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Adolescence is a developmental period characterized by significant changes in brain architecture and behaviour. The immaturity of the adolescent brain is associated with heightened vulnerability to exogenous agents, including alcohol. Alcohol is the most consumed drug among teenagers, and binge-drinking during adolescence is a major public health concern. Studies have suggested that adolescent alcohol exposure may interfere with the maturation of frontal brain regions and lead to long-lasting behavioural consequences. In this study, by using a slightly modified version of the Drinking in the Dark paradigm, adolescent C57Bl6 mice reach high blood alcohol concentration after voluntary binge-drinking. In order to assess short- and long-term consequences of adolescent alcohol exposure (AAE), a battery of behavioural tests was performed during late adolescence and during adulthood. We showed that AAE had no short-term effect on young mice behaviour but rather increased anxiety- and depressive-like behaviours, as well as alcohol consumption during adulthood. Moreover, alcohol binge-drinking during adolescence dramatically decreased recognition memory performances and behavioural flexibility in both adult males and females. Furthermore, we showed that voluntary consumption of alcohol during adolescence did not trigger any major activation of the innate immune system in the prefrontal cortex. Together, our data suggest that voluntary alcohol binge-drinking in adolescent mice induces a delayed appearance of behavioural impairments in adulthood., (© 2021 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Protein homeostasis is essential to cell function, and a compromised ability to reduce the load of misfolded and aggregated proteins is linked to numerous age-related diseases, including hearing loss. Here, we show that altered proteostasis consequent to Elongator complex deficiency also impacts the proper development of the cochlea and results in deafness. In the absence of the catalytic subunit Elp3, differentiating spiral ganglion neurons display large aggresome-like structures and undergo apoptosis before birth. The cochlear mechanosensory cells are able to survive proteostasis disruption but suffer defects in polarity and stereociliary bundle morphogenesis. We demonstrate that protein aggregates accumulate at the apical surface of hair cells, where they cause a local slowdown of microtubular trafficking, altering the distribution of intrinsic polarity proteins and affecting kinocilium position and length. Alleviation of protein misfolding using the chemical chaperone 4-phenylbutyric acid during embryonic development ameliorates hair cell polarity in Elp3-deficient animals. Our study highlights the importance of developmental proteostasis in the cochlea and unveils an unexpected link between proteome integrity and polarized organization of cellular components., (© 2019 The Authors.)

Importance: In several countries, 5 years after 13-valent pneumococcal conjugate vaccine (PCV13) implementation, serotype replacement has been reported for invasive pneumococcal disease, which raises concerns about the long-term outcome of PCV13 implementation. The long-term effect of vaccination on community-acquired pneumonia (CAP) remains unknown., Objective: To assess the long-term outcome of PCV13 implementation on CAP in children., Design, Setting, and Participants: This quasi-experimental, population-based, interrupted time-series analysis was based on a prospective multicenter study conducted from June 2009 to May 2017 in 8 French pediatric emergency departments. All patients 15 years and younger with chest radiography-confirmed CAP were included., Exposures: Community-acquired pneumonia., Main Outcomes and Measures: The number of CAP cases per 1000 pediatric emergency department visits over time, analyzed using a segmented regression model, adjusted for influenza-like illness syndromes., Results: We enrolled 12 587 children with CAP, including 673 cases of CAP with pleural effusion (5.3%), 4273 cases of CAP requiring hospitalization (33.9%), 2379 cases of CAP with high inflammatory biomarkers (18.9%), and 221 cases of proven pneumococcal CAP (1.8%). The implementation of PCV13 in 2010 was followed by a sharp decrease in the frequency of CAP (-0.8% per month [95% CI, -1.0% to -0.5% per month]), from 6.3 to 3.5 cases of CAP per 1000 pediatric emergency department visits until May 2014, then a slight increase since June 2014 (0.9% per month [95% CI, 0.4%-1.4% per month]), until 3.8 cases of CAP per 1000 pediatric emergency department visits in May 2017. There were marked immediate decreases in cases of CAP with pleural effusion (-48% [95% CI, -84% to -12%]), CAP requiring hospitalization (-30% [95% CI, -56% to -5%]), and CAP with high inflammatory biomarkers (-30% [95% CI, -54% to -6%]), without any rebound thereafter., Conclusions and Relevance: The changes associated with PCV13 use 7 years after implementation remain substantial, especially for CAP with pleural effusion, CAP requiring hospitalization, and CAP with high inflammatory biomarkers. Emerging non-PCV13 serotypes may be less likely involved in severe CAP than invasive pneumococcal disease.

Objectives: To assess the management of febrile urinary-tract infection (FUTIs) due to extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) in children, the Pediatric Infectious Diseases Group of the French Pediatric Society set up an active surveillance network in pediatric centers across France in 2014., Materials and Methods: We prospectively analysed data from 2014 to 2016 for all children < 18 years old who received antibiotic treatment for FUTI due to ESBL-E in 24 pediatric centers. Baseline demographic, clinical features, microbiological data and antimicrobials prescribed were collected., Results: 301 children were enrolled in this study. The median age was 1 year (IQR 0.02-17.9) and 44.5% were male. These infections occurred in children with history of UTIs (27.3%) and urinary malformations (32.6%). Recent antibiotic use was the main associated factor for FUTIs due to ESBL-E, followed by a previous hospitalization and travel history. Before drug susceptibility testing (DST), third-generation cephalosporins (3GC) PO/IV were the most-prescribed antibiotics (75.5%). Only 13% and 24% of children received amikacine alone for empirical or definitive therapy, respectively, whereas 88.7% of children had isolates susceptible to amikacin. In all, 23.2% of children received carbapenems in empirical and/or definitive therapy. Cotrimoxazole (24.5%), ciprofloxacin (15.6%) and non-orthodox clavulanate-cefixime combination (31.3%) were the most frequently prescribed oral options after obtaining the DST. The time to apyrexia and length of hospital stay did not differ with or without effective empirical therapy., Conclusions: We believe that amikacin should increasingly take on a key role in the choice of definitive therapy of FUTI due to ESBL-E in children by avoiding the use of carbapenems.

Background: Many countries have observed an early and strong impact of implementation of the 13-valent pneumococcal conjugate vaccine (PCV13) on community-acquired pneumonia (CAP). High levels of C-reactive protein (CRP) and procalcitonin (PCT) are considered biomarkers of bacterial infection (particularly infection due to pneumococcus); therefore, PCV13 implementation should have different effectiveness on CAP depending on the levels of these two biomarkers. To demonstrate this assumption, we analyzed the evolution of number of CAP cases seen in pediatric emergency departments in France after PCV13 implementation (in 2010) by levels of these two biomarkers., Methods: From June 2009 to May 2015, 8 pediatric emergency units prospectively enrolled all children (1month to 15years) with radiologically confirmed CAP., Results: A cohort of 9586 children with CAP was enrolled (median age 3years). CAP with pleural effusion (PE-CAP) and proven pneumococcal pneumonia (PP-CAP) accounted for 5.5% and 2.0% of cases. During the study period, the number of cases of overall CAP decreased by 25.4%, hospitalized CAP by 30.5%, PE-CAP by 63.4%, CAP with CRP level≥100mg/L by 50.9%, CAP with PCT level≥4ng/L by 60.4% and PP-CAP by 86.4%. We found no change in number of cases of CAP with low levels of CRP (<20 or <40mg/L) or PCT (<0.5ng/mL). The number of cases of CAP overall increased (20.0%) in the last year of the study as compared with the preceeding year but not cases with CRP level≥100mg/L and/or PCT level≥4ng/mL., Conclusion: PCV13 implementation has had a strong impact on number of CAP cases with high levels of CRP and/or PCT in children but no impact on that with low levels of these two biomarkers. Five years after PCV13 implementation, a sustained reduction in CAP cases is observed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The Elongator complex is required for proper development of the cerebral cortex. Interfering with its activity in vivo delays the migration of postmitotic projection neurons, at least through a defective α-tubulin acetylation. However, this complex is already expressed by cortical progenitors where it may regulate the early steps of migration by targeting additional proteins. Here we report that connexin-43 (Cx43), which is strongly expressed by cortical progenitors and whose depletion impairs projection neuron migration, requires Elongator expression for its proper acetylation. Indeed, we show that Cx43 acetylation is reduced in the cortex of Elp3cKO embryos, as well as in a neuroblastoma cell line depleted of Elp1 expression, suggesting that Cx43 acetylation requires Elongator in different cellular contexts. Moreover, we show that histones deacetylase 6 (HDAC6) is a deacetylase of Cx43. Finally, we report that acetylation of Cx43 regulates its membrane distribution in apical progenitors of the cerebral cortex.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and severe syndrome usually associated with a cytotoxicity deficiency, which leads to an excess of immune response driven by activated macrophages and cytotoxic T cells. In children, HLH can be genetic, as part of a familial lymphohistiocytosis, or secondary: the most frequent causes are systemic-onset juvenile idiopathic arthritis, hematological malignancies, and severe infections, especially with Ebstein-Barr virus or leishmaniosis. We report on the case of a 3-year-old girl with no past medical history, who presented inaugural Pseudomonas aeruginosa maxillary osteitis, with secondary HLH. The rarity of this osteitis, the characteristics of the pathogen, and the onset of HLH oriented the diagnosis toward primary immunodeficiencies, malignancies, or systemic diseases. Steroids were initiated at 2mg/kg/day and were very effective in improving the systemic symptoms. Antibiotic therapy was continued unchanged. A few days after discontinuation of steroids, while the patient was still under antibiotics, she presented with erythroderma. Skin biopsy revealed eosinophil infiltrate in line with the diagnosis of a drug reaction with eosinophilia and systemic symptoms (DRESS), even though we only observed very transient eosinophilia, up to 0.98G/L, during HLH. Stopping antibiotics normalized the symptoms without using systemic corticosteroids. Patch tests confirmed an allergy to piperacillin. These atypical manifestations of DRESS underline that causative diagnosis of HLH is challenging, and DRESS syndrome should be considered., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: The incidence of invasive group A streptococcus (GAS) infections is increasing worldwide, whereas there has been a dramatic decrease in pneumococcal invasive diseases. Few data describing GAS pleural empyema in children are available., Objective: To describe the clinical and microbiological features, management and outcome of GAS pleural empyema in children and compare them with those of pneumococcal empyema., Design, Setting and Patients: Fifty children admitted for GAS pleural empyema between January 2006 and May 2013 to 8 hospitals participating in a national pneumonia survey were included in a descriptive study and matched by age and centre with 50 children with pneumococcal empyema., Results: The median age of the children with GAS pleural empyema was 2 (range 0.1-7.6) years. Eighteen children (36%) had at least one risk factor for invasive GAS infection (corticosteroid use and/or current varicella). On admission, 37 patients (74%) had signs of circulatory failure, and 31 (62%) had a rash. GAS was isolated from 49/50 pleural fluid samples and from one blood culture. The commonest GAS genotype was emm1 (n=17/22). Two children died (4%). Children with GAS empyema presented more frequently with a rash (p<0.01), signs of circulatory failure (p=0.01) and respiratory disorders (p=0.02) and with low leucocyte levels (p=0.04) than children with pneumococcal empyema. Intensive care unit admissions (p<0.01), drainage procedures (p=0.04) and short-term complications (p=0.01) were also more frequent in patients with GAS empyema., Conclusions: Pleural empyema following varicella or presenting with rash, signs of circulatory failure and leucopenia may be due to GAS. These features should prompt the addition to treatment of an antitoxin drug, such as clindamycin., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Several neurodegenerative diseases are characterized by both cognitive and motor deficits associated with accumulation of tau aggregates in brain, brainstem, and spinal cord. The Tg30 murine tauopathy model expresses a human tau protein bearing two frontotemporal dementia with Parkinsonism linked to chromosome 17 pathogenic mutations and develops a severe motor deficit and tau aggregates in brain and spinal cord. To investigate the origin of this motor deficit, we analyzed the age-dependent innervation status of the neuromuscular junctions and mutant tau expression in Tg30 mice. The human transgenic tau was detected from postnatal day 7 onward in motoneurons, axons in the sciatic nerve, and axon terminals of the neuromuscular junctions. The development and maturation of neuromuscular junctions were not disrupted in Tg30 mice, but their maintenance was disturbed in adult Tg30 mice, resulting in a progressive and severe muscle denervation. This muscle denervation was associated with early electrophysiological signs of muscle spontaneous activities and histological signs of muscle degeneration. Early loss of synaptic vesicles in axon terminals preceding motor deficits, accumulation of Gallyas-positive aggregates, and cathepsin-positive vesicular clusters in axons in the sciatic nerve suggest that this denervation results from disturbances of axonal transport. This physiopathological mechanism might be responsible for motor signs observed in some human tauopathies, and for synaptic dysfunction resulting from alterations at the presynaptic level in these diseases., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Kawasaki disease is an acute and time-limited systemic vasculitis primarily affecting young children., Patient: We describe an 18-month-old girl with Kawasaki disease who developed cerebral infarction following complete occlusion of her right internal carotid artery., Results: The occlusion occurred 10 days after the onset of fever, while she was on high-dose aspirin, and the day after she received intravenous immunoglobulin treatment. We present the first literature review on this very rare complication., Conclusion: Stroke is a rare neurological complication in Kawasaki disease. Optimal treatment should be begun as soon as possible after diagnosis. Intravenous immunoglobulins seem to reduce the cerebrovascular complications, but evaluation of hydration status is strongly recommended before performing such treatment., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Infectious risk is more important in the transplanted child than in adult because children are less often immunised against pathogens ant more exposed than adults to numerous infectious agents (virus but also bacteria including pneumococcus). The application of the standard immunisation schedule must be a permanent concern of transplantation (Tx) teams. Some vaccines that are not planned in the standard immunization schedule are particularly advised for the child and his family circle, as well as for caregivers. Immunisation response must be evaluated by a serological follow-up before Tx, in particular during the pre-Tx diagnostic work-up, then regularly after Tx. The more frequent absence of immunisation against Epstein Barr Virus (EBV) in children explains the increased frequency of post-transplant lymphoproliferative disorder at the pediatric age., (Copyright © 2011. Published by Elsevier SAS.)

Aim: The aim of this study was to determine the vaccination coverage among the medical and paramedical health care workers of the pediatric intensive care and emergency department of Edouard Herriot hospital in Lyon, with respect to influenza, pertussis, varicella, and measles, 4 diseases with air transmission and vaccination recommendations., Method: During February and March 2007, a questionnaire was given by hand to 123 health care workers by a medical student working there or available in the intensive care unit., Results: The response rate to the questionnaire was 68.3%. The vaccination coverage against influenza was 42.8%; men and medical health care workers were better vaccinated. With respect to vaccination against pertussis, one third had received an injection in adulthood, adults under age 30 and medical health care workers were better vaccinated, but the difference was not statistically significant. Ten health care workers were not vaccinated and had no history of measles: only 1 had had a measles serology and none were vaccinated. Eleven had no history of varicella: 6 had had a varicella serology and none were vaccinated., Conclusions: Vaccination coverage against influenza is higher than what has been reported in the literature, possibly because of a mobile vaccination campaign against influenza made during winter 2006 in this pediatric department. Vaccination coverage against pertussis is encouraging and probably the consequence of an awareness of the gravity of the disease among infants. Individual information is necessary for health care workers on the nosocomial risk for influenza and pertussis in infants, and vaccination must be proposed. Serology against varicella and measles is compulsory for all health care workers with no history and no vaccination against these 2 diseases, to track and vaccinate the nonimmunized personnel. Occupational physicians have a very important role to play in meeting this goal.