Antibody persistence and booster responses to split-virion H5N1 avian influenza vaccine in young and elderly adults

Avian influenza continues to circulate and remains a global health threat not least because of the associated high mortality. In this study antibody persistence, booster vaccine response and cross-clade immune response between two influenza A(H5N1) vaccines were compared. Participants aged over 18-years who had previously been immunized with a clade 1, A/Vietnam vaccine were re-immunized at 6-months with 7.5 mu g of the homologous strain or at 22-months with a clade 2, alum-adjuvanted, A/Indonesia vaccine. Blood sampled at 6, 15 and 22-months after the primary course was used to assess antibody persistence. Antibody concentrations 6-months after primary immunisation with either A/Vietnam vaccine 30 mu g alum-adjuvanted vaccine or 7.5 mu g dose vaccine were lower than 21days after the primary course and waned further with time. Re-immunization with the clade 2, 30 mu g alum-adjuvanted vaccine confirmed cross-clade reactogenicity. Antibody crossreactivity between A(H5N1) clades suggests that in principle a prime-boost vaccination strategy may provide both early protection at the start of a pandemic and improved antibody responses to specific vaccination once available

A Delphi process to optimize quality and performance of drug evaluation in neonates

Background Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. The objective of this work was to identify the major criteria considered necessary for selecting neonatal intensive care units that are able to perform drug evaluations competently. Methodology and Main Findings This Delphi process was conducted with an international multidisciplinary panel of 25 experts from 13 countries, selected to be part of two committees (a scientific committee and an expert committee), in order to validate criteria required to perform drug evaluation in neonates. Eighty six items were initially selected and classified under 7 headings: “NICUs description - Level of care” (21), “Ability to perform drug trials: NICU organization and processes (15), “Research Experience” (12), “Scientific competencies and area of expertise” (8), “Quality Management” (16), “Training and educational capacity” (8) and “Public involvement” (6). Sixty-one items were retained and headings were rearranged after the first round, 34 were selected after the second round. A third round was required to validate 13 additional items. The final set includes 47 items divided under 5 headings. Conclusion A set of 47 relevant criteria will help to NICUs that want to implement, conduct or participate in drug trials within a neonatal network identify important issues to be aware of. Summary Points 1) Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. 2) The present Delphi study was conducted with an international multidisciplinary panel of 25 experts from 13 countries and aims to identify the major criteria considered necessary for selecting neonatal intensive care units (NICUs) that are able to perform drug evaluations competently. 3) Of the 86 items initially selected and classified under 7 headings - “NICUs description - Level of care” (21), “Ability to perform drug trials: NICU organization and processes (15), “Research Experience” (12), “Scientific competencies and area of expertise” (8), “Quality Management” (16), “Training and educational capacity” (8) and “Public involvement” (6) - 47 items were selected following a three rounds Delphi process. 4) The present consensus will help NICUs to implement, conduct or participate in drug trials within a neonatal network

Design of the Observing System Simulation Experiments with multi-platform in situ data and impact on fine- scale structures

This report presents the work plan of the Task 2.3: Observing System Simulation Experiments: impact of multi-platform observations for the validation of satellite observation

Analysis of the OSSEs with multi-platform in situ data and impact on fine-scale structures

This report includes recommendations for the planification of in situ experiments aimed to reconstruct fine-scale ocean currents (~20 km), such as those that will be conducted to validate SWOT satellite observations

Inter-model comparison of sub-seasonal tropical variability in aquaplanet experimets: effect of a warm pool

This study compares the simulation of sub-seasonal tropical variability by a set of six state-of-the-art AGCMs in two experiments in aqua-planet configuration: a zonally-symmetric experiment, and an experiment with a warm pool centered on the equator. In all six models, the presence of the warm pool generates zonal asymmetries in the simulated mean states in the form of a “Gill-type” response, made more complex by feedbacks between moisture, convective heating and circulation. Noticeable differences appear from one model to another. Only half the models simulate mean low-level equatorial westerlies over the warm pool area. The presence of the warm pool can also favor the development of large-scale variability consistent with observed Madden-Julian Oscillation (MJO) characteristics, but this happens only in half the models. Our results do not support the idea that the presence of the warm pool and/or of mean low-level equatorial westerlies are sufficient conditions for MJO-like variability to arise in the models. Comparing spectral characteristics of the simulated Convectively Coupled Equatorial Waves (CCEWs) in the aquaplanet experiments and the corresponding coupled atmosphere-ocean (i.e. CMIP) and atmosphere-only (i.e. AMIP) simulations, we also show that there is more consistency for a given model across its configurations, than for a given configuration across the six models. Overall, our results confirm that the simulation of sub-seasonal variability by given model is significantly influenced by the parameterization of sub-grid physical processes (most-likely cloud processes), both directly and through modulation of the mean state

Manejo actual de la otitis externa maligna. Una revisión sistemática.

INTRODUCTION: Malignant external otitis (OEM), or also called necrotizing external otitis, is a life-threatening infection, mainly affecting the external auditory canal, producing osteomyelitis of the temporal bone; extends to the base of the skull and surrounding tissue, causing sepsis; eventually compromising the cranial nerves and generating multisystemic. Objectives: To describe the current management of malignant external otitis. Specific objectives: 1) To determine the etiology of malignant external otitis. 2) To determine the complications of malignant external otitis. METHODS: A systematic review was performed according to the PRISMA 2020 guidelines with a search for scientific articles, with the term malignant external otitis. We recovered 40 articles corresponding to the last 5 years, obtained from databases such as Cochrane, academic Google, Medline, Mendeley, ScientDirect, IntechOpen. The risks of bias in the studies showed systematic differences due to the heterogeneity of the patients and the treatments between the groups. RESULTS: the management of malignant external otitis includes treatment with anti-pseudomonas antibiotics such as fluoroquinolones in combination with a beta-lactam and an antifungal such as amphotericin B, voriconazole, fluconazole, or echinocandin; in addition to treatment with surgical debridement of the ear canal and radical mastoidectomy, to avoid the risk of neurocranial sepsis, obtaining good results. DISCUSSION: Malignant external otitis is a pathology of rare occurrence that affects immune immunocompromised patients, whose morbidity and mortality is high, if not treated properly. Its main causal agents are: pseudomona aeruginosa, staphylococcus aureus, Candida spp, Aspergillus spp and Geotrichum. The importance of this research lies in optimizing care in the patient with OEM, making a timely clinical and imaging diagnosis, to provide an effective therapeutic alternative, based on broad-spectrum antibiotic therapy, antifungal treatment, and surgical treatment, to avoid complications.INTRODUCCIÓN: La otitis externa maligna (OEM), o también llamada otitis externa necrotizante, es una infección potencialmente mortal, que afecta principalmente al canal auditivo externo, produciendo osteomielitis del hueso temporal; se extiende hasta la base del cráneo y tejido circundante, provocando sepsis; llegando a comprometer los nervios craneales y generar afección multisistémica. Objetivos General: Describir el manejo actual de la otitis externa maligna. Objetivos específicos: 1) Determinar la etiología de la otitis externa maligna.  2) Determinar las complicaciones de la de la otitis externa maligna. MÉTODOS: se realizó una revisión sistemática según las guías PRISMA 2020 con búsqueda de artículos científicos, con el termino otitis externa maligna. Se recuperaron 40 artículos correspondientes a los últimos 5 años, obtenidos de bases de datos como Cochrane, Google académico, Medline, Mendeley, ScientDirect, IntechOpen. Los riesgos de sesgo en los estudios observaron diferencias sistemáticas por la heterogeneidad de los pacientes y los tratamientos entre los grupos.  RESULTADOS: el manejo de la otitis externa maligna incluye tratamiento con antibióticos anti pseudomona como las fluoroquinolonas en combinación con un betalactámico y un antifúngico como la anfotericina B, voriconazol, fluconazol o equinocandinas; además del tratamiento con desbridamiento quirúrgico del canal auditivo y mastoidectomía radical, para evitar el riesgo de sepsis neurocraneal, obteniéndose buenos resultados.  DISCUSIÓN: La otitis externa maligna, es una patología de rara ocurrencia que afecta a pacientes inmunocomprometidos, cuya morbimortalidad es alta, si no se trata adecuadamente. Sus principales agentes causales son: pseudomona aeruginosa, estafilococo aureus, Cándida spp, Aspergillus spp y Geotrichum. La importancia de esta investigación radica en optimizar la atención en el paciente con OEM, realizando un diagnóstico clínico e imagenológico oportuno, para brindar una alternativa terapéutica eficaz, basada en antibioticoterapia de amplio espectro, el tratamiento antifúngico, complementario al tratamiento quirúrgico, para evitar complicaciones

Genome Evolution of Two Genetically Homogeneous Infectious Bursal Disease Virus Strains During Passages in vitro and ex vivo in the Presence of a Mutagenic Nucleoside Analog

The avibirnavirus infectious bursal disease virus (IBDV) is responsible for a highly contagious and sometimes lethal disease of chickens (Gallus gallus). IBDV genetic variation is well-described for both field and live-attenuated vaccine strains, however, the dynamics and selection pressures behind this genetic evolution remain poorly documented. Here, genetically homogeneous virus stocks were generated using reverse genetics for a very virulent strain, rvv, and a vaccine-related strain, rCu-1. These viruses were serially passaged at controlled multiplicities of infection in several biological systems, including primary chickens B cells, the main cell type targeted by IBDV in vivo. Passages were also performed in the absence or presence of a strong selective pressure using the antiviral nucleoside analog 7-deaza-2′-C-methyladenosine (7DMA). Next Generation Sequencing (NGS) of viral genomes after the last passage in each biological system revealed that (i) a higher viral diversity was generated in segment A than in segment B, regardless 7DMA treatment and viral strain, (ii) diversity in segment B was increased by 7DMA treatment in both viruses, (iii) passaging of IBDV in primary chicken B cells, regardless of 7DMA treatment, did not select cell-culture adapted variants of rvv, preserving its capsid protein (VP2) properties, (iv) mutations in coding and non-coding regions of rCu-1 segment A could potentially associate to higher viral fitness, and (v) a specific selection, upon 7DMA addition, of a Thr329Ala substitution occurred in the viral polymerase VP1. The latter change, together with Ala270Thr change in VP2, proved to be associated with viral attenuation in vivo. These results identify genome sequences that are important for IBDV evolution in response to selection pressures. Such information will help tailor better strategies for controlling IBDV infection in chickens

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Production of Infectious Genotype 1b Virus Particles in Cell Culture and Impairment by Replication Enhancing Mutations

With the advent of subgenomic hepatitis C virus (HCV) replicons, studies of the intracellular steps of the viral replication cycle became possible. These RNAs are capable of self-amplification in cultured human hepatoma cells, but save for the genotype 2a isolate JFH-1, efficient replication of these HCV RNAs requires replication enhancing mutations (REMs), previously also called cell culture adaptive mutations. These mutations cluster primarily in the central region of non-structural protein 5A (NS5A), but may also reside in the NS3 helicase domain or at a distinct position in NS4B. Most efficient replication has been achieved by combining REMs residing in NS3 with distinct REMs located in NS4B or NS5A. However, in spite of efficient replication of HCV genomes containing such mutations, they do not support production of infectious virus particles. By using the genotype 1b isolate Con1, in this study we show that REMs interfere with HCV assembly. Strongest impairment of virus formation was found with REMs located in the NS3 helicase (E1202G and T1280I) as well as NS5A (S2204R), whereas a highly adaptive REM in NS4B still allowed virus production although relative levels of core release were also reduced. We also show that cells transfected with the Con1 wild type genome or the genome containing the REM in NS4B release HCV particles that are infectious both in cell culture and in vivo. Our data provide an explanation for the in vitro and in vivo attenuation of cell culture adapted HCV genomes and may open new avenues for the development of fully competent culture systems covering the therapeutically most relevant HCV genotypes

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat