Population pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing regimens.

PURPOSE: This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme. METHODS: Children treated with ciprofloxacin were included. Pharmacokinetics were described using non-linear mixed-effect modelling and validated with an external dataset. Monte Carlo simulations investigated dosing regimens to achieve a target AUC0-24 h/MIC ratio ≥ 125. RESULTS: A total of 189 children (492 concentrations) were included. A two-compartment model with first-order absorption and elimination best described the data. An allometric model was used to describe bodyweight (BW) influence, and effects of estimated glomerular filtration rate (eGFR) and age were significant on ciprofloxacin clearance. CONCLUSION: The recommended IV dose of 10 mg/kg q8h, not exceeding 400 mg q8h, would achieve AUC0-24 h to successfully treat bacteria with MICs ≤ 0.25 (e.g. Salmonella, Escherichia coli, Proteus, Haemophilus, Enterobacter, and Klebsiella). A dose increase to 600 mg q8h in children > 40 kg and to 15 mg/kg q8h (max 400 mg q8h, max 600 mg q8h if augmented renal clearance, i.e., eGFR > 200 mL/min/1.73 m2) in children < 40 kg would be needed for the strains with highest MIC (16% of Pseudomonas aeruginosa and 47% of Staphylococcus aureus). The oral recommended dose of 20 mg/kg q12h (not exceeding 750 mg) would cover bacteria with MICs ≤ 0.125 but may be insufficient for bacteria with higher MIC and a dose increase according bodyweight and eGFR would be needed. These doses should be prospectively confirmed, and a therapeutic drug monitoring could be used to refine them individually.

A simple novel approach for detecting blood-brain barrier permeability using GPCR internalization.

AIMS: Impairment of blood-brain barrier (BBB) is involved in numerous neurological diseases from developmental to aging stages. Reliable imaging of increased BBB permeability is therefore crucial for basic research and preclinical studies. Today, the analysis of extravasation of exogenous dyes is the principal method to study BBB leakage. However, these procedures are challenging to apply in pups and embryos and may appear difficult to interpret. Here we introduce a novel approach based on agonist-induced internalization of a neuronal G protein-coupled receptor widely distributed in the mammalian brain, the somatostatin receptor type 2 (SST2). METHODS: The clinically approved SST2 agonist octreotide (1 kDa), when injected intraperitoneally does not cross an intact BBB. At sites of BBB permeability, however, OCT extravasates and induces SST2 internalization from the neuronal membrane into perinuclear compartments. This allows an unambiguous localization of increased BBB permeability by classical immunohistochemical procedures using specific antibodies against the receptor. RESULTS: We first validated our approach in sensory circumventricular organs which display permissive vascular permeability. Through SST2 internalization, we next monitored BBB opening induced by magnetic resonance imaging-guided focused ultrasound in murine cerebral cortex. Finally, we proved that after intraperitoneal agonist injection in pregnant mice, SST2 receptor internalization permits analysis of BBB integrity in embryos during brain development. CONCLUSIONS: This approach provides an alternative and simple manner to assess BBB dysfunction and development in different physiological and pathological conditions.

High-fidelity vibrokinetic stimulation induces sustained changes in intercortical coherence during a cinematic experience.

OBJECTIVE: High-fidelity vibrokinetic (HFVK) technology is widely used to enhance the immersiveness of audiovisual (AV) entertainment experiences. However, despite evidence that HFVK technology does subjectively enhance AV immersion, the underlying mechanism has not been clarified. Neurophysiological studies could provide important evidence to illuminate this mechanism, thereby benefiting HFVK stimulus design, and facilitating expansion of HFVK technology. APPROACH: We conducted a between-subjects (VK, N = 11; Control, N = 9) exploratory study to measure the effect of HFVK stimulation through an HFVK seat on electroencephalographic cortical activity during an AV cinematic experience. Subjective appreciation of the experience was assessed and incorporated into statistical models exploring the effects of HFVK stimulation across cortical brain areas. We separately analyzed alpha-band (8-12 Hz) and theta-band (5-7 Hz) activities as indices of engagement and sensory processing, respectively. We also performed theta-band (5-7 Hz) coherence analyses using cortical seed areas identified from the theta activity analysis. MAIN RESULTS: The right fusiform gyrus, inferiotemporal gyrus, and supramarginal gyrus, known for emotion, AV-spatial, and vestibular processing, were identified as seeds from theta analyses. Coherence from these areas was uniformly enhanced in HFVK subjects in right motor areas, albeit predominantly in those who were appreciative. Meanwhile, compared to control subjects, HFVK subjects exhibited uniform interhemispheric decoherence with the left insula, which is important for self-processing. SIGNIFICANCE: The results collectively point to sustained decoherence between sensory and self-processing as a possible mechanism for how HFVK increases immersion, and that coordination of emotional, spatial, and vestibular processing hubs with the motor system may be required for appreciation of the HFVK-enhanced experience. Overall, this study offers the first ever demonstration that HFVK stimulation has a real and sustained effect on brain activity during a cinematic experience.

Invasive pulmonary aspergillosis in an ICU patient with Legionnaires' disease: A diagnostic challenge.

Aspergillus fumigatus can cause a wide range of diseases, from hypersensitivity to invasive infection. Invasive disease usually occurs in severely immunocompromised patients with deep and prolonged neutropenia. It is a less well-recognized complication in critically ill patients without traditional risk factors. We describe a case of early invasive pulmonary aspergillosis (IPA) secondary to Legionella pneumophila serogroup 1 pneumonia in a patient on an intensive care unit (ICU). In addition to commonly accepted risk factors for IPA in ICU patients, we hypothesis that L. pneumophilia pneumonia could enhance this type of infection. We also reviewed all published cases of coinfection with L. pneumophila and A. fumigatus to assess whether Legionnaires' disease could be a risk factor for IPA.

Neonatal and pediatric ECMO organization in France: A national survey.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) in France has increased since the H1N1 pandemic in 2009. By contrast, neonatal and pediatric ECMO support in France was known to be limited to a few centers offering congenital cardiac surgery. The purpose of this survey conducted in 2017 was to identify the neonatal and pediatric ECMO centers in France as well as networks existing between ECMO and non-ECMO centers. RESULTS: Seventy-two neonatal or pediatric intensive care unit medical directors answered the survey (84% of the centers surveyed). Twenty were identified as ECMO centers, defined as a unit able to start ECMO with its own resources. ECMO centers ranged from 470,000 to 1,180,000 inhabitants (neonates or children under 18). Thirteen of them (65%) reported that they were affiliated with a congenital cardiac surgery department. A total of 187 patients were supported with ECMO in these centers in 2016. Only six of these centers estimated an activity greater than 15 cases per year over the last 5 years. Nearly 30% of ECMO runs were indicated before or after congenital heart surgery. Four of the ECMO centers offered off-site facilities (mobile team). Non-ECMO centers are likely to be neonatal intensive care units. Nine of them (18.7%) declared knowing an ECMO center that provided mobile care with predefined organization, 11 (22.9%) reported knowing an ECMO center providing a mobile activity without predefined organization, nine (18.%), and 18 (37.5%) ICUs declared they knew of the existence of an ECMO program but did not report any possibility of mobile care or any procedure for transfer. CONCLUSIONS: Of the centers reporting the highest case volumes, four offered mobile ECMO abilities. Well-organized networks for the most severe neonates and children were not identified in France.

[Feasibility and benefits of training to screen for chronic obstructive pulmonary disease]. / Faisabilité et bénéfices de la formation au dépistage du trouble ventilatoire obstructif.

INTRODUCTION: Though still under-diagnosed, chronic obstructive pulmonary disease (COPD) currently affects nearly 3.5 million people in France. The present study presents the results of continuing medical education sessions on COPD screening by electronic mini-spirometry. METHODS: From April 2013 to December 2015, the sessions involved 73 health professionals. The study analysed three questionnaires administered before, after, and long after sessions led by experts within a professional associative network. RESULTS: The sessions proved efficient in increasing the participants' theoretical knowledge. It increased the percentage of correct answers regarding the nature of COPD (90 % vs. 81%), the functions, features, and outputs of mini-spirometers, and the treatment recommendations. The sessions led to non-negligible changes in everyday medical practice regarding the acquisition of a mini-spirometer (+13 devices), the presentation of COPD to the patients (+33 practitioners), the dialogue on tobacco use (+32 practitioners), vaccination (+33 practitioners), and compliance with the treatment recommendations (+43 practitioners). CONCLUSION: These results encourage both holding and following up such sessions. The specialized professional environment ensures knowledge updates and offers subsequent assistance. Further improving these sessions will increase their benefits in terms of diagnosis, treatment, and health economy.

[Lower extremity arteriopathy disease in the elderly: A systematic review]. / Artériopathie distale du sujet âgé : revue de la littérature.

Lower Extremity Arteriopathy Disease in the elderly is frequent with an ongoing increase of it prevalence and incidence mainly due to diabetes, hypertension and aging of the population. Despite improvement of revascularization therapy, outcome in this population is poor affected by frailty of elderly patient. Aging is associated with a higher prevalence of below the knee disease and wound, often with diagnostic delay leading to a major rate of amputation, mortality and alteration of quality of life. Moreover, it leads to an important health cost for society. This review aims to describe main features of LEAD in the elderly, providing keys for early recognition and managing of such disease in this population.

[Extracorporeal membrane oxygenation in critically ill neonates and children]. / Place de l'assistance respiratoire et circulatoire extracorporelle de courte durée (ECMO), post-cardiotomie exclue, dans la prise en charge des défaillances graves du nouveau-né et de l'enfant.

Extracorporeal membrane oxygenation is used as a last resort during neonatal and pediatric resuscitation in case of refractory circulatory or respiratory failure under maximum conventional therapies. Different types of ECMO can be used depending on the initial failure. The main indications for ECMO are refractory respiratory failure (acute respiratory distress syndrome, status asthmaticus, severe pneumonia, meconium aspiration syndrome, pulmonary hypertension) and refractory circulatory failure (cardiogenic shock, septic shock, refractory cardiac arrest). The main contraindications are a gestational age under 34 weeks or birth weight under 2kg, severe underlying pulmonary disease, severe immune deficiency, a neurodegenerative disease and hereditary disease of hemostasis. Neurological impairment can occur during ECMO (cranial hemorrhage, seizure or stroke). Nosocomial infections and acute kidney injury are also frequent complications of ECMO. The overall survival rate of ECMO is about 60 %. This survival rate can change depending on the initial disease: from 80 % for meconium aspiration syndrome to less than 10 % for out-of-hospital refractory cardiac arrest. Recently, mobile ECMO units have been created. These units are able to perform ECMO out of a referral center for untransportable critically ill patients.

Early Recruitment of Cerebral Microcirculation by Neuronal Nitric Oxide Synthase Inhibition in a Juvenile Ischemic Rat Model.

BACKGROUND: The development of collateral circulation is proposed as an inherent compensatory mechanism to restore impaired blood perfusion after ischemia, at least in the penumbra. We have studied the dynamic macro- and microcirculation after ischemia-reperfusion in the juvenile rat brain and evaluated the impact of neuronal nitric oxide synthase (nNOS) inhibition on the collateral flow. METHODS: Fourteen-day-old (P14) rats were subjected to ischemia-reperfusion and treated with either PBS or 7-nitroindazole (7-NI, an nNOS inhibitor, 25 mg/kg). Arterial blood flow (BF) was measured using 2D-color-coded pulsed ultrasound imaging. Laser speckle contrast (LSC) imaging and sidestream dark-field videomicroscopy were used to measure cortical and microvascular BF, respectively. RESULTS: In basal conditions, 7-NI reduced BF in the internal carotids (by ∼ 25%) and cortical (by ∼ 30%) BF, as compared to PBS. During ischemia, the increased mean BF velocity in the basilar trunk after both PBS and 7-NI demonstrated the establishment of collateral support and patency. Upon re-flow, BF immediately recovered to basal values in the internal carotid arteries under both conditions. The 7-NI group showed increased collateral flow in the penumbral tissue during early re-flow compared to PBS, as shown with both LSC imaging and side-stream dark-field videomicroscopy. The proportion of perfused capillaries was significantly increased under 7-NI as compared to PBS when given before ischemia (67.0 ± 3.9 vs. 46.8 ± 8.8, p < 0.01). Perfused capillaries (63.1 ± 17.7 vs. 81.1 ± 20.7, p < 0.001) and the BF index (2.4 ± 0.6 vs. 1.3 ± 0.1, p < 0.001) significantly increased under 7-NI given at the re-flow onset. CONCLUSIONS: Collateral support in the penumbra is initiated during ischemia, and may be increased during early re-flow by neuronal NOS inhibition (given in pre- and post-treatment), which may preserve brain tissue in juvenile rats.

Bridge to transplantation using paracorporeal biventricular assist devices or the syncardia temporary total artificial heart: is there a difference?

AIM: Biventricular support can be achieved using paracorporeal ventricular assist devices (p-BiVAD) or the Syncardia temporary total artificial heart (t-TAH). The purpose of the present study was to compare survival and morbidity between these devices. METHODS: Data from 2 French neighboring hospitals were reviewed. Between 1996 and 2009, 148 patients (67 p-BiVADs and 81 t-TAH) underwent primary, planned biventricular support. There were 128 (86%) males aged 44±13 years. RESULTS: Preoperatively, p-BiVAD recipients had significantly lower systolic and diastolic blood pressures, more severe hepatic cytolysis and higher white blood cell counts than t-TAH recipients. In contrast, t-TAH patients had significantly higher rates of pre-implant ECLS and hemofiltration. Mean support duration was 79±100 days for the p-BiVAD group and 71±92 for t-TAH group (P=0.6). Forty two (63%) p-BiVAD recipients were bridged to transplantation (39, 58%) or recovery (3, 5%), whereas 51 (63%) patients underwent transplantation in the t-TAH group. Death on support was similar between groups (p-BiVAD, 26 (39%); t-TAH, 30 (37%); P=0.87). Survival while on device was not significantly different between patient groups and multivariate analysis showed that only preimplant diastolic blood pressure and alanine amino-transferase levels were significant predictors of death. Post-transplant survival in the p-BiVAD group was 76±7%, 70±8%, and 58±9% at 1, 3, and 5 years after transplantation, respectively, and was similar to that of the t-TAH group (77±6%, 72±6%, and 70±7%, P=0.60). CONCLUSION: Survival while on support and up to 5 years after heart transplantation was not significantly different in patients supported by p-BiVADs or t-TAH. Multivariate analysis revealed that survival while on transplantation was not affected by the type of device implanted.

[Proposal for a systematic analysis of polygraphy or polysomnography for identifying and scoring abnormal events occurring during non-invasive ventilation]. / Proposition pour une analyse systématique de la polygraphie et de la polysomnographie afin d'identifier les évènements anormaux survenant pendant la ventilation non invasive.

Non-invasive ventilation (NIV) is recognised as an effective treatment for chronic hypercapnic respiratory failure. Monitoring NIV during sleep may be preferable to daytime assessment. This paper reports the findings of an international consensus group, which systematically analysed nocturnal polygraphic or polysomnographic tracings recorded with either volume-cycled or pressure-cycled ventilators. A systematic description of nocturnal respiratory events, which occur during NIV, is proposed: leaks, obstruction at different levels of the upper airway (glottis and/or pharynx), with or without decrease of respiratory drive and asynchrony.

[Ventilator modes and settings during non-invasive ventilation: effects on respiratory events and implications for their identification. 2011]. / Modes ventilatoires et réglages en ventilation non invasive : retentissement sur les évènements respiratoires et implications dans leur identification.

Compared with invasive ventilation, non-invasive ventilation (NIV) has two unique characteristics: its non-hermetic nature and the fact that the ventilator-lung assembly cannot be considered as a single-compartment model because of the presence of variable resistance represented by the upper airways. When NIV is initiated, the ventilator settings are determined empirically based on clinical evaluation and blood gas variations. However, NIV is predominantly applied during sleep. Consequently, to assess overnight patient-machine "agreement" and efficacy of ventilation, more specific and sophisticated monitoring is needed. The effectiveness of NIV might therefore be more correctly assessed by sleep studies than by daytime assessment. The simplest monitoring can be done from flow and pressure curves from the mask or the ventilator circuit. Examination of these tracings can give useful information to evaluate if the settings chosen by the operator were the right ones for that patient. However, as NIV allows a large range of ventilatory parameters and settings, it is mandatory to have information about this to better understand patient-ventilator interaction. Ventilatory modality, mode of triggering, pressurization slope, use or not of positive end expiratory pressure and type of exhalation as well as ventilator performances may all have physiological consequences. Leaks and upper airway resistance variations may, in turn, modify these patterns. This article discusses the equipment available for NIV, analyses the effect of different ventilator modes and settings and of exhalation and connecting circuits on ventilatory traces and gives the background necessary to understand their impact on nocturnal monitoring of NIV.

Dicer-2- and Piwi-mediated RNA interference in Rift Valley fever virus-infected mosquito cells.

Rift Valley fever virus (RVFV) is a Phlebovirus (Bunyaviridae family) transmitted by mosquitoes. It infects humans and ruminants, causing dramatic epidemics and epizootics in Africa, Yemen, and Saudi Arabia. While recent studies demonstrated the importance of the nonstructural protein NSs as a major component of virulence in vertebrates, little is known about infection of mosquito vectors. Here we studied RVFV infection in three different mosquito cell lines, Aag2 cells from Aedes aegypti and U4.4 and C6/36 cells from Aedes albopictus. In contrast with mammalian cells, where NSs forms nuclear filaments, U4.4 and Aag2 cells downregulated NSs expression such that NSs filaments were never formed in nuclei of U4.4 cells and disappeared at an early time postinfection in the case of Aag2 cells. On the contrary, in C6/36 cells, NSs nuclear filaments were visible during the entire time course of infection. Analysis of virus-derived small interfering RNAs (viRNAs) by deep sequencing indicated that production of viRNAs was very low in C6/36 cells, which are known to be Dicer-2 deficient but expressed some viRNAs presenting a Piwi signature. In contrast, Aag2 and U4.4 cells produced large amounts of viRNAs predominantly matching the S segment and displaying Dicer-2 and Piwi signatures. Whereas 21-nucleotide (nt) Dicer-2 viRNAs were prominent during early infection, the population of 24- to 27-nt Piwi RNAs (piRNAs) increased progressively and became predominant later during the acute infection and during persistence. In Aag2 and U4.4 cells, the combined actions of the Dicer-2 and Piwi pathways triggered an efficient antiviral response permitting, among other actions, suppression of NSs filament formation and allowing establishment of persistence. In C6/36 cells, Piwi-mediated RNA interference (RNAi) appeared to be sufficient to mount an antiviral response against a secondary infection with a superinfecting virus. This study provides new insights into the role of Dicer and Piwi in mosquito antiviral defense and the development of the antiviral response in mosquitoes.