Increased mortality in hematological malignancy patients with acute respiratory failure from undetermined etiology : a Groupe de Recherche en Réanimation Respiratoire en Onco-Hématologique (Grrr-OH) study

Background: Acute respiratory failure (ARF) is the most frequent complication in patients with hematological malignancies and is associated with high morbidity and mortality. ARF etiologies are numerous, and despite extensive diagnostic workflow, some patients remain with undetermined ARF etiology. Methods: This is a post-hoc study of a prospective multicenter cohort performed on 1011 critically ill hematological patients. Relationship between ARF etiology and hospital mortality was assessed using a multivariable regression model adjusting for confounders. Results: This study included 604 patients with ARF. All patients underwent noninvasive diagnostic tests, and a bronchoscopy and bronchoalveolar lavage (BAL) was performed in 155 (25.6%). Definite diagnoses were classified into four exclusive etiological categories: pneumonia (44.4%), non-infectious diagnoses (32.6%), opportunistic infection (10.1%) and undetermined (12.9%), with corresponding hospital mortality rates of 40, 35, 55 and 59%, respectively. Overall hospital mortality was 42%. By multivariable analysis, factors associated with hospital mortality were invasive pulmonary aspergillosis (OR 7.57 (95% CI 3.06-21.62); p 7 (OR 3.32 (95% CI 2.15-5.15); p < 0.005) and an undetermined ARF etiology (OR 2.92 (95% CI 1.71-5.07); p < 0.005). Conclusions: In patients with hematological malignancies and ARF, up to 13% remain with undetermined ARF etiology despite comprehensive diagnostic workup. Undetermined ARF etiology is independently associated with hospital mortality. Studies to guide second-line diagnostic strategies are warranted

The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program

SummaryThe pathways regulating formation of the germinal center (GC) dark zone (DZ) and light zone (LZ) are unknown. In this study we show that FOXO1 transcription factor expression was restricted to the GC DZ and was required for DZ formation, since its absence in mice led to the loss of DZ gene programs and the formation of LZ-only GCs. FOXO1-negative GC B cells displayed normal somatic hypermutation but defective affinity maturation and class switch recombination. The function of FOXO1 in sustaining the DZ program involved the trans-activation of the chemokine receptor CXCR4, and cooperation with the BCL6 transcription factor in the trans-repression of genes involved in immune activation, DNA repair, and plasma cell differentiation. These results also have implications for the role of FOXO1 in lymphomagenesis because they suggest that constitutive FOXO1 activity might be required for the oncogenic activity of deregulated BCL6 expression

The traces of World War I in Brussels

The hundredth anniversary of World War I has put the spotlight on this period once again. The media coverage of the commemorations is unprecedented and even surprising for a conflict which has remained in the memorial shadow of the even more deadly World War II. While there was every reason to believe that the Great War was only a distant memory, it must also be noted that it is still the object of true curiosity on the part of the general public. The hundredth anniversary has also led to a number of publications, most of which are in keeping with the revival of historical research surrounding World War I for the past twenty years or so. The case of Belgium – the scene of fighting in a territory which was almost completely occupied – has thus been well studied. However, while several recent studies have used Brussels as a framework, a global summary specifically devoted to the capital does not exist. This synopsis thus summarises the material traces and immaterial heritage of the conflict in Brussels. The aim is therefore not to trace the history of Brussels during World War I or to present the latest works on this subject, but rather to answer some simple questions asked by the inhabitants of Brussels today: What remains of World War I in the capital? Who is interested in it, and why? How does this conflict resonate today in Brussels’ memories? How are they reflected in the urban space? In other words, this synopsis reverses the historical temporality to observe the results of the sifting of time.Le centenaire de la Première Guerre mondiale a remis cette période sous les feux des projecteurs. Le retentissement médiatique des premières commémorations a été tout à fait inédit, voire surprenant, pour un conflit longtemps resté dans l’ombre d’une Seconde Guerre mondiale plus meurtrière encore. Si tout portait à croire que la Grande Guerre n’était plus qu’un lointain souvenir, force est de constater qu’elle fait encore l’objet d’une réelle curiosité de la part du grand public. Ce centenaire a aussi engendré une multitude de publications dont beaucoup s’inscrivent dans le renouveau des recherches historiques sur la Première Guerre mondiale en cours depuis une grosse vingtaine d’années. Le cas de la Belgique, théâtre de combats et territoire presque totalement occupé, a été abondamment étudié. Par contre si une série de travaux récents ont pris Bruxelles pour cadre d’analyse, une synthèse globale spécifiquement consacrée à la capitale fait encore défaut. Cette première note synthétise donc les traces matérielles et les héritages immatériels du conflit à Bruxelles. L’ambition n’est dès lors pas de retracer l’histoire de Bruxelles pendant la Première Guerre mondiale, ni même de présenter les derniers travaux sur ce sujet mais de répondre à quelques questions simples que se posent aujourd’hui les Bruxellois : que reste-t-il de la Première Guerre mondiale dans la capitale ? Qui s’y intéresse et pourquoi ? Quelles résonances ce conflit a-t-il encore aujourd’hui dans les mémoires bruxelloises ? Comment se répercutent-elles dans l’espace urbain ? En d’autres mots, cette note prend le parti de renverser la temporalité historique pour observer le résultat opéré par le tri du temps.De honderdste verjaardag van de Eerste Wereldoorlog heeft die periode weer voor het voetlicht gebracht. De belangstelling van de media voor de eerste herdenkingen is ongezien en zelfs verrassend voor een conflict dat lange tijd in de schaduw van de nog moorddadigere Tweede Wereldoorlog is gebleven. Alles wees erop dat de “Groote Oorlog” niet meer dan een verre herinnering was, maar we moeten vaststellen dat het grote publiek er echt meer over wil weten. Ter gelegenheid van de honderdste verjaardag zijn er ook veel werken gepubliceerd, waarvan een groot aantal aansluit bij de hernieuwde belangstelling van de laatste twintig jaar voor historisch onderzoek over de Eerste Wereldoorlog. Het geval België, waar strijd werd geleverd en waarvan het grondgebied bijna volledig bezet was, is zeer uitgebreid bestudeerd. Verschillende recente studies gaan over Brussel, maar er ontbreekt nog een allesomvattende synthese die specifiek aan de hoofdstad is gewijd. Deze eerste nota geeft dus een overzicht van de materiele en immateriële sporen van het conflict in Brussel. De synthesenota heeft niet de bedoeling om de geschiedenis van Brussel tijdens de Eerste Wereldoorlog te beschrijven noch de recentste werken over dat onderwerp te presenteren, maar om antwoorden te geven op enkele eenvoudige vragen die de Brusselaars zich vandaag stellen: wat blijft er over van de Eerste Wereldoorlog in Brussel? Wie interesseert zich daarvoor? Waarom? Welke plaats neemt het conflict vandaag nog in het Brusselse geheugen in? Hoe komt dat tot uiting in de stedelijke ruimte? Met andere woorden, de nota gaat omgekeerd chronologisch te werk en gaat na wat de tand des tijds heeft doorstaan

In de sporen van de Eerste Wereldoorlog in Brussel

De honderdste verjaardag van de Eerste Wereldoorlog heeft die periode weer voor het voetlicht gebracht. De belangstelling van de media voor de eerste herdenkingen is ongezien en zelfs verrassend voor een conflict dat lange tijd in de schaduw van de nog moorddadigere Tweede Wereldoorlog is gebleven. Alles wees erop dat de “Groote Oorlog” niet meer dan een verre herinnering was, maar we moeten vaststellen dat het grote publiek er echt meer over wil weten. Ter gelegenheid van de honderdste verjaardag zijn er ook veel werken gepubliceerd, waarvan een groot aantal aansluit bij de hernieuwde belangstelling van de laatste twintig jaar voor historisch onderzoek over de Eerste Wereldoorlog. Het geval België, waar strijd werd geleverd en waarvan het grondgebied bijna volledig bezet was, is zeer uitgebreid bestudeerd. Verschillende recente studies gaan over Brussel, maar er ontbreekt nog een allesomvattende synthese die specifiek aan de hoofdstad is gewijd. Deze eerste nota geeft dus een overzicht van de materiele en immateriële sporen van het conflict in Brussel. De synthesenota heeft niet de bedoeling om de geschiedenis van Brussel tijdens de Eerste Wereldoorlog te beschrijven noch de recentste werken over dat onderwerp te presenteren, maar om antwoorden te geven op enkele eenvoudige vragen die de Brusselaars zich vandaag stellen: wat blijft er over van de Eerste Wereldoorlog in Brussel? Wie interesseert zich daarvoor? Waarom? Welke plaats neemt het conflict vandaag nog in het Brusselse geheugen in? Hoe komt dat tot uiting in de stedelijke ruimte? Met andere woorden, de nota gaat omgekeerd chronologisch te werk en gaat na wat de tand des tijds heeft doorstaan.Le centenaire de la Première Guerre mondiale a remis cette période sous les feux des projecteurs. Le retentissement médiatique des premières commémorations a été tout à fait inédit, voire surprenant, pour un conflit longtemps resté dans l’ombre d’une Seconde Guerre mondiale plus meurtrière encore. Si tout portait à croire que la Grande Guerre n’était plus qu’un lointain souvenir, force est de constater qu’elle fait encore l’objet d’une réelle curiosité de la part du grand public. Ce centenaire a aussi engendré une multitude de publications dont beaucoup s’inscrivent dans le renouveau des recherches historiques sur la Première Guerre mondiale en cours depuis une grosse vingtaine d’années. Le cas de la Belgique, théâtre de combats et territoire presque totalement occupé, a été abondamment étudié. Par contre si une série de travaux récents ont pris Bruxelles pour cadre d’analyse, une synthèse globale spécifiquement consacrée à la capitale fait encore défaut. Cette première note synthétise donc les traces matérielles et les héritages immatériels du conflit à Bruxelles. L’ambition n’est dès lors pas de retracer l’histoire de Bruxelles pendant la Première Guerre mondiale, ni même de présenter les derniers travaux sur ce sujet mais de répondre à quelques questions simples que se posent aujourd’hui les Bruxellois : que reste-t-il de la Première Guerre mondiale dans la capitale ? Qui s’y intéresse et pourquoi ? Quelles résonances ce conflit a-t-il encore aujourd’hui dans les mémoires bruxelloises ? Comment se répercutent-elles dans l’espace urbain ? En d’autres mots, cette note prend le parti de renverser la temporalité historique pour observer le résultat opéré par le tri du temps.The hundredth anniversary of World War I has put the spotlight on this period once again. The media coverage of the commemorations is unprecedented and even surprising for a conflict which has remained in the memorial shadow of the even more deadly World War II. While there was every reason to believe that the Great War was only a distant memory, it must also be noted that it is still the object of true curiosity on the part of the general public. The hundredth anniversary has also led to a number of publications, most of which are in keeping with the revival of historical research surrounding World War I for the past twenty years or so. The case of Belgium – the scene of fighting in a territory which was almost completely occupied – has thus been well studied. However, while several recent studies have used Brussels as a framework, a global summary specifically devoted to the capital does not exist. This synopsis thus summarises the material traces and immaterial heritage of the conflict in Brussels. The aim is therefore not to trace the history of Brussels during World War I or to present the latest works on this subject, but rather to answer some simple questions asked by the inhabitants of Brussels today: What remains of World War I in the capital? Who is interested in it, and why? How does this conflict resonate today in Brussels’ memories? How are they reflected in the urban space? In other words, this synopsis reverses the historical temporality to observe the results of the sifting of time

Reappraisal of Vipera aspis Venom Neurotoxicity

BACKGROUND: The variation of venom composition with geography is an important aspect of intraspecific variability in the Vipera genus, although causes of this variability remain unclear. The diversity of snake venom is important both for our understanding of venomous snake evolution and for the preparation of relevant antivenoms to treat envenomations. A geographic intraspecific variation in snake venom composition was recently reported for Vipera aspis aspis venom in France. Since 1992, cases of human envenomation after Vipera aspis aspis bites in south-east France involving unexpected neurological signs were regularly reported. The presence of genes encoding PLA(2) neurotoxins in the Vaa snake genome led us to investigate any neurological symptom associated with snake bites in other regions of France and in neighboring countries. In parallel, we used several approaches to characterize the venom PLA(2) composition of the snakes captured in the same areas. [br/] METHODOLOGY/PRINCIPAL FINDINGS: We conducted an epidemiological survey of snake bites in various regions of France. In parallel, we carried out the analysis of the genes and the transcripts encoding venom PLA(2)s. We used SELDI technology to study the diversity of PLA(2) in various venom samples. Neurological signs (mainly cranial nerve disturbances) were reported after snake bites in three regions of France: Languedoc-Roussillon, Midi-Pyrénées and Provence-Alpes-Côte d'Azur. Genomes of Vipera aspis snakes from south-east France were shown to contain ammodytoxin isoforms never described in the genome of Vipera aspis from other French regions. Surprisingly, transcripts encoding venom neurotoxic PLA(2)s were found in snakes of Massif Central region. Accordingly, SELDI analysis of PLA(2) venom composition confirmed the existence of population of neurotoxic Vipera aspis snakes in the west part of the Massif Central mountains. [br/] CONCLUSIONS/SIGNIFICANCE: The association of epidemiological studies to genetic, biochemical and immunochemical analyses of snake venoms allowed a good evaluation of the potential neurotoxicity of snake bites. A correlation was found between the expression of neurological symptoms in humans and the intensity of the cross-reaction of venoms with anti-ammodytoxin antibodies, which is correlated with the level of neurotoxin (vaspin and/or ammodytoxin) expression in the venom. The origin of the two recently identified neurotoxic snake populations is discussed according to venom PLA(2) genome and transcriptome data

Impact of early enteral versus parenteral nutrition on mortality in patients requiring mechanical ventilation and catecholamines: study protocol for a randomized controlled trial (NUTRIREA-2)

BACKGROUND: Nutritional support is crucial to the management of patients receiving invasive mechanical ventilation (IMV) and the most commonly prescribed treatment in intensive care units (ICUs). International guidelines consistently indicate that enteral nutrition (EN) should be preferred over parenteral nutrition (PN) whenever possible and started as early as possible. However, no adequately designed study has evaluated whether a specific nutritional modality is associated with decreased mortality. The primary goal of this trial is to assess the hypothesis that early first-line EN, as compared to early first-line PN, decreases day 28 all-cause mortality in patients receiving IMV and vasoactive drugs for shock. METHODS/DESIGN: The NUTRIREA-2 study is a multicenter, open-label, parallel-group, randomized controlled trial comparing early PN versus early EN in critically ill patients requiring IMV for an expected duration of at least 48 hours, combined with vasoactive drugs, for shock. Patients will be allocated at random to first-line PN for at least 72 hours or to first-line EN. In both groups, nutritional support will be started within 24 hours after IMV initiation. Calorie targets will be 20 to 25 kcal/kg/day during the first week, then 25 to 30 kcal/kg/day thereafter. Patients receiving PN may be switched to EN after at least 72 hours in the event of shock resolution (no vasoactive drugs for 24 consecutive hours and arterial lactic acid level below 2 mmol/L). On day 7, all patients receiving PN and having no contraindications to EN will be switched to EN. In both groups, supplemental PN may be added to EN after day 7 in patients with persistent intolerance to EN and inadequate calorie intake. We plan to recruit 2,854 patients at 44 participating ICUs. DISCUSSION: The NUTRIREA-2 study is the first large randomized controlled trial designed to assess the hypothesis that early EN improves survival compared to early PN in ICU patients. Enrollment started on 22 March 2013 and is expected to end in November 2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01802099 (registered 27 February 2013)