate assay with crystal violet staining to compare biofilm production by 216 H. influenzae strains: 41 in MEF from children with AOM treatment failure (group MEF), 43 in NP samples from healthy children (NP group 1), 88 in NP samples from children with a first AOM episode (NP group 2, n = 43) or recurrent (NP group 3, n = 45) and 44 in NP samples from children with AOM associated with conjunctivitis (NP group 4)., Results: At all, 106/216 (49%) H. influenzae strains produced biofilm as did 26/43 (60.5%) in NP samples from healthy children. Biofilm production in MEF samples and NP samples did not significantly differ (40.5% vs 60.5%, 55.8%, 56.8% and 31.1% for NP groups 1, 2, 3 and 4, respectively). On multivariate analysis, only presence of conjunctivitis was significantly associated with low biofilm production (OR = 0.3, CI [0.16-0.60], p = 0.001). The ampicillin resistance of H. influenzae produced by penicillin-binding protein modification was significantly associated with low biofilm production (p = 0.029)., Conclusion: We found no association of biofilm production and AOM treatment failure or recurrence. Biofilm production was low from H. influenzae strains associated with conjunctivitis-otitis syndrome and from strains with modified penicillin-binding protein.

We report on results of an all-sky search for high-energy neutrino events interacting within the IceCube neutrino detector conducted between May 2010 and May 2012. The search follows up on the previous detection of two PeV neutrino events, with improved sensitivity and extended energy coverage down to about 30 TeV. Twenty-six additional events were observed, substantially more than expected from atmospheric backgrounds. Combined, both searches reject a purely atmospheric origin for the 28 events at the 4σ level. These 28 events, which include the highest energy neutrinos ever observed, have flavors, directions, and energies inconsistent with those expected from the atmospheric muon and neutrino backgrounds. These properties are, however, consistent with generic predictions for an additional component of extraterrestrial origin.

We present the first statistically significant detection of neutrino oscillations in the high-energy regime (>20 GeV) from an analysis of IceCube Neutrino Observatory data collected in 2010 and 2011. This measurement is made possible by the low-energy threshold of the DeepCore detector (~20 GeV) and benefits from the use of the IceCube detector as a veto against cosmic-ray-induced muon background. The oscillation signal was detected within a low-energy muon neutrino sample (20-100 GeV) extracted from data collected by DeepCore. A high-energy muon neutrino sample (100 GeV-10 TeV) was extracted from IceCube data to constrain systematic uncertainties. The disappearance of low-energy upward-going muon neutrinos was observed, and the nonoscillation hypothesis is rejected with more than 5σ significance. In a two-neutrino flavor formalism, our data are best described by the atmospheric neutrino oscillation parameters |Δm(32)(2)|=(2.3(-0.5)(+0.6))×10(-3) eV(2) and sin(2)(2θ(23))>0.93, and maximum mixing is favored.

We report on the observation of two neutrino-induced events which have an estimated deposited energy in the IceCube detector of 1.04±0.16 and 1.14±0.17 PeV, respectively, the highest neutrino energies observed so far. These events are consistent with fully contained particle showers induced by neutral-current ν(e,μ,τ) (ν(e,μ,τ)) or charged-current ν(e) (ν(e)) interactions within the IceCube detector. The events were discovered in a search for ultrahigh energy neutrinos using data corresponding to 615.9 days effective live time. The expected number of atmospheric background is 0.082±0.004(stat)(-0.057)(+0.041)(syst). The probability of observing two or more candidate events under the atmospheric background-only hypothesis is 2.9×10(-3) (2.8σ) taking into account the uncertainty on the expected number of background events. These two events could be a first indication of an astrophysical neutrino flux; the moderate significance, however, does not permit a definitive conclusion at this time.

We report the first measurement of the atmospheric electron neutrino flux in the energy range between approximately 80 GeV and 6 TeV, using data recorded during the first year of operation of IceCube's DeepCore low-energy extension. Techniques to identify neutrinos interacting within the DeepCore volume and veto muons originating outside the detector are demonstrated. A sample of 1029 events is observed in 281 days of data, of which 496±66(stat)±88(syst) are estimated to be cascade events, including both electron neutrino and neutral current events. The rest of the sample includes residual backgrounds due to atmospheric muons and charged current interactions of atmospheric muon neutrinos. The flux of the atmospheric electron neutrinos is consistent with models of atmospheric neutrinos in this energy range. This constitutes the first observation of electron neutrinos and neutral current interactions in a very large volume neutrino telescope optimized for the TeV energy range.

We have performed a search for muon neutrinos from dark matter annihilation in the center of the Sun with the 79-string configuration of the IceCube neutrino telescope. For the first time, the DeepCore subarray is included in the analysis, lowering the energy threshold and extending the search to the austral summer. The 317 days of data collected between June 2010 and May 2011 are consistent with the expected background from atmospheric muons and neutrinos. Upper limits are set on the dark matter annihilation rate, with conversions to limits on spin-dependent and spin-independent scattering cross sections of weakly interacting massive particles (WIMPs) on protons, for WIMP masses in the range 20-5000  GeV/c2. These are the most stringent spin-dependent WIMP-proton cross section limits to date above 35  GeV/c2 for most WIMP models.

Background: To assess the acceptability of a vaccine against meningococcus B by pediatricians and GP and to analyze how the vaccine could be implemented in France, InfoVac-France has set up a national survey., Methods: An email explained the purpose of this study and the practitioners of InfoVac-France network answered an online questionnaire (e-CRF)., Results: Of the 6905 pediatricians and GP who saw the mail sent by InfoVac-France between 11 and 24 January, 2012, 1351 (13.5 %) completed the e-CERF : 361 GP (26.7%), 797 pediatricians (59%) and 193 other doctors (14.3%). The majority of practitioners (96.1%) believe that is important to implement a vaccine against meningococcus B in the French immunization schedule. In 80.5% of cases, practitioners do not want to vaccine three times routinely during a single consultation and more than half (53.5%) would prefer to use this vaccine alone. The best schedule of primary vaccination (80.6%) is the injection at 3, 5 and 6 months. The arguments considered likely to encourage parents to accept the vaccination would be the incidence of the disease, severity of meningitis (82.1%) and the rapid mortality (82.8%)., Conclusion: This survey by InfoVac-France shows that the practitioners know the epidemiology of meningococcal B invasive disease in children. They would support the implementation of this vaccine for children under 2 years with a primary vaccination at 3, 5 and 6 months., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Background: Since 2001 in France, a nasopharyngeal carriage study was set up for children six to 24 months old. Any data are available for older children (25 to 60 months). The aim of this study is to compare the nasopharyngeal carriage in children with acute otitis media (AOM) or healthy between both age groups (6/24 months versus 25/60 months). Moreover, during the study period, the 13-valent pneumococcal conjugate vaccine (PCV13) has replaced PCV7 in June 2010., Methods: From October 2010 to June 2011, 58 pediatricians obtained nasopharyngeal swabs from children 6-60 months with acute otitis media (AOM) or healthy controls, to analyse the carriage of pneumococcus, Haemophilus influenzae, Moraxella catarrhalis, group A streptococcus and Staphylococcus aureus., Results: Of the 1557 enrolled children, 1258 were 6 to 24 months old (315 healthy and 943 AOM) and 299 were 25 to 60 months (102 healthy and 197 AOM). More then 85% were PCV7 vaccinated and the children of 25/60 months were rarely PCV13 vaccinated (14.1%) compared to younger children (69.9%, P<0.001). For children 6/24 months, the Streptococcus pneumoniae carriage was higher in AOM group (57.3%) versus healthy (28.9%). By contrast for older children, the difference (58.4% versus 50%) was not significant. In the healthy group, older children carried more often S. pneumoniae than younger children (50% versus 28.9%, P<0.0001). This trend was also observed for H. influenzae carriage (49% versus 18.7%, P<0.0001). Multivariate analysis in the healthy group showed that siblings and day care center (or school) increased the carriage of S. pneumoniae and H. influenzae., Conclusion: These data from nasopharyngeal carriage in children 6 to 60 months old showed that pneumococcus and H. influenzae carriage is high for patients under 2 years, especially in the healthy group. Moreover, these data from the transition PCV7/PCV13, will serve as baseline in France to evaluate the impact of PCV13., (Published by Elsevier SAS.)

IceCube has become the first neutrino telescope with a sensitivity below the TeV neutrino flux predicted from gamma-ray bursts if gamma-ray bursts are responsible for the observed cosmic-ray flux above 10(18)  eV. Two separate analyses using the half-complete IceCube detector, one a dedicated search for neutrinos from pγ interactions in the prompt phase of the gamma-ray burst fireball and the other a generic search for any neutrino emission from these sources over a wide range of energies and emission times, produced no evidence for neutrino emission, excluding prevailing models at 90% confidence.

Background: Hepatitis A vaccination is recommended to people traveling to countries where the disease is endemic. Until recently, people originating from developing countries were considered to be "naturally" immunized. Because of improving socioeconomic conditions, hepatitis A incidence has decreased in most previously highly endemic countries during the last three decades, especially in the younger age groups., Methods: We analyzed hepatitis A seroprevalence of 989 travelers who had been born and lived at least 1 year in a developing country, wanted to travel to a hepatitis A endemic area, and consulted at the vaccination center of the Institut Pasteur of Paris between September 1, 2008 and February 28, 2010., Results: Hepatitis A serology results were available for 646 subjects. Overall seroprevalence was 82.4%. A total of 90, 82.6, 81.2, 68.4, 56.9, and 50% of people of sub-Saharan African, Near and Middle Eastern, North African, Asian, Latin American, and Eastern European origin had hepatitis A antibodies, respectively. The difference in seroprevalence according to the continent of origin, age, and length of stay in an endemic country was significant (p < 0.0001). More than 75% of seronegatives and less than 50% of seropositives were younger than 36 years. Almost three quarters of the positive group (while less than half of the negative group) lived longer than 18 years in a developing country. Multivariate analysis showed that seroprevalence increases with age, length of stay in a country at risk, and varies significantly from one continent to another., Conclusion: We recommend extending serologic confirmation of immigrants' hepatitis A immunity. If time is lacking, vaccination should be considered., (© 2011 International Society of Travel Medicine.)

Aside from limb tremor, bradykinesia, rigidity and gait disturbances, Parkinson's disease (PD) is also characterized by non-motor symptoms. A cognitive decline can occur early in the disease course and undoubtedly impact of the patient's quality of life. Dementia affects 80% of patients 20 years after disease onset but a small subgroup of patients remain free of dementia even after decades with PD. Risk factors and diagnosis of dementia can be easily assessed using bed-side clinical instruments. Advances in genetics and imagery will allow improving the diagnosis and therapeutic strategy dementia in Parkinson's disease.

This study describes the neuropsychological assessment of 34 patients with questionable Alzheimer's disease (QAD) followed up for 3 years. Several measures were selected from the California Verbal Learning Test (CVLT) and compared to other cognitive tasks to assess the best neuropsychological indices for (a) detecting early memory impairment in QAD and (b) predicting conversion to AD. Concerning detection, the results indicated that a recall measure depending on semantic categorization (short-delay cued recall) signaled a memory deficit in stable QAD patients, suggesting that episodic and semantic memory problems are involved in the early cognitive impairments of stable QAD patients. However, the conversion to AD was best predicted by the initial performance at the recency index (score reflecting high reliance on working memory), corroborating the idea that AD patients (even at the questionable stage) essentially rely on preserved phonological loop functioning in memory tasks. Finally, an additional impairment in visuospatial memory (Rey's figure) provided a good discriminant value to distinguish converters from stable QAD patients, showing that various cognitive disabilities deteriorate in AD.

Point source searches with the IceCube neutrino telescope have been restricted to one hemisphere, due to the exclusive selection of upward going events as a way of rejecting the atmospheric muon background. We show that the region above the horizon can be included by suppressing the background through energy-sensitive cuts. This improves the sensitivity above PeV energies, previously not accessible for declinations of more than a few degrees below the horizon due to the absorption of neutrinos in Earth. We present results based on data collected with 22 strings of IceCube, extending its field of view and energy reach for point source searches. No significant excess above the atmospheric background is observed in a sky scan and in tests of source candidates. Upper limits are reported, which for the first time cover point sources in the southern sky up to EeV energies.

A search for muon neutrinos from neutralino annihilations in the Sun has been performed with the IceCube 22-string neutrino detector using data collected in 104.3 days of live time in 2007. No excess over the expected atmospheric background has been observed. Upper limits have been obtained on the annihilation rate of captured neutralinos in the Sun and converted to limits on the weakly interacting massive particle (WIMP) proton cross sections for WIMP masses in the range 250-5000 GeV. These results are the most stringent limits to date on neutralino annihilation in the Sun.

Valvular heart disease, inducing valvular regurgitation, has been described in users of drugs such as anorectic agents and ergot derivates. 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") also leads in vitro to the proliferation of cardiac valvular interstitial cells by activation of the 5-hydroxytryptamine 2B receptor. The aim of this study was to determine the occurrence of valvulopathy in young adults taking MDMA. Twenty-nine subjects using or having used MDMA and 29 gender- and age-matched controls were blindly evaluated with echocardiography. Eight subjects (28%) who took MDMA had abnormal echocardiographic results using the United States Food and Drug Administration's criteria for appetite suppressant-induced valvular heart disease, compared with none in the control group (p = 0.0045). Six (21%) subjects had mitral regurgitation of 1/4 and 4 (14%) of > or =2/4, compared with none in the control group (p = 0.002). The mean mitral regurgitant area ratios (jet/atrium) were 12 +/- 9.8% and 5 +/- 1.3%, respectively (p = 0.007). Tricuspid regurgitation > or =2/4 was present in 13 MDMA users (45%) and absent in controls (p <0.001). The mean tricuspid regurgitant area ratios were 19 +/- 9.5% and 9 +/- 4.5%, respectively (p <0.001). Four MDMA users (14%) had mild aortic regurgitation (p = 0.11). Valvular "strands" were present in 6 MDMA users (21%) and in none of the controls (p = 0.02). In conclusion, MDMA may lead to mild to moderate valvular heart disease and valvular strands.

The aim of this study was to evaluate the discriminant validity of the RI-48 test, a shorter French version of the Category Cued Recall portion of the Double Memory Test developed initially by Buschke and colleagues (1997), in the diagnosis of mild and very mild Alzheimer disease (AD). The distinctive feature of the RI-48 task is that encoding specificity was increased by adding an immediate cued recall stage at the encoding phase. The results show that the RI-48 task seems to be well adapted to the clinical context and to have good psychometric properties, in particular a lack of a ceiling effect. Moreover, this task appears to be especially well suited for the diagnosis of both mild and very mild AD (sensitivity of 93% and 83.8%). From a more theoretical point of view, this study confirms the importance of optimizing the encoding specificity for the diagnosis of very mild AD, since the more encoding specificity is accentuated, the more discriminating power is increased for the diagnosis of very mild AD.

Although the zeta-associated protein of 70 kDa (ZAP-70) is overexpressed in patients with chronic lymphocytic leukemia (CLL) displaying unmutated IGVH genes and poor prognosis, a previous microarray study from our group identified overexpression of LPL and ADAM29 genes among unmutated and mutated CLL, respectively. To assess the prognostic value of these genes, we quantified their expression by real-time quantitative polymerase chain reaction (PCR) in a cohort of 127 patients with CLL and correlated this with clinical outcome, IGVH mutational status, and ZAP-70 protein expression. IGVH mutational status, ZAP-70, and the LPL and ADAM29 mRNA ratios (L/A ratio) were predictive of event-free survival for the whole cohort and for patients with stage A disease. In patients in stage B and C, the L/A ratio was an independent prognostic factor, whereas ZAP-70 did not predict survival. Simultaneous usage of the L/A ratio and ZAP-70 expression allowed an almost perfect (99%) assessment of the IGVH status in the 80% of patients with concordant results (L/A+, ZAP-70+ or L/A-, ZAP-70-). LPL and ADAM29 gene expression could also be determined by a simple competitive multiplex reverse transcription PCR assay. Overall, quantification of LPL and ADAM29 gene expression is a strong prognostic indicator in CLL, providing better prognostic assessment than ZAP-70 in advanced stages of the disease.

Early diagnosis of Alzheimer's disease is difficult, but neuropsychological tests become quite sensitive, and neuroimaging gives useful information. Criteria for differential diagnosis appear in the literature, but vascular dementia remains an ill-defined concept. There are ongoing researches on possible therapeutic interferences with formation of histological brain lesions. Meanwhile, treatments are symptomatic and should be started as early as possible. Both inhibitors of acetylcholinesterase and cognitive rehabilitation in day-care centres fulfill therapeutic criteria for dementia, i.e. improvement or stabilization of cognitive impairment and daily life activities.

The phonological loop and central executive functioning were examined in patients with Alzheimer's disease (AD) and in normal elderly subjects. AD patients showed abnormal functioning of the phonological loop and decreased performance on tasks assessing the central executive. However, when AD patients were separated into two groups on the basis of their span level, both groups showed deficits of the central executive but only patients with the lower span level presented a dysfunction of the phonological loop as well as impaired performance in tasks of phonological discrimination, articulation rate and speed of processing. These results are interpreted in terms of progression of the disease, with high-span level patients being less severely demented and displaying deficits only in higher-level cognitive functions (such as manipulation of information stored in working memory) whereas patients with a low span level have impairments encompassing a series of more basic processes.