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Abstract Background Long-term pulmonary sequelae, including 1-year thoracic computed tomography (CT) sequelae of paediatric acute respiratory distress syndrome (ARDS) remain unknown. The purpose of the study was to determine pulmonary abnormalities in child survivors of pulmonary (p-ARDS) and extra-pulmonary ARDS (ep-ARDS) 1 year after paediatric intensive care unit discharge (PICUD). Methods Prospective multicentre study in four paediatric academic centres between 2005 and 2014. Patients with ARDS were assessed 1 year after PICUD with respiratory symptom questionnaire, thoracic CT and pulmonary function tests (PFT). Results 39 patients (31 p-ARDS) aged 1.1–16.2 years were assessed. Respiratory symptoms at rest or exercise and/or respiratory maintenance treatment were reported in 23 (74%) of children with p-ARDS but in 1 (13%) of those with ep-ARDS. Thoracic CT abnormalities were observed in 18 (60%) of children with p-ARDS and 4 (50%) of those with ep-ARDS. Diffuse and more important CT abnormalities, such as ground glass opacities or mosaic perfusion patterns, were observed in 5 (13%) of children, all with p-ARDS. PFT abnormalities were observed in 30 (86%) of patients: lung hyperinflation and/or obstructive pattern in 12 (34%) children, restrictive abnormalities in 6 (50%), mild decrease in diffusing capacity in 2 (38%) and 6-min walking distance decrease in 11 (73%). Important PFT abnormalities were observed in 7 (20%) children, all with p-ARDS. Increasing driving pressure (max plateau pressure—max positive end-expiratory pressure) was correlated with increasing CT-scan abnormalities and increasing functional residual capacity (more hyperinflation) (p

Abstract Background Extracorporeal cardiopulmonary resuscitation (E-CPR) is used for the treatment of refractory cardiac arrest. However, the optimal target to reach for mean arterial pressure (MAP) remains to be determined. We hypothesized that MAP levels critically modify cerebral hemodynamics during E-CPR and tested two distinct targets (65–75 vs 80–90 mmHg) in a porcine model. Methods Pigs were submitted to 15 min of untreated ventricular fibrillation followed by 30 min of E-CPR. Defibrillations were then delivered until return of spontaneous circulation (ROSC). Extracorporeal circulation was initially set to an average flow of 40 ml/kg/min. The dose of epinephrine was set to reach a standard or a high MAP target level (65–75 vs 80–90 mmHg, respectively). Animals were followed during 120-min after ROSC. Results Six animals were included in both groups. During E-CPR, high MAP improved carotid blood flow as compared to standard MAP. After ROSC, this was conversely decreased in high versus standard MAP, while intra-cranial pressure was superior. The pressure reactivity index (PRx), which is the correlation coefficient between arterial blood pressure and intracranial pressure, also demonstrated inverted patterns of alteration according to MAP levels during E-CPR and after ROSC. In standard-MAP, PRx was transiently positive during E-CPR before returning to negative values after ROSC, demonstrating a reversible alteration of cerebral autoregulation during E-CPR. In high-MAP, PRx was negative during E-CPR but became sustainably positive after ROSC, demonstrating a prolonged alteration in cerebral autoregulation after ROSC. It was associated with a significant decrease in cerebral oxygen consumption in high- versus standard-MAP after ROSC. Conclusions During early E-CPR, MAP target above 80 mmHg is associated with higher carotid blood flow and improved cerebral autoregulation. This pattern is inverted after ROSC with a better hemodynamic status with standard versus high-MAP.

BackgroundCerebral hypoperfusion and impaired oxygen delivery during pediatric critical illness may result in acute neurologic injury with subsequent long-term effects on neurodevelopmental outcome. Yet, the impact of norepinephrine on cerebral hemodynamics is unknown in children with shock. We aimed to describe the norepinephrine effects on cerebral perfusion and oxygenation during pediatric shock.Patients and MethodsWe conducted an observational multicentre prospective study in 3 French pediatric intensive care units. Children

Background: The use and perceived value of transcranial Doppler (TCD) scope in paediatric critical care medicine has not been extensively documented.Objective: To describe the use of TCD to assess non-traumatic brain injury in patients admitted to four paediatric intensive care units (PICUs) in France.Methods: We prospectively included all children (aged under 18) assessed with inpatient TCD between November 2014 and October 2015 at one of the four PICUs. The physicians completed a questionnaire within 4 h of performing TCD.Results: 152 children were included. The primary diagnosis was neurological disease in 106 patients (70%), including post ischemic-anoxic brain insult (n = 42, 28%), status epilepticus (n = 19, 13%), and central nervous system infection/inflammation (n = 15, 10%). TCD was the first-line neuromonitoring assessment in 110 patients (72%) and was performed within 24 h of admission in 112 patients (74%). The most common indications for TCD were the routine monitoring of neurological disorders (n = 85, 56%) and the detection of asymptomatic neurological disorders (n = 37, 24). Concordance between the operator's interpretation of TCD and the published normative values was observed for 21 of the 75 (28%) TCD abnormal findings according to the published normative values. The physicians considered that TCD was of value for the ongoing clinical management of 131 (86%) of the 152 patients.Conclusion: TCD is commonly used in French PICUs and tends to be performed early after admission on patients with a broad range of diseases. The physicians reported that the TCD findings often helped their clinical decision making. In view of the subjectivity of bedside interpretation, true TCD contribution to clinical care remains to be determined. Objective studies of the impact of TCD on patient management and clinical outcomes are therefore warranted.

Abstract Background Protein N-glycosylation is initiated within the endoplasmic reticulum through the synthesis of a lipid-linked oligosaccharides (LLO) precursor. This precursor is then transferred en bloc on neo-synthesized proteins through the action of the oligosaccharyltransferase giving birth to glycoproteins. The N-linked glycans bore by the glycoproteins are then processed into oligomannosides prior to the exit of the glycoproteins from the endoplasmic reticulum and its entrance into the Golgi apparatus. In this compartment, the N-linked glycans are further maturated in complex type N-glycans. This process has been well studied in a lot of eukaryotes including higher plants. In contrast, little information regarding the LLO precursor and synthesis of N-linked glycans is available in microalgae. Methods In this report, a user-friendly extraction method combining microsomal enrichment and solvent extractions followed by purification steps is described. This strategy is aiming to extract LLO precursor from microalgae. Then, the oligosaccharide moiety released from the extracted LLO were analyzed by multistage tandem mass spectrometry in two models of microalgae namely the green microalgae, Chlamydomonas reinhardtii and the diatom, Phaeodactylum tricornutum. Results The validity of the developed method was confirmed by the analysis of the oligosaccharide structures released from the LLO of two xylosyltransferase mutants of C. reinhardtii confirming that this green microalga synthesizes a linear Glc3Man5GlcNAc2 identical to the one of the wild-type cells. In contrast, the analysis of the oligosaccharide released from the LLO of the diatom P. tricornutum demonstrated for the first time a Glc2Man9GlcNAc2 structure. Conclusion The method described in this article allows the fast, non-radioactive and reliable multistage tandem mass spectrometry characterization of oligosaccharides released from LLO of microalgae including the ones belonging to the Phaeodactylaceae and Chlorophyceae classes, respectively. The method is fully adaptable for extracting and characterizing the LLO oligosaccharide moiety from microalgae belonging to other phyla.

Cerebral stroke, traumatic brain injury, and hypoxic ischemic encephalopathy are among the most frequently occurring brain injuries. A complex pathogenesis, characterized by a synergistic interaction between alterations of the cerebrovascular system, cell death, and inflammation, is at the basis of the brain damage that leads to behavioral and neurodevelopmental disabilities in affected subjects. Sildenafil is a selective inhibitor of the enzyme phosphodiesterase 5 (PDE5) that is able to cross the blood–brain barrier. Preclinical data suggest that sildenafil may be a good candidate for the prevention or repair of brain injury in both adults and neonates. The aim of this review is to summarize the evidence supporting the neuroprotective action of sildenafil and discuss the possible benefits of the association of sildenafil with current therapeutic strategies.

Perinatal arterial stroke is the most frequent form of cerebral infarction in children. Neonatal seizures are the most frequent symptom during the neonatal period. The current management of perinatal stroke is based on supportive care. It is currently unknown if treatment of the seizures modifies the outcome, and no clinical studies have focused on seizures during neonatal stroke. We studied the effect of phenobarbital and levetiracetam on an ischemic-reperfusion stroke model in P7 rats using prolonged electroencephalographic recordings and a histologic analysis of the brain (24 h after injury). The following two types of epileptic events were observed: 1) bursts of high amplitude spikes during ischemia and the first hours of reperfusion and 2) organized seizures consisting in discharges of a 1–2 Hz spike-and-wave. Both phenobarbital and levetiracetam decreased the total duration of the bursts of high amplitude spikes. Phenobarbital also delayed the start of seizures without changing the total duration of epileptic discharges. The markedly limited efficacy of the antiepileptic drugs studied in our neonatal stroke rat model is frequently observed in human neonatal seizures. Both drugs did not modify the stroke volume, which suggests that the modification of the quantity of bursts of high amplitude spikes does not influence the infarct size. In the absence of a reduction in seizure burden by the antiepileptic drugs, we increased the seizure burden and stroke volume by combining our neonatal stroke model with a lithium-pilocarpine-induced status epilepticus. Our data suggest that the reduction of burst of spikes did not influence the stroke volume. The presence of organized seizure with a pattern close to what is observed in human newborns seems related to the presence of the infarct. Further research is required to determine the relationship between seizure burden and infarct volume.

We quantify the heavily oil-dominated WEF nexus in three Gulf Cooperation Council (GCC) countries (Kuwait, Qatar and Saudi Arabia) across spatial scales and over time, using available empirical data at the national level, and explore the exposure to nexus stresses (groundwater depletion) in other countries through virtual water trade. At the domestic scale, WEF trade-offs are fairly limited; while all sectors require considerable amounts of energy, the requirements for water and food production are modest compared to other uses. At the international scale, revenues from oil exports in the GCC allow the region to compensate for low food production and scarce water availability. This dependency is dynamic over time, increasing when oil prices are low and food prices are high. We show how reducing domestic trade-offs can lead to higher exposure internationally, with rice imports originating in regions where groundwater is being depleted. However, Saudi Arabia’s increased wheat imports, after reversing its food self-sufficiency policy, have had limited effects on groundwater depletion elsewhere. Climate change mitigation links the WEF nexus to the global scale. While there is great uncertainty about future international climate policy, our analysis illustrates how implementation of measures to account for the social costs of carbon would reduce the oil and gas revenues available to import food and desalinate water in the GCC.

Extracorporeal membrane oxygenation support is indicated in severe and refractory respiratory or circulatory failures. Neurological complications are typically represented by acute ischemic or hemorrhagic lesions, which induce higher morbidity and mortality. The primary goal of this study was to assess the prognostic value of cerebral tissue oxygen saturation (StcO2) on mortality in neonates and young infants treated with ECMO. A secondary objective was to evaluate the association between StcO2 and the occurrence of cerebral lesions.This was a prospective study in infants < 3 months of age admitted to a pediatric intensive care unit and requiring ECMO support.The assessment of cerebral perfusion was made by continuous StcO2 monitoring using near-infrared spectroscopy (NIRS) sensors placed on the two temporo-parietal regions. Neurological lesions were identified by MRI or transfontanellar echography.Thirty-four infants

Monocytes are phagocytic effector cells in the blood and precursors of resident and inflammatory tissue macrophages. The aim of the current study was to analyse and compare their contribution to innate immune surveillance of the lung in the steady state with macrophage and dendritic cells (DC). ECFP and EGFP transgenic reporters based upon Csf1r and Cx3cr1 distinguish monocytes from resident mononuclear phagocytes. We used these transgenes to study the migratory properties of monocytes and macrophages by functional imaging on explanted lungs. Migratory monocytes were found to be either patrolling within large vessels of the lung or locating at the interface between lung capillaries and alveoli. This spatial organisation gives to monocytes the property to capture fluorescent particles derived from both vascular and airway routes. We conclude that monocytes participate in steady-state surveillance of the lung, in a way that is complementary to resident macrophages and DC, without differentiating into macrophages.

The lack of efficient neuroprotective strategies for neonatal stroke could be ascribed to pathogenic ischemic processes differentiating adults and neonates. We explored this hypothesis using a rat model of neonatal ischemia induced by permanent occlusion of the left distal middle cerebral artery combined with 50 min of occlusion of both common carotid arteries (CCA). Postconditioning was performed by repetitive brief release and occlusion (30 s, 1 and/or 5 min) of CCA after 50 min of CCA occlusion. Alternative reperfusion was generated by controlled release of the bilateral CCA occlusion. Blood-flow velocities in the left internal carotid artery were measured using color-coded pulsed Doppler ultrasound imaging. Cortical perfusion was measured using laser Doppler. Cerebrovascular vasoreactivity was evaluated after inhalation with the hypercapnic gas or inhaled nitric oxide (NO). Whatever the type of serial mechanical interruptions of blood flow at reperfusion, postconditioning did not reduce infarct volume after 72 hours. A gradual perfusion was found during early re-flow both in the left internal carotid artery and in the cortical penumbra. The absence of acute hyperemia during early CCA re-flow, and the lack of NO-dependent vasoreactivity in P7 rat brain could in part explain the inefficiency of ischemic postconditioning after ischemia-reperfusion.

Des essais comparatifs de clones de vigne sont analysés et discutés du point de vue de la précision expérimentale. Des propositions sont faites pour tenter d'améliorer l'exploitation de l'information recueillie en particulier : • par la prise en compte de la notion de stabilité d'un clone selon différentes conditions (années, localités, modes de conduite, porte-greffes) ; • par l'étude de la variation inter-clones sur l'ensemble des caractères mesurés par l'Analyse en Composantes Principales. +++ Comparative trials of vine clones are analysed and experimental precision is discussed. Methods aimed at improving the use of collected data are proposed, in particular : • by taking into account the notion of clone stability under different conditions (year, locality, training system, root-stock); • by studying the effect of interclonal variation on the whole of the characters, measured by the Principal Components Analysis. * La mise en place, l'exécution du protocole de ces essais et la collecte des données ont été réalisées par le Lycée Viticole de Beaune et l'Association Technique des Viticulteurs de Bourgogne.

The ‘Jardin du roi’, the king’s garden was founded in 1635 for the cultivation of medicinal plants indigenous to France and to acclimatise plants imported from abroad. The garden was also used for the teaching of different branches of botany. From the 1670s, however, lessons belonging to other disciplines, associated like botany with the ‘healing arts’, that is to say anatomy and surgery. These were practical lessons and the fact that they were free and were delivered in French and not Latin, along with the qualities of the earliest professors, soon raised the king’s garden to a leading position in France, even in Europe, for medical and surgical teaching. This success is also to be explained by the weaknesses of the traditional teaching institutions, the faculty of medicine and the college of surgeons. This was the context in which the first anatomical amphitheatre was constructed in 1705-1710, followed by a more grandiose building designed in 1787 by Edme Verniquet, at the initiative of the garden’s intendant, Buffon. This amphitheatre was rearranged and enlarged in 1794-1795 by Jacques Molinos and it was here, in January 1795 that the first session of the ‘Ecole normale’ took place, soon to become the ‘Ecole normale supérieure’.

Any study of the hospital heritage will come up against two major obstacles. The first difficulty is in defining the territorial perimeter of the study, a region with some sort of geographical and political coherence, considering that the architectural issues were transnational one, as early as the eighteenth century. The second obstacle derives from the first in that the corpus to be studied is a national one, at least, and the categories of buildings to be considered were spread out all over the national territory, witnessing extraordinary development from the middle of the nineteenth century. Hospitals, hospices, mental asylums, sanatoriums... there were several thousands of them at the end of the twentieth century. This mere number might appear to be an insurmountable obstacle to a study that aims at being both exhaustive and in-depth. But the researcher nonetheless has a precious tool in the multitude of publications, mainly articles in the press, dealing with this subject and often taking into consideration the questions of architectural design. There is probably no other building type that is so thoroughly addressed by published texts, although of course this is at the same time another drawback since reading all these articles takes time. Nonetheless, the variety of viewpoints expressed in these articles allows the researcher not to go off in search of unpublished archival sources. The disadvantage of these published sources, however, is that they tend to present analyses of the predominant architectural types, marked by the ideology, the tyranny, of progress, at the expense of other designs following other conceptions and consequently unpublished and unknown to us.

Medical education directly delivered at the bedside, i.e. clinical lessons, was one of the great eighteenth-century educational innovations affecting medical learning. The initiative to establish such training is generally attributed to the Dutch physician Herman Boerhaave, who conceived the institution upon his appointment as professor at the University of Leiden, in 1714. In Paris it was only from 1780 that the physician Louis Desbois de Rochefort started clinical lecturing at the Hôpital de la Charité. The superiority gained by that hospital due to the novelty of the teaching that was provided in it explained why, when health schools were created by the National Convention on 14 Frimaire An III (December 4, 1794), it was the place that was chosen to establish the first school of clinical medicine that would be provided with premises most specially adapted to its function. Because of the budgetary contingencies associated with the political situation, the yard happened to be interrupted several times, but was eventually carried through. Major adjustments made in connection with those works, by the architect Nicolas-Marie Clavareau, in what was the chapel of the Hôpital de la Charité, resulted in an architectural work of its own. By an irony of history, the main part of the chapel has recently met again with a worshipping vocation, becoming in 1943 the Parisian church for the Ukrainian Catholic community, without this leading to the disappearance of the amenities designed for the installation of the school of clinical medicine. They thus constitute an exceptional testimony of the architecture of the Revolutionary era that shone far more with its projects than with its achievements.

The sanatorium of Montigny-en-Ostrevent was built between 1904 and 1905 and is comprised of an ensemble of small pavilions set in a park. The pavilions were destined not only for people suffering from tuberculosis but also for the healthy members of their families. In its architecture, the establishment was inspired by the Saranac Lake sanatorium in the United States, although, at Montigny-en-Ostrevent, the accommodation for the families was an innovation. The sanatorium was conceived by Albert Calmette, director of the Pasteur Institute at Lille and founder of the ‘Ligue du Nord’ against tuberculosis, the commissioning client for the construction. The architect Léonce Hainez designed some elegant buildings in the Art Nouveau style and managed to give the whole the appearance of a holiday village, rather than a sanitary establishment. However, in spite of the generous social intentions of the place’s designers, this original sanatorium was not a success and the First World War put a brutal end to its existence.

Les immeubles aux étages disposés en gradins-terrasses qui, depuis un demi-siècle, connaissent une extraordinaire vogue dans l’architecture balnéaire, sont issus des réflexions de médecins sur le mode de traitement le plus approprié pour des malades affectés d’une tuberculose pulmonaire ou phtisie. Ce fut avec la création en Allemagne, à la fin du xixe siècle, d’un nouveau type d’établissement hospitalier, le sanatorium, conçu comme outil de traitement spécifique de cette affection alors redoutable, que naquit le parti architectural qui allait engendrer l’idée d’étager en gradins les terrasses ou balcons ouverts au-devant des chambres de malades. Plus précisément, ce furent les galeries dites de cure d’air, éléments constitutifs du sanatorium dès son origine, qui, après des déclinaisons diverses, se muèrent en système à gradins-terrasses. Cette mutation elle-même résultait d’une inflexion de la cure sanatoriale qui adjoignit, à la cure d’air traditionnelle, un traitement par le rayonnement solaire ou héliothérapie. Les phtisiologues suisses, promoteurs à l’aube du xxe siècle de cette héliothérapie prétendirent, contrairement à leurs homologues allemands, que le soleil exerçait une action bénéfique et non nocive sur la phtisie. Ils proposèrent donc de découvrir les galeries de cure pour qu’elles fussent inondées de lumière, ce qui constitua le point de départ des recherches pour obtenir pareil effet. La mise en application du système des galeries de cure disposées en gradins se heurtait toutefois à des difficultés constructives ; en sus, les retraits des gradins amenuisaient notablement les surfaces des planchers entre chaque niveau et celui immédiatement supérieur ; enfin, une majorité de médecins continuait à douter de la valeur médicatrice de l’héliothérapie. C’est pourquoi seul un petit nombre de sanatoriums et de fort rares immeubles d’habitations adoptèrent ce système de construction avant la Première Guerre mondiale, puis surtout durant la période de l’entre-deux-guerres. Du fait que les hôpitaux prirent modèle sur l’architecture des sanatoriums à partir des années 1930, on rencontre aussi quelques uns de ces édifices conçus selon les mêmes principes architectoniques. Au lendemain de la guerre, le système de gradins-terrasses ne fit plus recette, tout au moins dans l’architecture hospitalière, en raison sans doute des surcoûts engendrés par sa mise en œuvre. Aussi fallut-il attendre les années 1960 avec l’essor inouï du tourisme de masse en bord de mer, pour que ce système retrouvât la faveur des architectes et se trouvât appliqué à très grande échelle et avec un succès devenu planétaire qui ne se dément toujours pas.

Multiple myeloma (MM) is characterized by an immunosuppressive microenvironment that enables tumor development. One of the mechanisms of immune evasion used by MM cells is the inhibition of natural killer (NK) cell effector functions; thus, the restoration of NK cell antitumor activity represents a key goal to increase tumor cell recognition, avoid tumor escape and potentially enhancing the effect of other drugs. In this study, we evaluated the ability of the investigational medicine NKTR-255, an IL-15 receptor agonist, to engage the IL-15 pathway and stimulate NK cells against MM cells. We observed that incubation with NKTR-255 was able to tilt the balance toward an activated phenotype in NK cells isolated from peripheral blood mononuclear cells of patients with MM, with increased expression of activating receptors on the surface of treated NK cells. This resulted in an enhanced degranulation, cytokine release, and anti-tumor cytotoxicity when the NK cells were exposed to both MM cell lines and primary MM cells. We further evaluated the in vivo effect of NKTR-255 in fully humanized immunocompetent mice subcutaneously engrafted with H929 MM cells. Compared with placebo, weekly injection of the mice with NKTR-255 increased the number of circulating NK cells in peripheral blood and delayed tumor growth. Finally, we observed that combination of NKTR-255 with the anti-CD38 antibody, daratumumab, was effective against MM cells in vitro and in vivo. Taken together, our data suggest a significant impact of NKTR-255 in inducing NK cell function against MM cells with important translational implications., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)