The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

Precision Medicine; Pediatric and Adolescent Patients; Recurrent MalignanciesMedicina de Precisión; Pacientes pediátricos y adolescentes; Neoplasias malignas recurrentesMedicina de precisió; Pacients pediàtrics i adolescents; Neoplasmes malignes recurrentsMAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/ refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies—56% of them within early clinical trials—mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA)

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Comprendre et dépasser les limitations induites par l'utilisation de nanofils de silicium/silicium amorphe (a-Si ˸H) dans les cellules solaires

Le potentiel utilisable de l'énergie solaire représente plus du double de la consommation finale humaine en 2019. Néanmoins, seulement 0.2 % du potentiel est aujourd'hui utilisé par la technologie photovoltaïque. Le silicium cristallin (95 % du marché actuel) est très avancé, puisque les modules actuellement produits ont une efficacité autour de 20 %. Néanmoins, l'efficacité de conversion n'est pas le seul facteur pour choisir une technologie photovoltaïque. En particulier, son impact environnemental, sa résistance aux conditions extérieures ou son adéquation à l'application choisie sont également déterminants. Des technologies alternatives ont donc leur place dans le mix photovoltaïque. En particulier, le silicium amorphe constitue un matériau abondant qui ne nécessite pas une purification coûteuse en énergie. De plus, il est non toxique, aux excellentes propriétés optiques. Il présente des limitations électriques, mais l'utilisation de nanofils cœur-coquille remédie à ce problème en séparant les directions d'absorption de la lumière et de collection des porteurs de charge. La croissance peut se faire sur tout type de substrat (typiquement du verre), à faible température. Ainsi on peut obtenir des performances correctes sur de larges surfaces et à faible coût. J'ai montré que les cellules à base de nanofils cœur-coquille silicium/silicium amorphe (Si NW/a-Si:H) sont d'abord limitées par leur contact supérieur, qui doit être à la fois conducteur et transparent. J'ai développé une électrode hybride, faite d'ITO, capable de connecter les nanofils Si NW/a-Si:H, et de nanofils d'argent, qui forment un maillage conducteur. Une optimisation directement sur la cellule est nécessaire et a permis une augmentation de l'efficacité de conversion de 4.3 % à 6.6 %. L'un des inconvénients principaux des nanofils d'argent est leur dégradation dans le temps. Nous les avons encapsulés dans une couche de ZnO dopé au titane pour les protéger. J'ai suivi la dégradation des nanofils par l'observation en microscopie électronique à balayage, et par des mesures de transmittance et réflectance totales et de résistance de couche. Cette étude a montré que les nanofils d'argent, même nus, sont stables sur une échelle d'un an. Néanmoins, ils n'ont pas été exposés à d'importants niveaux de courant ou d'illumination. Or, la lumière et le courant peuvent accélérer la dégradation et seront nécessairement présents lors de l'utilisation d'Ag NWs sur des cellules solaires. La même étude sous illumination et/ou courant serait donc utile. Les cellules faites de Si NW/a-Si:H avec le contact hybride devraient être flexibles. Néanmoins, l'observation au MEB a montré des fissures dans les cellules à nanofils. Ceux-ci étant denses, ils ont un comportement qui s'approche des couches minces et perdent leur flexibilité. Nous avons aussi voulu comprendre le changement de performance sous forte illumination. La comparaison des courbes I-V pour une cellule Si NW/a-Si:H, une cellule planaire de silicium amorphe et une cellule de référence en silicium cristallin a montré plusieurs phénomènes, réversibles ou non. En particulier, cela a mis en évidence l'effet Staebler-Wronski, caractéristique de a-Si:H, et les conséquences du substrat de verre sur l'élévation de la température et la baisse drastique d'efficacité. Par ailleurs, j'ai pu utiliser la technique EBIC (courant induit par faisceau électronique) sur de nombreuses structures. J'ai observé les cellules à base de Si NW/a-Si:H en vue de haut. J'ai également caractérisé des cellules solaires à nanofils III-V sur silicium pour tandem. Enfin, j'ai aussi caractérisé des nanofils GaN/InGaN, destinés à la fabrication de diodes électro-luminescentes.The exploitable solar potential corresponds to more than twice the final human consumption of energy in 2019. Yet, only 0.2 % of thus potential is used today for photovoltaic conversion. Crystalline silicon, which holds 95 % of the market, is an advanced technology, with currently made modules showing a power conversion efficiency around 20 %. However, the power conversion efficiency is not the only parameter to consider when choosing a photovoltaic technology. Its environmental impact, the dependence of its power conversion efficiency on the illumination and temperature conditions, and the match between the PV technology characteristics and the application are also key factors. Consequently, there is room for other technologies than c-Si, including less efficient ones. In particular, amorphous silicon is an abundant material with no need for an energy-costly purification process. Besides, it is non-toxic and displays excellent optical properties. The main drawback is its poor material quality, limiting the transport distance if the minority charge carriers. This issue can be solved in core-shell nanowires, where the direction for the absorption of the light and for the collection of charge carriers are separated. Moreover, these cells can be grown on various substrates (usually glass) at low temperatures. Low-cost, large-area working solar cells can hence be obtained. I showed that the solar cells made of silicon/amorphous silicon (a-Si:H) core-shell nanowires are first limited by the top contact. It has to be both transparent and conductive. I developed a hybrid electrode, made of ITO (able to connect every single Si nanowire) and silver nanowires (able to make a conductive network on top of the Si NW/a-Si:H). We optimized the electrode properties directly on the device and increased the power conversion efficiency from 4.3 % to 6.6 %. One of the main shortcomings of the silver nanowires is their degradation with time. I encapsulated them in a titanium-doped ZnO layer to protect them. I monitored their degradation with scanning electron microscopy, measurements of total transmittance and reflectance, and measurements of the sheet resistance. This study showed that bare silver nanowires are not degraded over a year. Yet, they had not been exposed to light or current stress. Light and current would nonetheless be present in the use of the solar cell. The same study under illumination or with current would be needed. The cells made of Si NW/a-Si:H with the hybrid contact are expected to be flexible. However, SEM observations showed cracks in the Si NW array. Because they are dense, they behave almost as a thin film and lose their flexible feature. We also wanted to understand the change in performance under high illumination. Comparing I-V curves of a Si NW/a-Si:H with a planar a-Si :H and a crystalline silicon solar cells evidenced different phenomena, reversible or not. In particular, it showed the Staebler-Wronski effect, typical of a-Si:H, and the consequences of the glass substrate on the increase of temperature and the drastic loss in performance. In addition, I used the EBIC technique (electron beam induced current) on various structures. I observed the Si NW/a-Si:H in plane-view. I also characterized III-V nanowire on silicon for tandem solar cells. Finally, I also characterized GaN/InGaN nanowires for electroluminescent diodes

Comprendre et dépasser les limitations induites par l'utilisation de nanofils de silicium/silicium amorphe (a-Si ˸H) dans les cellules solaires

The exploitable solar potential corresponds to more than twice the final human consumption of energy in 2019. Yet, only 0.2 % of thus potential is used today for photovoltaic conversion. Crystalline silicon, which holds 95 % of the market, is an advanced technology, with currently made modules showing a power conversion efficiency around 20 %. However, the power conversion efficiency is not the only parameter to consider when choosing a photovoltaic technology. Its environmental impact, the dependence of its power conversion efficiency on the illumination and temperature conditions, and the match between the PV technology characteristics and the application are also key factors. Consequently, there is room for other technologies than c-Si, including less efficient ones. In particular, amorphous silicon is an abundant material with no need for an energy-costly purification process. Besides, it is non-toxic and displays excellent optical properties. The main drawback is its poor material quality, limiting the transport distance if the minority charge carriers. This issue can be solved in core-shell nanowires, where the direction for the absorption of the light and for the collection of charge carriers are separated. Moreover, these cells can be grown on various substrates (usually glass) at low temperatures. Low-cost, large-area working solar cells can hence be obtained. I showed that the solar cells made of silicon/amorphous silicon (a-Si:H) core-shell nanowires are first limited by the top contact. It has to be both transparent and conductive. I developed a hybrid electrode, made of ITO (able to connect every single Si nanowire) and silver nanowires (able to make a conductive network on top of the Si NW/a-Si:H). We optimized the electrode properties directly on the device and increased the power conversion efficiency from 4.3 % to 6.6 %. One of the main shortcomings of the silver nanowires is their degradation with time. I encapsulated them in a titanium-doped ZnO layer to protect them. I monitored their degradation with scanning electron microscopy, measurements of total transmittance and reflectance, and measurements of the sheet resistance. This study showed that bare silver nanowires are not degraded over a year. Yet, they had not been exposed to light or current stress. Light and current would nonetheless be present in the use of the solar cell. The same study under illumination or with current would be needed. The cells made of Si NW/a-Si:H with the hybrid contact are expected to be flexible. However, SEM observations showed cracks in the Si NW array. Because they are dense, they behave almost as a thin film and lose their flexible feature. We also wanted to understand the change in performance under high illumination. Comparing I-V curves of a Si NW/a-Si:H with a planar a-Si :H and a crystalline silicon solar cells evidenced different phenomena, reversible or not. In particular, it showed the Staebler-Wronski effect, typical of a-Si:H, and the consequences of the glass substrate on the increase of temperature and the drastic loss in performance. In addition, I used the EBIC technique (electron beam induced current) on various structures. I observed the Si NW/a-Si:H in plane-view. I also characterized III-V nanowire on silicon for tandem solar cells. Finally, I also characterized GaN/InGaN nanowires for electroluminescent diodes.Le potentiel utilisable de l'énergie solaire représente plus du double de la consommation finale humaine en 2019. Néanmoins, seulement 0.2 % du potentiel est aujourd'hui utilisé par la technologie photovoltaïque. Le silicium cristallin (95 % du marché actuel) est très avancé, puisque les modules actuellement produits ont une efficacité autour de 20 %. Néanmoins, l'efficacité de conversion n'est pas le seul facteur pour choisir une technologie photovoltaïque. En particulier, son impact environnemental, sa résistance aux conditions extérieures ou son adéquation à l'application choisie sont également déterminants. Des technologies alternatives ont donc leur place dans le mix photovoltaïque. En particulier, le silicium amorphe constitue un matériau abondant qui ne nécessite pas une purification coûteuse en énergie. De plus, il est non toxique, aux excellentes propriétés optiques. Il présente des limitations électriques, mais l'utilisation de nanofils cœur-coquille remédie à ce problème en séparant les directions d'absorption de la lumière et de collection des porteurs de charge. La croissance peut se faire sur tout type de substrat (typiquement du verre), à faible température. Ainsi on peut obtenir des performances correctes sur de larges surfaces et à faible coût. J'ai montré que les cellules à base de nanofils cœur-coquille silicium/silicium amorphe (Si NW/a-Si:H) sont d'abord limitées par leur contact supérieur, qui doit être à la fois conducteur et transparent. J'ai développé une électrode hybride, faite d'ITO, capable de connecter les nanofils Si NW/a-Si:H, et de nanofils d'argent, qui forment un maillage conducteur. Une optimisation directement sur la cellule est nécessaire et a permis une augmentation de l'efficacité de conversion de 4.3 % à 6.6 %. L'un des inconvénients principaux des nanofils d'argent est leur dégradation dans le temps. Nous les avons encapsulés dans une couche de ZnO dopé au titane pour les protéger. J'ai suivi la dégradation des nanofils par l'observation en microscopie électronique à balayage, et par des mesures de transmittance et réflectance totales et de résistance de couche. Cette étude a montré que les nanofils d'argent, même nus, sont stables sur une échelle d'un an. Néanmoins, ils n'ont pas été exposés à d'importants niveaux de courant ou d'illumination. Or, la lumière et le courant peuvent accélérer la dégradation et seront nécessairement présents lors de l'utilisation d'Ag NWs sur des cellules solaires. La même étude sous illumination et/ou courant serait donc utile. Les cellules faites de Si NW/a-Si:H avec le contact hybride devraient être flexibles. Néanmoins, l'observation au MEB a montré des fissures dans les cellules à nanofils. Ceux-ci étant denses, ils ont un comportement qui s'approche des couches minces et perdent leur flexibilité. Nous avons aussi voulu comprendre le changement de performance sous forte illumination. La comparaison des courbes I-V pour une cellule Si NW/a-Si:H, une cellule planaire de silicium amorphe et une cellule de référence en silicium cristallin a montré plusieurs phénomènes, réversibles ou non. En particulier, cela a mis en évidence l'effet Staebler-Wronski, caractéristique de a-Si:H, et les conséquences du substrat de verre sur l'élévation de la température et la baisse drastique d'efficacité. Par ailleurs, j'ai pu utiliser la technique EBIC (courant induit par faisceau électronique) sur de nombreuses structures. J'ai observé les cellules à base de Si NW/a-Si:H en vue de haut. J'ai également caractérisé des cellules solaires à nanofils III-V sur silicium pour tandem. Enfin, j'ai aussi caractérisé des nanofils GaN/InGaN, destinés à la fabrication de diodes électro-luminescentes

Préface

Préface à Tiphaine Besnard, Les prostituées à la Salpêtrière et dans le discours médial, 1850-1914. Une folle débauche, Paris, L'Harmattan, 201

Poétique de la lecture de la traduction (James Joyce, Vladimir Nabokov, João Guimarães Rosa)

A la croisée de deux champs théoriques et pratiques, la lecture de la traduction se place dřemblée comme une pratique problématique. Ce travail cherche à rendre compte, en mettant lřaccent (contre la notion traditionnelle de perte qui lui est traditionnellement attachée) sur la positivité de la traduction, dřune poétique de la lecture de la traduction. Il sřinscrit ainsi à la fois dans le champ de la traductologie (quřil cherche à renouveler en mettant lřaccent sur la lecture du texte traduit) et de la réception (auquel il contribue en soumettant ses concepts à un type de texte, la traduction, quřil avait jusquřalors ignoré). Il tente ainsi de mettre au jour (à travers Ulysses de Joyce) certaines modalités propres à la lecture en traduction. Interrogeant le rapport entre lřoriginal et ses traductions, il invite (grâce à une lecture transtextuelle de lřensemble des traductions de Grande Sertão : Veredas de Guimarães Rosa) à considérer la traduction comme un texte spécifique, qui demande un mode de lecture particulier si lřon veut quřelle soit autre chose quřun pis-aller. On découvre alors quřelle est un concept clé pour mieux comprendre des problèmes de poétique et de lecture qui ne peuvent se résoudre que par elle. Lire en traduction, cřest aussi lire un traducteur et cřest en ce sens quřon cherche à définir (examinant lřoeuvre de traducteur de Nabokov) les spécificités de ce qui pourrait constituer un sujet traduisant. La lecture des traductions peut ainsi être conçue comme une poétique à part entière, au sens où elle engage notre rapport critique aux textes et aux théories.At the crossroads between two theoretical and practical fields, the act of reading translation positions itself as a problematic practice. This thesis tries to give an account of a poetics of reading translation, by emphasizing the positive side of translation (as opposed to the traditional notion of loss usually attached to it). It therefore lies within the framework of both translation studies (which it tries to renew by stressing the reading of the translated text) and reader-response theory (which it contributes to by submitting its concepts to a type of text, i.e. translation, it had so far ignored). It thus attempts to bring to light (through Joyce's Ulysses) certain modalities exclusive to reading in translation. Questioning the relation between the original text and its translations, and thanks to a transtextual reading of all the translations of Grande Sertão : Veredas by Guimarães Rosa, it induces us to regard a translation as a specific text, which calls for a particular mode of reading Ŕ if we want it to be more than second best. We then find out that translation is a key concept to better understand problems of poetics and reading that can only be solved by it. Reading in translation is also reading a translator, and it is in this sense that we seek to define the specificities of what could constitute a translating subject (by examining Nabokov's achievements as a translator). Reading translations can consequently be conceived as a poetics in its own right, in the sense that it involves our critical relationship to texts and theories.ST DENIS-BU PARIS8 (930662101) / SudocSudocFranceF

Préface

Préface à Tiphaine Besnard, Les prostituées à la Salpêtrière et dans le discours médial, 1850-1914. Une folle débauche, Paris, L'Harmattan, 201

Fonctionnalisation de la lignine pour la préparation de matériaux agro-sourcés

National audienc