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Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

The article addresses organization of Late Bronze Age mining in the Southern Trans-Urals, in particular the degrees of its specialization and the scale of exchange operations. The main object is bone remains from the cultural layer of the II millennium BC of the Novotemirsky mine. The species and age composition of domestic animals are similar to the settlement materials of the Sintashta, Srubnaya-Alakul, and Sargary-Alekseevo settlements of the region. Comparison of 87 Sr/86 Sr variations in local bioavailable strontium baseline proxies and archaeological samples has indicated that the range of cattle grazing was located mainly within the immediate vicinity of the Novotemirsky mine. The results suggest that the mining organization model implemented at the Novotemirsky mine was similar to the Alakul culture of the Ural-Mugodzhary mining and metallurgical center and was characterized by the absence of specialized miner settlements, and the participation of the population of nearby villages in labor and meals organization at the mines, as well as by the poor development of trade and exchange operations.

The pandemic virus of Influenza A (H1N1)pdm09 (new Californian strains of 2009) became the absolutely new variant of flu virus, which was not previously circulating among humans and to which most people don't have immunity emerges and it could be transmited among humans. The 2009 pandemic virus had been spread globally quikly, and on 11 June 2009, the World Health Organization (WHO) declared the first influenza pandemic since 1968–1969[1]. Genetic analysis of new virus A(H1N1)pdm09 showed that it is 4-fold reassortant and already contains internal segments, that belong to the viruses of human influenza, birds and two separate lines of flu of pigs: the North-American and Eurasian lines[2]. April 2010, laboratory-confirmed infections of pH1N1 influenza virus was identified in 212 countries and overseas territories in April 2010, and fact of more than 18,000 laboratory-confirmed deaths was reported to the WHO worldwide. And in Ukraine have been reported the information of more than 1128 deaths in Ukraine in the same period was reported by Ministry of Health of Ukraine[4].Research evaluation of virus of Influenza A (H1N1)pdm09 was carried out by Ukrainian scientists and it was detected[3], Ukrainian isolates of influenza virus had a high genetic identity (99%) to the pandemic strains A(H1N1)pdm09, this was observed in the period of 2009-2010 inother countries.This pandemic A(H1N1)pdm09 virus has been widely circulating across the globe since 2009, and now it is established in human populations as a seasonal influenza virus. But during the epidemic season of 2015-2016 inUkraine pandemic influenza virus subtypes A(H1N1) pdm09 caused a considerable deaths among the human population of Ukraine. During 40 week it was registered 370 laboratory confirmed deaths caused by influenza, and 81,4% cases were caused by pandemic influenza A (H1N1)pdm09 virus [4].Therefore modern diagnostics of the Californian strains of virus A(H1N1) pdm09 and monitoring of pandemic strains of virus subtypes A (H1N1) pdm09 across the south and east areas of Ukraine, where the birds influenza viruses A(H5N1) circulate naturally[5] remain actual problem for today.The goal of our research work was to evaluate a Multiplex TaqMan Real-Time RT-PCR for the rapid and specific diagnostic of pandemic influenza virus A (H1N1) pdm09 in clinical samples of patients with influenza.Materials and methods. We used Human Influenza virus reference strains А/FM1/47 (H1N1), А/Panama/2007/99 (H3N2), А/New Caledonia/20/99 (H1N1), B/Hong Kong/330/01 were kindly provided for our study by Svitlana L. Rybalko and WHO Collaborating Center for Influenza (CDC, USA) for evaluation the specificity levels. Human respiratory samples (nasopharyngeal swabs and aspirates, sputum) from Viral Influenza (VI) patients (n=10) were kindly provided by Irina G. Kostenko (the Main Military Clinical Hospital of Ukraine). The clinical samples were validated by Seeplex® Influenza A(H1N1pandemic) RT-PCR assay (Seegene Inc., South Korea) and TaqMan Influenza A (H1N1) Assay Sets [10]. The polymerase chain reaction in real time (Real-Time RT-PCR) was done for Applied Biosystems(ABI PRIZM 7000/7500).Results: It was found that the Multiplex TaqMan Real-Time RT-PCR assay, designed primers and the TaqMan-probes(test kit «DIA Influenza H1N1») identifed the RNA of influenza pandemic California strains of A ( H1N1) pdm09 in clinical samples with 100% sensitivity and specificity.Ten-fold dilutions of A (H1N1) pdm09 recombinant plasmids pIMC-13(M-gene), pIHC-21(H5-gene) и pINC-20(N1-gene) were used for the determination of detection limits and the amplification efficiency of the assay. Samples were tested in triplicate for each dilution. Therefore, analytical sensitivity of test is 10 copies per reaction.Outlook: The proposed TaqMan Real-Time RT-PCR assay is an effective tool for fast and precise detection and diagnostic of the pandemic strains of influenza virus A (H1N1)pdm09. ; Актуальність – сучасна діагностика пандемічних штамів вірусу грипу молекулярними методами. Мета – провести оцінку мультиплексного варіанту методу TaqMan Real-Time RT-PCR аналізу для швидкої та специфічної діагностики пандемічного вірусу грипу A(H1N1)pdm в клінічних зразках хворих на грип. Методи: Полімеразна ланцюгова реакція в режимі реального часу(Real-Time RT-PCR). Встановлено, що методика мультиплексного TaqMan Real-Time RT-PCR аналізу та розроблені праймери та TaqMan-зонди, що входять до складу вітчизняної тест-системи «DIA Influenza H1N1» здатні виявляти зі 100 % чутливістю та специфічністю РНК Каліфорнійських штамів пандемічного вірусу грипу A(H1N1)pdm серед клінічних зразків з сезонними штамами вірусу грипу. Аналітична чутливість тесту визначена на рівні 10 копій в реакції. Запропонована методика TaqMan Real-Time RT-PCR є ефективним інструментом швидкого та точного виявлення високопатогенних пандемічних штамів вірусу грипу A(H1N1)pdm 2009 року.

The multilayer (10 layers) Al doped ZnO (AZO) thin films were deposited on glass substrate by sol-gel & dipping method. X-Ray diffraction measurements showed that the AZO films were polycrystalline with a hexagonal wurtzite structure. The morphological properties of the films were analyzed by atomic force microscopy showing continuous and homogeneous film, completely covering the substrates. The thickness, optical constants, optical band gap (Eg) and transmittance (T) of AZO films were assessed by spectroscopic ellipsometry on UV-vis-NIR spectral range. The AZO film has high transmittance above 80% in the visible region and the optical band-gap energy around 3.7 eV. The electrical characteristics regarding conductivity, mobility and carrier concentrations, were measured by Hall Effect measurements (van der Pauw method). The bulk carrier concentration of the AZO film with 10 layers was found to be 1.16x1019 cm-3. The vibrational bands were obtained by Raman analysis. Defects due to oxygen vacancies in the prepared AZO films were evidenced by photoluminescence spectroscopy (PL). The optical and electrical properties of the AZO thin films proved the possibility to be used in optoelectronic applications.

As the COVID-19 pandemic began in early 2020, primary care influenza sentinel surveillance networks within the Influenza - Monitoring Vaccine Effectiveness in Europe (I-MOVE) consortium rapidly adapted to COVID-19 surveillance. This study maps system adaptations and lessons learned about aligning influenza and COVID-19 surveillance following ECDC / WHO/Europe recommendations and preparing for other diseases possibly emerging in the future. Using a qualitative approach, we describe the adaptations of seven sentinel sites in five European Union countries and the United Kingdom during the first pandemic phase (March–September 2020). Adaptations to sentinel systems were substantial (2/7 sites), moderate (2/7) or minor (3/7 sites). Most adaptations encompassed patient referral and sample collection pathways, laboratory testing and data collection. Strengths included established networks of primary care providers, highly qualified testing laboratories and stakeholder commitments. One challenge was the decreasing number of samples due to altered patient pathways. Lessons learned included flexibility establishing new routines and new laboratory testing. To enable simultaneous sentinel surveillance of influenza and COVID-19, experiences of the sentinel sites and testing infrastructure should be considered. The contradicting aims of rapid case finding and contact tracing, which are needed for control during a pandemic and regular surveillance, should be carefully balanced.

I-MOVE-COVID-19 primary care study team (in addition to authors above): Nick Andrews, Jamie Lopez Bernal, Heather Whitaker, Caroline Guerrisi, Titouan Launay, Shirley Masse, Sylvie van der Werf, Vincent Enouf, John Cuddihy, Adele McKenna, Michael Joyce, Cillian de Gascun, Joanne Moran, Ana Miqueleiz, Ana Navascués, Camino Trobajo-Sanmartín, Carmen Ezpeleta, Paula López Moreno, Javier Gorricho, Eva Ardanaz, Fernando Baigorria, Aurelio Barricarte, Enrique de la Cruz, Nerea Egüés, Manuel García Cenoz, Marcela Guevara, Conchi Moreno-Iribas, Carmen Sayón, Verónica Gomez, Baltazar Nunes, Rita Roquete, Adriana Silva, Aryse Melo, Inês Costa, Nuno Verdasca, Patrícia Conde, Diogo FP Marques, Anna Molesworth, Leanne Quinn, Miranda Leyton, Selin Campbell, Janine Thoulass, Jim McMenamin, Ana Martínez Mateo, Luca Basile, Daniel Castrillejo, Carmen Quiñones Rubio, Concepción Delgado-Sanz, Jesús Oliva. ; The I-MOVE-COVID-19 network collates epidemiological and clinical information on patients with coronavirus disease (COVID-19), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virological characterisation in 11 European countries [1]. One component of I-MOVE-COVID-19 is the multicentre vaccine effectiveness (VE) study at primary care/outpatient level in nine European study sites in eight countries. We measured overall and product-specific COVID-19 VE against symptomatic SARS-CoV-2 infection among those aged 65 years and older. We also measured VE by time since vaccination. ; This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 101003673. ; info:eu-repo/semantics/publishedVersion

Background and objectives The 52‐week, randomized, double‐blind, noninferiority, government‐funded NOR‐SWITCH trial demonstrated that switching from infliximab originator to less expensive biosimilar CT‐P13 was not inferior to continued treatment with infliximab originator. The NOR‐SWITCH extension trial aimed to assess efficacy, safety and immunogenicity in patients on CT‐P13 throughout the 78‐week study period (maintenance group) versus patients switched to CT‐P13 at week 52 (switch group). The primary outcome was disease worsening during follow‐up based on disease‐specific composite measures. Methods Patients were recruited from 24 Norwegian hospitals, 380 of 438 patients who completed the main study: 197 in the maintenance group and 183 in the switch group. In the full analysis set, 127 (33%) had Crohn's disease, 80 (21%) ulcerative colitis, 67 (18%) spondyloarthritis, 55 (15%) rheumatoid arthritis, 20 (5%) psoriatic arthritis and 31 (8%) chronic plaque psoriasis. Results Baseline characteristics were similar in the two groups at the time of switching (week 52). Disease worsening occurred in 32 (16.8%) patients in the maintenance group vs. 20 (11.6%) in the switch group (per‐protocol set). Adjusted risk difference was 5.9% (95% CI −1.1 to 12.9). Frequency of adverse events, anti‐drug antibodies, changes in generic disease variables and disease‐specific composite measures were comparable between arms. The study was inadequately powered to detect noninferiority within individual diseases. Conclusion The NOR‐SWITCH extension showed no difference in safety and efficacy between patients who maintained CT‐P13 and patients who switched from originator infliximab to CT‐P13, supporting that switching from originator infliximab to CT‐P13 is safe and efficacious.

Background and objectives The 52‐week, randomized, double‐blind, noninferiority, government‐funded NOR‐SWITCH trial demonstrated that switching from infliximab originator to less expensive biosimilar CT‐P13 was not inferior to continued treatment with infliximab originator. The NOR‐SWITCH extension trial aimed to assess efficacy, safety and immunogenicity in patients on CT‐P13 throughout the 78‐week study period (maintenance group) versus patients switched to CT‐P13 at week 52 (switch group). The primary outcome was disease worsening during follow‐up based on disease‐specific composite measures. Methods Patients were recruited from 24 Norwegian hospitals, 380 of 438 patients who completed the main study: 197 in the maintenance group and 183 in the switch group. In the full analysis set, 127 (33%) had Crohn's disease, 80 (21%) ulcerative colitis, 67 (18%) spondyloarthritis, 55 (15%) rheumatoid arthritis, 20 (5%) psoriatic arthritis and 31 (8%) chronic plaque psoriasis. Results Baseline characteristics were similar in the two groups at the time of switching (week 52). Disease worsening occurred in 32 (16.8%) patients in the maintenance group vs. 20 (11.6%) in the switch group (per‐protocol set). Adjusted risk difference was 5.9% (95% CI −1.1 to 12.9). Frequency of adverse events, anti‐drug antibodies, changes in generic disease variables and disease‐specific composite measures were comparable between arms. The study was inadequately powered to detect noninferiority within individual diseases. Conclusion The NOR‐SWITCH extension showed no difference in safety and efficacy between patients who maintained CT‐P13 and patients who switched from originator infliximab to CT‐P13, supporting that switching from originator infliximab to CT‐P13 is safe and efficacious. ; publishedVersion ; Open Access CC-BY

Publisher's version (útgefin grein) ; Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health. ; This work has been supported by MRC grant MC_U106179472 (FD, KO, JRBP), Samuel Oschin Comprehensive Cancer Institute Developmental Funds, Center for Bioinformatics and Functional Genomics and Department of Biomedical Sciences Developmental Funds (MRJ), NCI P30CA177558 (CH), NCI UM1CA186107 (PK), European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) and the European Union's Horizon 2020 research and innovation program under grant agreements No 692065 (TL, RM, AS) and 692145 (RM), NICHD R01HD065029 (RS), Estonian Ministry of Education and Research (grant IUT34-16 to TL), NICHD R01HD057450 (MU), NICHD P50HD044405 (AD), NICHD R01HD057223 (AD), R01HD085227 (MGH, AD), deCode Genetics (GT, UT, KS, US), Raine Medical Research Foundation Priming Grant (BHM), SCGOPHCG RAC 2015-16/034 (SGW, BGAS), 2016-17/018 (BGAS), NIHR BRC, Wellcome Trust, MRC (TDS), Eris M. Field Chair in Diabetes Research (MOG), NIDDK P30 DK063491 (MOG), NIDDK U01DK094431, U01DK048381 (DE), NICHD U10HD38992 (RL), Estonian Ministry of Education and Research (grant IUT34-16), Enterprise Estonia (grant EU48695); the EU-FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP, grant SARM, EU324509 to AS), Wellcome (090532, 098381, 203141); European Commission (ENGAGE: HEALTH-F4-2007-201413 to MIM), MRC G0802782, MR/M012638/1 (SF), Li Ka Shing Foundation, WT-SSI/John Fell Funds, NIHR Biomedical Research Centre, Oxford, Widenlife and NICHD 5P50HD028138-27 (CML), NICHD R01HD065029, ADA 1-10-CT-57, Harvard Clinical and Translational Science Center, from the National Center for Research Resources 1UL1 RR025758 (CKW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ; Peer Reviewed

River networks are among Earth's most threatened hot-spots of biodiversity and provide key ecosystem services (e.g., supply drinking water and food, climate regulation) essential to sustaining human well-being. Climate change and increased human water use are causing more rivers and streams to dry, with devastating impacts on biodiversity and ecosystem services. Currently, more than a half of the global river networks consist of drying channels, and these are expanding dramatically. However, drying river networks (DRNs) have received little attention from scientists and policy makers, and the public is unaware of their importance. Consequently, there is no effective integrated biodiversity conservation or ecosystem management strategy of DRNs.A multidisciplinary team of 25 experts from 11 countries in Europe, South America, China and the USA will build on EU efforts to assess the cascading effects of climate change on biodiversity, ecosystem functions and ecosystem services of DRNs through changes in flow regimes and water use. DRYvER (DRYing riVER networks) will gather and upscale empirical and modelling data from nine focal DRNs (case studies) in Europe (EU) and Community of Latin American and Caribbean States (CELAC) to develop a meta-system framework applicable to Europe and worldwide. It will also generate crucial knowledge-based strategies, tools and guidelines for economically-efficient adaptive management of DRNs. Working closely with stakeholders and end-users, DRYvER will co-develop strategies to mitigate and adapt to climate change impacts in DRNs, integrating hydrological, ecological (including nature-based solutions), socio-economic and policy perspectives. The end results of DRYvER will contribute to reaching the objectives of the Paris Agreement and placing Europe at the forefront of research on climate change.

In 2012, the Baby‐friendly Hospital Initiative for Neonatal Wards (Neo‐BFHI) began providing recommendations to improve breastfeeding support for preterm and ill infants. This cross‐sectional survey aimed to measure compliance on a global level with the Neo‐BFHI's expanded Ten Steps to successful breastfeeding and three Guiding Principles in neonatal wards. In 2017, the Neo‐BFHI Self‐Assessment questionnaire was used in 15 languages to collect data from neonatal wards of all levels of care. Answers were summarized into compliance scores ranging from 0 to 100 at the ward, country, and international levels. A total of 917 neonatal wards from 36 low‐, middle‐, and high‐income countries from all continents participated. The median international overall score was 77, and median country overall scores ranged from 52 to 91. Guiding Principle 1 (respect for mothers), Step 5 (breastfeeding initiation and support), and Step 6 (human milk use) had the highest scores, 100, 88, and 88, respectively. Step 3 (antenatal information) and Step 7 (rooming‐in) had the lowest scores, 63 and 67, respectively. High‐income countries had significantly higher scores for Guiding Principles 2 (family‐centered care), Step 4 (skin‐to‐skin contact), and Step 5. Neonatal wards in hospitals ever‐designated Baby‐friendly had significantly higher scores than those never designated. Sixty percent of managers stated they would like to obtain Neo‐BFHI designation. Currently, Neo‐BFHI recommendations are partly implemented in many countries. The high number of participating wards indicates international readiness to expand Baby‐friendly standards to neonatal settings. Hospitals and governments should increase their efforts to better support breastfeeding in neonatal wards.