Pediatric Measles Vaccine Expressing a Dengue Antigen Induces Durable Serotype-specific Neutralizing Antibodies to Dengue Virus

Dengue disease is an increasing global health problem that threatens one-third of the world's population. Despite decades of efforts, no licensed vaccine against dengue is available. With the aim to develop an affordable vaccine that could be used in young populations living in tropical areas, we evaluated a new strategy based on the expression of a minimal dengue antigen by a vector derived from pediatric live-attenuated Schwarz measles vaccine (MV). As a proof-of-concept, we inserted into the MV vector a sequence encoding a minimal combined dengue antigen composed of the envelope domain III (EDIII) fused to the ectodomain of the membrane protein (ectoM) from DV serotype-1. Immunization of mice susceptible to MV resulted in a long-term production of DV1 serotype-specific neutralizing antibodies. The presence of ectoM was critical to the immunogenicity of inserted EDIII. The adjuvant capacity of ectoM correlated with its ability to promote the maturation of dendritic cells and the secretion of proinflammatory and antiviral cytokines and chemokines involved in adaptive immunity. The protective efficacy of this vaccine should be studied in non-human primates. A combined measles–dengue vaccine might provide a one-shot approach to immunize children against both diseases where they co-exist

Hospitalisations des femmes enceintes vivant avec le VIH à l’ère des combinaisons antirétrovirales en France, de 2005 à 2017

Médecine. Gynécologie obstétriqueIntroduction : A l’ère des combinaisons antirétrovirales puissantes, la santé des femmes enceintes vivant avec le VIH s’est considérablement améliorée, et le taux de transmission materno-fœtale est actuellement inférieur à 1%. Ces thérapies n’ont cessé d’évoluer, mais des effets indésirables ont été décrits et suscitent des inquiétudes. Des études antérieures menées aux Etats-Unis depuis l’avènement des thérapies combinées ont montré une amélioration des issues obstétricales des femmes enceintes vivant avec le VIH, bien qu’elles restent plus défavorables que celles de la population non infectée. Objectif : Évaluer les hospitalisations, ainsi que 4 pathologies obstétricales principales (prééclampsie, diabète, cholestase et hémorragie) des femmes enceintes vivant avec le VIH en France entre 2005 et 2017. Matériel - méthodes : Nous avons mené une étude observationnelle prospective multicentrique sur la cohorte de l’Enquête Périnatale Française. Nous avons inclus toutes les mères ayant accouché entre 2005 et 2017 dans 25 maternités de France (ARNS CO1). Les variables étudiées étaient socio-démographiques, les pathologies obstétricales principales, les motifs d’hospitalisation, ainsi que l’évolution temporelle et géographique. Résultats : Au total, 8634 patientes ont été incluses. Le taux d’hospitalisation global était stable dans le temps de 29,9% et de 23,0% pour les séjours ≥ 2 jours, était plus important à Paris et Ile-de-France pour les séjours totaux (31,1% vs 25,5%, p-0,001). La durée moyenne de séjour était de 7,5 jours. Il y avait entre autres 17,5% d’hospitalisations pour causes obstétricales (dont 6,5% pour MAP, 1,3% pour HTA et 1,6% pour prééclampsie), 3,2% pour causes infectieuses, 4,1% pour causes hépato-gastro-entérologiques, 3,8% pour soins liés à l’infection par le VIH. Seules les hospitalisations pour infections ont statistiquement diminué dans le temps (p-0,001). Le taux d’hospitalisation n’était pas lié au délai entre infection par le VIH et début de grossesse, ni par le moment de l’initiation d’un traitement. En revanche, les femmes diagnostiquées depuis moins de 5 ans, ou ayant consulté la 1e fois au 3e trimestre, ou ayant initié le traitement pendant la grossesse étaient plus fréquemment hospitalisées pour soins liés au VIH (p-0,001). L’incidence de la prééclampsie et du diabète gestationnel ont significativement augmenté dans le temps (p-0,001) alors que leur taux d’hospitalisation a diminué (p-0,001 et p=0,12). Conclusion : Le taux d’hospitalisation et les motifs sont restés stables au cours du temps sauf pour les infections. L’incidence de la prééclampsie et le diabète gestationnel augmentent mais les hospitalisations diminuent. Les résultats semblent comparables à la population non infectée. Cette première étude sur les hospitalisations des femmes enceintes vivant avec le VIH en France nous encourage à poursuivre nos pratiques médicales françaises qui semblent permettre un taux d’hospitalisation et de complications peu différents de la population générale française.Introduction: In the era of HAART (Highly Active AntiRetroviral Therapy), the health of pregnant HIV-infected women has improved considerably, and the rate of perinatal transmission is currently less than 1%. These therapies are constantly evolving, but side effects have been described and cause concern. Previous studies conducted in the United States of America since the advent of HAART have shown improved obstetric outcomes in pregnant HIV-infected women, although they remain worse than uninfected women. Objective: To describe hospitalizations, and 4 major obstetric issues (preeclampsia, gestational diabetes, cholestasis and hemorrhage) of pregnant HIV-infected women living in France between 2005 and 2017. Design and Methods: We conducted a multicenter prospective study on the French Perinatal cohort (EPF), that included all mothers who gave birth between 2005 and 2017 in 25 maternity hospitals in France (ARNS CO1). The variables were socio-demographic, main obstetric issues, causes of hospitalization, and its evolution in time and on the territory. Results: 8634 patients were included. The overall hospitalization rate was stable over time by 29.9% and 23.0% for stays ≥ 2 days, was higher in Paris and Ile-de-France for total stays (31.1% vs 25.5%, p -0.001). The average length of stay was 7.5 days. Amongst other things, there were 17.5% of obstetrical hospitalizations (6.5% for MAP, 1.3% for hypertension and 1.6% for preeclampsia), 3.2% for infectious diseases, 4.1 % for hepatogastroenterological diseases, 3.8% for care related to HIV infection. Only hospitalizations for infections decreased statistically over time (p -0.001). The hospitalization rate was not related to the time between HIV infection and beginning of pregnancy, nor the moment of treatment initiation. In contrast, women diagnosed less than 5 years ago, or who first consulted in the 3rd trimester, or who initiated treatment during pregnancy were more frequently hospitalized for HIV-related care (p -0.001). The incidence of preeclampsia and gestational diabetes significantly increased over time (p -0.001) while their hospitalization rate decreased (p -0.001 and p = 0.12). Conclusion: The hospitalization rate and causes remained stable over time except for infections. Preeclampsia and gestational diabetes are increasing but hospitalizations are decreasing. The results seem comparable to the uninfected population. This first study on the hospitalization of pregnant HIV-infected women in France invites us to continue our french medical practices that seem to allow a rate of hospitalization and complications not so different than uninfected women

Protocol to locally express cxcl12a during zebrafish olfactory organ development by combining IR-LEGO with live imaging

Summary: Temporal and spatial regulation of gene expression is crucial for proper embryonic development. Infrared laser-evoked gene operator (IR-LEGO) can provide information for various developmental processes. Here, we present a protocol to locally express cxcl12a during zebrafish olfactory organ development1 using a combination of IR-LEGO and live imaging. We describe steps for implementing IR-LEGO, biological sample preparation, live imaging, data collection, and analysis. This protocol can be applied to virtually any genetically modified experimental organism. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics

Learning Constraint. Exploring Nurses’ Narratives of Psychiatric Work in the Early Years of French Community Psychiatry

International audienceThis article uses narrative analysis to understand how mental health professionals working in a pilot experiment in community psychiatry in France between 1960 and 1980 made sense of their work experiences. Based on a collection of essays written by these professionals as part of their training as well as on other archival materials, the article explores writing practices in postwar French psychiatry as ways of constructing and negotiating moral commitments to work. The first three sections of the article give some background on mental health nursing in France in the immediate postwar period. The subsequent three sections examine how the professionals elaborated on their experiences in their writings, focusing on three different levels: first, the narrative voice used in the essays; second, the learning processes described by trainees; and finally, the ways in which they negotiated discursively the requirement to do emotionally well at work

Impact of Arsenic Trioxide in the Treatment of Higher Risk Acute Promyelocytic Leukemia

International audienceINTRODUCTION: Acute promyelocytic leukemia (APL) accounts for 5-8% of all cases of acute myeloid leukemia (AML). The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) without chemotherapy is currently the reference treatment of standard APL (ie with baseline white blood count (WBC)<10 G/L), curing about 90% of the patients. However, the prognosis of high-risk APL (ie with WBC>10 G/L) remains more challenging, with higher rates of early death and relapse. Here we compared the French practices for the treatment of high-risk APL patients whether patients were treated with ATRA-Chemo or ATRA-ATO according to physician decision, and evaluate the response rates, overall survival (OS) and leukemia-free survival (LFS) in the real-life settings. PATIENTS AND METHODS: ATO (in combination with ATRA) became accessible in France for the first line treatment of standard risk APL in 2012, but some patients with high-risk APL also received the same combination (generally with some form of cytoreductive chemotherapy) from that date. We retrospectively analyzed cases of high-risk APL diagnosed between 2010 and 2021 in 12 French centers, constituting a cohort of 135 patients with diagnostic of APL confirmed by cytogenetic, FISH and molecular biology assays. RESULTS: Among the 135 patients with WBC>10 G/L, 88 (65%) were classified as APL variant according to FAB classification. Median age was 46 years (range 18-89) and 62 % were male. Median diagnostic WBC was 39.1 G/L (range 10-270) and median platelet count was 27 G/L (range 5-344). At diagnosis, 112 patients (83%) had hemorrhagic manifestations and disseminated intravascular coagulation (DIC) was observed in 124 patients (92%). Pulmonary and cerebral leucostasis were reported in 10 (7%) and 14 (10%) patients, respectively. Eighty-five patients received corticosteroid prophylaxis (81 (95%) with Dexamethasone and 5 (5%) with Prednisolone). Induction therapy consisted in ATRA-ATO for 50 patients (38%) while 85 patients (62%) were treated with ATRA combined with chemotherapy (anthracycline and cytarabin) but without ATO. All patients treated with ATO were cytoreduced: 7 with Hydroxyurea (14%), 17 with Idarubicin (34%) and 26 with both (52%). 29 patients treated without ATO during induction were cytoreduced with Hydroxurea (34%). Most patients experienced one or more adverse events during induction, including sepsis (49 in the ATO group versus 71 in the non ATO group, 98% versus 83.5%, p=0.01), differentiation syndrome (20 in the ATO group versus 27 in the non ATO group, 40% versus 31.7%, p=0.33), transaminase increased (14 in ATO group versus 11 in the non ATO group, 28% versus 12.9%, p=0.03), and bleeding (7 in the ATO group versus 13 in the non ATO group, 14% versus 15.3%, p=0.8). Following induction, 110 patients (81%) achieved complete remission (CR): 45 in the ATO group and 65 in the non ATO group (90% versus 76.4%, p=0.052). One patient (receiving ATRA with chemotherapy) was refractory, and 24 patients experienced early death (5 in the ATO group and 19 in the non ATO group, 10% versus 22.3%, p=0.069) mostly due to hemorrhage or sepsis. Median time between diagnosis and early death was 4.5 days (0-42). Relapse was observed in 6 (5.5 %) patients (5 patients treated without ATO and 1 patient with ATO during induction). After a median follow-up of 34.6 months (0-121.1), OS at 3 years was significantly higher for the ATO group (89.9% (81.8-98.7) versus 75.1% (66.3-84.9) for the non ATO group, p= 0.035, Figure). LFS at 3 years was significantly higher for the ATO group (87.6% (78.7-97.4) versus 71.2% (62-81.7) for the non ATO group, p=0.028). CONCLUSIONS: The survival outcomes were significantly poorer in high-risk APL patients treated without ATO during induction, regardless of the cytoreduction strategy. The toxicity profile of ATO was acceptable. Combining ATO and ATRA limits the use of cytotoxic chemotherapy, which could reduce myelosuppression and long-term complications such as cardiotoxicity and secondary myeloid neoplasms. Early disease-related mortality, due to haemorrhagic or infectious complications, remains the major issue for these patients but tend to be reduced in those receiving ATRA-ATO based regiment. This retrospective study shows that ATO-ATRA and limited chemotherapy could be a better approach than ATRA and standard intensive chemotherapy in terms of early deaths, LFS and OS

Tumeurs frontières de l'ovaire. Recommandations pour la pratique clinique du CNGOF – Texte court

International audienceThis work was carried out under the aegis of the CNGOF (Collège national des gynécologues et obstétriciens français) and proposes guidelines based on the evidence available in the literature. The objective was to define the diagnostic and surgical management strategy, the fertility preservation and surveillance strategy in Borderline Ovarian Tumor (BOT). No screening modality can be proposed in the general population. An expert pathological review is recommended in case of doubt concerning the borderline nature, the histological subtype, the invasive nature of the implant, for all micropapillary/cribriform serous BOT or in the presence of peritoneal implants, and for all mucinous or clear cell tumors (grade C). Macroscopic MRI analysis should be performed to differentiate the different subtypes of BOT: serous, seromucinous and mucinous (intestinal type) (grade C). If preoperative biomarkers are normal, follow up of biomarkers is not recommended (grade C). In cases of bilateral early serous BOT with a desire to preserve fertility and/or endocrine function, it is recommended to perform a bilateral cystectomy if possible (grade B). In case of early mucinous BOT, with a desire to preserve fertility and/or endocrine function, it is recommended to perform a unilateral adnexectomy (grade C). Secondary surgical staging is recommended in case of serous BOT with micropapillary appearance and uncomplete inspection of the abdominal cavity during initial surgery (grade C). For early-stage serous or mucinous BOT, it is not recommended to perform a systematic hysterectomy (grade C). Follow up after BOT must be pursued for more than 5 years (grade B). Conservative treatment involving at least the conservation of the uterus and a fragment of the ovary in a patient wishing to conceive may be proposed in advanced stages of BOT (grade C). A new surgical treatment that preserves fertility after a first non-invasive recurrence may be proposed in women of childbearing age (grade C). It is recommended to offer a specialized consultation for Reproductive Medicine when diagnosing BOT in a woman of childbearing age. Hormonal contraceptive use after serous or mucinous BOT is not contraindicated (grade C)

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II\ue2\u80\u93IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56\uc2\ub76 [SEM 4\uc2\ub75] vs 68\uc2\ub73 [4\uc2\ub75]; rank-based treatment difference \ue2\u88\u9211\uc2\ub77, 95% CI \ue2\u88\u9224\uc2\ub73 to 0\uc2\ub796; p=0\uc2\ub70698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals