Ebola virus glycoprotein stimulates IL-18 dependent natural killer cell responses

BACKGROUNDNK cells are activated by innate cytokines and viral ligands to kill virus-infected cells. These functions are enhanced during secondary immune responses and after vaccination by synergy with effector T cells and virus-specific antibodies. In human Ebola virus infection, clinical outcome is strongly associated with the initial innate cytokine response, but the role of NK cells has not been thoroughly examined.METHODSThe novel 2-dose heterologous Adenovirus type 26.ZEBOV (Ad26.ZEBOV) and modified vaccinia Ankara-BN-Filo (MVA-BN-Filo) vaccine regimen is safe and provides specific immunity against Ebola glycoprotein, and is currently in phase 2 and 3 studies. Here, we analyzed NK cell phenotype and function in response to Ad26.ZEBOV, MVA-BN-Filo vaccination regimen and in response to in vitro Ebola glycoprotein stimulation of PBMCs isolated before and after vaccination.RESULTSWe show enhanced NK cell proliferation and activation after vaccination compared with baseline. Ebola glycoprotein-induced activation of NK cells was dependent on accessory cells and TLR-4-dependent innate cytokine secretion (predominantly from CD14+ monocytes) and enriched within less differentiated NK cell subsets. Optimal NK cell responses were dependent on IL-18 and IL-12, whereas IFN-γ secretion was restricted by high concentrations of IL-10.CONCLUSIONThis study demonstrates the induction of NK cell effector functions early after Ad26.ZEBOV, MVA-BN-Filo vaccination and provides a mechanism for the activation and regulation of NK cells by Ebola glycoprotein.TRIAL REGISTRATIONClinicalTrials.gov NCT02313077.FUNDINGUnited Kingdom Medical Research Council Studentship in Vaccine Research, Innovative Medicines Initiative 2 Joint Undertaking, EBOVAC (grant 115861) and Crucell Holland (now Janssen Vaccines and Prevention B.V.), European Union's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations (EFPIA)

Antibody-Dependent Natural Killer Cell Activation after Ebola Vaccination

BACKGROUND:Antibody Fc-mediated functions, such as antibody-dependent cellular cytotoxicity, contribute to vaccine-induced protection against viral infections. Fc-mediated function of anti-Ebola glycoprotein antibodies suggest that Fc-dependent activation of effector cells, including NK cells, could play a role in vaccination against Ebola virus disease. METHODS:We analysed the effect of anti-Ebola glycoprotein antibody in the serum of U.K.-based volunteers vaccinated with the novel 2-dose heterologous Adenovirus type 26.ZEBOV, Modified Vaccinia Ankara-BN-Filo vaccine regimen, on primary human NK cell activation. RESULTS:We demonstrate primary human NK cell CD107a and IFN-γ expression, combined with downregulation of CD16, in response to recombinant Ebola virus glycoprotein and post-vaccine dose 1 and dose 2 sera. These responses varied significantly with vaccine regimen and NK cell activation was found to correlate with anti-glycoprotein antibody concentration. We also reveal an impact of NK cell differentiation phenotype on antibody-dependent NK cell activation, with highly differentiated CD56dimCD57+ NK cells being the most responsive. CONCLUSIONS:This study thus highlights the dual importance of vaccine-induced antibody concentration and NK cell differentiation status in promoting Fc-mediated activation of NK cells after vaccination, raising a potential role for antibody-mediated NK cell activation in vaccine-induced immune responses

Durable natural killer cell responses after heterologous two-dose Ebola vaccination

Natural killer (NK) cells are implicated among immune effectors after vaccination against viral pathogens, including Ebola virus. The two-dose heterologous Ebola virus vaccine regimen, adenovirus type 26.ZEBOV followed by modified vaccinia Ankara-BN-Filo (EBOVAC2 consortium, EU Innovative Medicines Initiative), induces NK cell activation and anti-Ebola glycoprotein (GP) antibody-dependent NK cell activation post-dose 1, which is further elevated post-dose 2. Here, in a multicentre, phase 2 clinical trial (EBL2001), we demonstrate durable ex vivo NK cell activation 180 days after dose 2, with responses enriched in CD56(bright) NK cells. In vitro antibody-dependent responses to immobilised Ebola GP increased after dose 1, and remained elevated compared to pre-vaccination levels in serum collected 180 days later. Peak NK cell responses were observed post-dose 2 and NK cell IFN-γ responses remained significantly elevated at 180 days post-dose 2. Individual variation in NK cell responses were influenced by both anti-Ebola GP antibody concentrations and intrinsic interindividual differences in NK cell functional capacity. In summary, this study demonstrates durable NK cell responses after Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccination and could inform the immunological evaluation of future iterations of the vaccine regimen and vaccination schedules

Viola gelida, a new, rare and vulnerable rosulate species from the high Andes of Atacama Region, Chile

Se provee la descripción para Viola gelida, conocida sólo de dos sitios cercanos en el desierto seco y frío de gran altura. Se identifican las características que distinguen su estrecha relación con Viola exsul y otros parientes cercanos. Además, se discute el contexto de su descubrimiento en un estudio de impacto ambiental obligatorio

A randomized comparison ofrepeat stenting with balloon angioplasty in patients with in-stent restenosis

AbstractObjectivesThis randomized trial compared repeat stenting with balloon angioplasty (BA) in patients with in-stent restenosis (ISR).BackgroundStent restenosis constitutes a therapeutic challenge. Repeat coronary interventions are currently used in this setting, but the recurrence risk remains high.MethodsWe randomly assigned 450 patients with ISR to elective stent implantation (224 patients) or conventional BA (226 patients). Primary end point was recurrent restenosis rate at six months. Secondary end points included minimal lumen diameter (MLD), prespecified subgroup analyses, and a composite of major adverse events.ResultsProcedural success was similar in both groups, but in-hospital complications were more frequent in the balloon group. After the procedure MLD was larger in the stent group (2.77 ± 0.4 vs. 2.25 ± 0.5 mm, p < 0.001). At follow-up, MLD was larger after stenting when the in-lesion site was considered (1.69 ± 0.8 vs. 1.54 ± 0.7 mm, p = 0.046). However, the binary restenosis rate (38% stent group, 39% balloon group) was similar with the two strategies. One-year event-free survival (follow-up 100%) was also similar in both groups (77% stent vs. 71% balloon, p = 0.19). Nevertheless, in the prespecified subgroup of patients with large vessels (≥3 mm) the restenosis rate (27% vs. 49%, p = 0.007) and the event-free survival (84% vs. 62%, p = 0.002) were better after repeat stenting.ConclusionsIn patients with ISR, repeat coronary stenting provided better initial angiographic results but failed to improve restenosis rate and clinical outcome when compared with BA. However, in patients with large vessels coronary stenting improved the long-term clinical and angiographic outcome

Early Developmental Stages of Crustacean Decapods Associated with Floating Seaweed in Fiord and Channels from Southern Chile

Durante el crucero "CIMAR 9 Fiordos" realizado en agosto y noviembre de 2003 en los fiordos y canales de la regi&oacute;n de Ays&eacute;n, Chile, se cuantific&oacute; la abundancia de macroalgas flotando a la deriva (MFD) y se identific&oacute; los estados tempranos de desarrollo de crust&aacute;ceos dec&aacute;podos (megalopas y juveniles, ETD) asociados a ellas. Las macroalgas Macrocystis spp. y Durvillaea antarctica fueron las m&aacute;s abundantes. Para ambos meses monitoreados se registraron las mayores abundancias de MFD en la zona norte del &aacute;rea de estudio y en el sector sur del canal Moraleda. Las abundancias de macroalgas fueron sustancialmente m&aacute;s altas en primavera (noviembre) que en invierno (agosto). Del mismo modo, s&oacute;lo en primavera se encontr&oacute; ETD asociados a estas macroalgas, pero en abundancias relativamente bajas (m&aacute;ximo de 5 ind. por muestra). Las especies de crust&aacute;ceos dec&aacute;podos encontradas en MFD son especies principalmente intermareales. En un estudio sobre MFD, realizado en la misma localidad y durante primavera de 2002 (CIMAR 8 Fiordos), se encontr&oacute; mayores abundancias de ETD asociados que en el presente estudio. Se concluye que en la &aacute;rea de estudio hay un suplemento relativamente consistente y alto de MFD, pero existe elevada variabilidad inter e intra-anual de la presencia de ETD en estas macroalgas. Por lo tanto, se sugiere examinar con mayor detalle esta asociaci&oacute;n para determinar la importancia de MFD en el proceso de reclutamiento de especies de crust&aacute;ceos dec&aacute;podos

Estados Tempranos de Desarrollo de Crustáceos Decápodos Asociados a Macroalgas Flotando a la Deriva en Fiordos y Canales del Sur de Chile

Durante el crucero "CIMAR 9 Fiordos" realizado en agosto y noviembre de 2003 en los fiordos y canales de la regi&oacute;n de Ays&eacute;n, Chile, se cuantific&oacute; la abundancia de macroalgas flotando a la deriva (MFD) y se identific&oacute; los estados tempranos de desarrollo de crust&aacute;ceos dec&aacute;podos (megalopas y juveniles, ETD) asociados a ellas. Las macroalgas Macrocystis spp. y Durvillaea antarctica fueron las m&aacute;s abundantes. Para ambos meses monitoreados se registraron las mayores abundancias de MFD en la zona norte del &aacute;rea de estudio y en el sector sur del canal Moraleda. Las abundancias de macroalgas fueron sustancialmente m&aacute;s altas en primavera (noviembre) que en invierno (agosto). Del mismo modo, s&oacute;lo en primavera se encontr&oacute; ETD asociados a estas macroalgas, pero en abundancias relativamente bajas (m&aacute;ximo de 5 ind. por muestra). Las especies de crust&aacute;ceos dec&aacute;podos encontradas en MFD son especies principalmente intermareales. En un estudio sobre MFD, realizado en la misma localidad y durante primavera de 2002 (CIMAR 8 Fiordos), se encontr&oacute; mayores abundancias de ETD asociados que en el presente estudio. Se concluye que en la &aacute;rea de estudio hay un suplemento relativamente consistente y alto de MFD, pero existe elevada variabilidad inter e intra-anual de la presencia de ETD en estas macroalgas. Por lo tanto, se sugiere examinar con mayor detalle esta asociaci&oacute;n para determinar la importancia de MFD en el proceso de reclutamiento de especies de crust&aacute;ceos dec&aacute;podos

Cost-effectiveness of a European ST-segment elevation myocardial infarction network: results from the Catalan Codi Infart network

Objectives: To evaluate the cost-effectiveness of the ST-segment elevation myocardial infarction (STEMI) network of Catalonia (Codi Infart). Design Cost-utility analysis. Setting: The analysis was from the Catalonian Autonomous Community in Spain, with a population of about 7.5 million people. Participants: Patients with STEMI treated within the autonomous community of Catalonia (Spain) included in the IAM CAT II-IV and Codi Infart registries. Outcome measures costs included hospitalisation, procedures and additional personnel and were obtained according to the reperfusion strategy. Clinical outcomes were defined as 30-day avoided mortality and quality-adjusted life-years (QALYs), before (N=356) and after network implementation (N=2140). Results: A substitution effect and a technology effect were observed; aggregate costs increased by 2.6%. The substitution effect resulted from increased use of primary coronary angioplasty, a relatively expensive procedure and a decrease in fibrinolysis. Primary coronary angioplasty increased from 31% to 89% with the network, and fibrinolysis decreased from 37% to 3%. Rescue coronary angioplasty declined from 11% to 4%, and no reperfusion from 21% to 4%. The technological effect was related to improvements in the percutaneous coronary intervention procedure that increased efficiency, reducing the average length of the hospital stay. Mean costs per patient decreased from 8306 to 7874 for patients with primary coronary angioplasty. Clinical outcomes in patients treated with primary coronary angioplasty did not change significantly, although 30-day mortality decreased from 7.5% to 5.6%. The incremental cost-effectiveness ratio resulted in an extra cost of 4355 per life saved (30-day mortality) and 495 per QALY. Below a cost threshold of 30,000, results were sensitive to variations in costs and outcomes. Conclusions: The Catalan STEMI network (Codi Infart) is cost-efficient. Further studies are needed in geopolitical different scenarios

Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders (TAND): New Findings on Age, Sex, and Genotype in Relation to Intellectual Phenotype

Background: Knowledge is increasing about TSC-Associated Neuropsychiatric Disorders (TAND), but little is known about the potentially confounding effects of intellectual ability (IA) on the rates of TAND across age, sex, and genotype. We evaluated TAND in (a) children vs. adults, (b) males vs. females, and (c) TSC1 vs. TSC2 mutations, after stratification for levels of IA, in a large, international cohort. Methods: Individuals of any age with a documented visit for TSC in the 12 months prior to enrolment were included. Frequency and percentages of baseline TAND manifestations were presented by categories of IA (no intellectual disability [ID, intelligence quotient (IQ)>70]; mild ID [IQ 50–70]; moderate-to-profound ID [IQ<50]). Chi-square tests were used to test associations between ID and TAND manifestations. The association between TAND and age (children vs. adults), sex (male vs. female), and genotype (TSC1 vs. TSC2) stratified by IA levels were examined using the Cochran–Mantel–Haenszel tests. Results: Eight hundred and ninety four of the 2,211 participants had formal IQ assessments. There was a significant association (P < 0.05) between levels of IA and the majority of TAND manifestations, except impulsivity (P = 0.12), overactivity (P = 0.26), mood swings (P = 0.08), hallucinations (P = 0.20), psychosis (P = 0.06), depressive disorder (P = 0.23), and anxiety disorder (P = 0.65). Once controlled for IA, children had higher rates of overactivity, but most behavioral difficulties were higher in adults. At the psychiatric level, attention deficit hyperactivity disorder (ADHD) was seen at higher rates in children while anxiety and depressive disorders were observed at higher rates in adults. Compared to females, males showed significantly higher rates of impulsivity and overactivity, as well as autism spectrum disorder (ASD) and ADHD. No significant age or sex differences were observed for academic difficulties or neuropsychological deficits. After controlling for IA no genotype-TAND associations were observed, except for higher rates of self-injury in individuals with TSC2 mutations. Conclusions: Findings suggest IA as risk marker for most TAND manifestations. We provide the first evidence of male preponderance of ASD and ADHD in individuals with TSC. The study also confirms the association between TSC2 and IA but, once controlling for IA, disproves the previously reported TSC2 association with ASD and with most other TAND manifestations