University of Crete

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. METHODS: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). FINDINGS: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6-58·8) of global deaths and 41·2% (39·8-42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. INTERPRETATION: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. FUNDING: Bill & Melinda Gates Foundation.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is thatthere is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the completeprocess including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increasedautophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in manycases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as forreviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multipleassays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagyrelated protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

Rhinosinusitis is a significant and increasing health problem which results in a large financial burden on society. This evidence based position paper describes what is known about rhinosinusitis and nasal polyps, offers evidence based recommendations on diagnosis and treatment, and considers how we can make progress with research in this area. Rhinitis and sinusitis usually coexist and are concurrent in most individuals; thus, the correct terminology is now rhinosinusitis. Rhinosinusitis (including nasal polyps) is defined as inflammation of the nose and the paranasal sinuses characterised by two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip), +/- facial pain/pressure, +/- reduction or loss of smell; and either endoscopic signs of polyps and/or mucopurulent discharge primarily from middle meatus and/or; oedema/mucosal obstruction primarily in middle meatus, and/or CT changes showing mucosal changes within the ostiomeatal complex and/or sinuses. The paper gives different definitions for epidemiology, first line and second line treatment and for research. Furthermore the paper describes the anatomy and (patho)physiology, epidemiology and predisposing factors, inflammatory mechanisms, evidence based diagnosis, medical and surgical treatment in acute and chronic rhinosinusitis and nasal polyposis in adults and children. Evidence based schemes for diagnosis and treatment are given for the first and second line clinicians. Moreover attention is given to complications and socio-economic cost of chronic rhinosinusitis and nasal polyps. Last but not least the relation to the lower airways is discussed.

Abstract. The present paper reviews existing knowledge with regard to Organic Aerosol (OA) of importance for global climate modelling and defines critical gaps needed to reduce the involved uncertainties. All pieces required for the representation of OA in a global climate model are sketched out with special attention to Secondary Organic Aerosol (SOA): The emission estimates of primary carbonaceous particles and SOA precursor gases are summarized. The up-to-date understanding of the chemical formation and transformation of condensable organic material is outlined. Knowledge on the hygroscopicity of OA and measurements of optical properties of the organic aerosol constituents are summarized. The mechanisms of interactions of OA with clouds and dry and wet removal processes parameterisations in global models are outlined. This information is synthesized to provide a continuous analysis of the flow from the emitted material to the atmosphere up to the point of the climate impact of the produced organic aerosol. The sources of uncertainties at each step of this process are highlighted as areas that require further studies.

MOTIVATION: Sequence-based methods to delimit species are central to DNA taxonomy, microbial community surveys and DNA metabarcoding studies. Current approaches either rely on simple sequence similarity thresholds (OTU-picking) or on complex and compute-intensive evolutionary models. The OTU-picking methods scale well on large datasets, but the results are highly sensitive to the similarity threshold. Coalescent-based species delimitation approaches often rely on Bayesian statistics and Markov Chain Monte Carlo sampling, and can therefore only be applied to small datasets. RESULTS: We introduce the Poisson tree processes (PTP) model to infer putative species boundaries on a given phylogenetic input tree. We also integrate PTP with our evolutionary placement algorithm (EPA-PTP) to count the number of species in phylogenetic placements. We compare our approaches with popular OTU-picking methods and the General Mixed Yule Coalescent (GMYC) model. For de novo species delimitation, the stand-alone PTP model generally outperforms GYMC as well as OTU-picking methods when evolutionary distances between species are small. PTP neither requires an ultrametric input tree nor a sequence similarity threshold as input. In the open reference species delimitation approach, EPA-PTP yields more accurate results than de novo species delimitation methods. Finally, EPA-PTP scales on large datasets because it relies on the parallel implementations of the EPA and RAxML, thereby allowing to delimit species in high-throughput sequencing data. AVAILABILITY AND IMPLEMENTATION: The code is freely available at www.exelixis-lab.org/software.html. .

Insects are the most speciose group of animals, but the phylogenetic relationships of many major lineages remain unresolved. We inferred the phylogeny of insects from 1478 protein-coding genes. Phylogenomic analyses of nucleotide and amino acid sequences, with site-specific nucleotide or domain-specific amino acid substitution models, produced statistically robust and congruent results resolving previously controversial phylogenetic relations hips. We dated the origin of insects to the Early Ordovician [~479 million years ago (Ma)], of insect flight to the Early Devonian (~406 Ma), of major extant lineages to the Mississippian (~345 Ma), and the major diversification of holometabolous insects to the Early Cretaceous. Our phylogenomic study provides a comprehensive reliable scaffold for future comparative analyses of evolutionary innovations among insects.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects. RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.

Delineation of the left ventricular cavity, myocardium, and right ventricle from cardiac magnetic resonance images (multi-slice 2-D cine MRI) is a common clinical task to establish diagnosis. The automation of the corresponding tasks has thus been the subject of intense research over the past decades. In this paper, we introduce the "Automatic Cardiac Diagnosis Challenge" dataset (ACDC), the largest publicly available and fully annotated dataset for the purpose of cardiac MRI (CMR) assessment. The dataset contains data from 150 multi-equipments CMRI recordings with reference measurements and classification from two medical experts. The overarching objective of this paper is to measure how far state-of-the-art deep learning methods can go at assessing CMRI, i.e., segmenting the myocardium and the two ventricles as well as classifying pathologies. In the wake of the 2017 MICCAI-ACDC challenge, we report results from deep learning methods provided by nine research groups for the segmentation task and four groups for the classification task. Results show that the best methods faithfully reproduce the expert analysis, leading to a mean value of 0.97 correlation score for the automatic extraction of clinical indices and an accuracy of 0.96 for automatic diagnosis. These results clearly open the door to highly accurate and fully automatic analysis of cardiac CMRI. We also identify scenarios for which deep learning methods are still failing. Both the dataset and detailed results are publicly available online, while the platform will remain open for new submissions.

Anopheles gambiae is the principal vector of malaria, a disease that afflicts more than 500 million people and causes more than 1 million deaths each year. Tenfold shotgun sequence coverage was obtained from the PEST strain of A. gambiae and assembled into scaffolds that span 278 million base pairs. A total of 91% of the genome was organized in 303 scaffolds; the largest scaffold was 23.1 million base pairs. There was substantial genetic variation within this strain, and the apparent existence of two haplotypes of approximately equal frequency ("dual haplotypes") in a substantial fraction of the genome likely reflects the outbred nature of the PEST strain. The sequence produced a conservative inference of more than 400,000 single-nucleotide polymorphisms that showed a markedly bimodal density distribution. Analysis of the genome sequence revealed strong evidence for about 14,000 protein-encoding transcripts. Prominent expansions in specific families of proteins likely involved in cell adhesion and immunity were noted. An expressed sequence tag analysis of genes regulated by blood feeding provided insights into the physiological adaptations of a hematophagous insect.

We present a general framework for the formal specification and algorithmic analysis of hybrid systems. A hybrid system consists of a discrete program with an analog environment. We model hybrid systems as finite automata equipped with variables that evolve continuously with time according to dynamical laws. For verification purposes, we restrict ourselves to linear hybrid systems, where all variables follow piecewise-linear trajectories. We provide decidability and undecidability results for classes of linear hybrid systems, and we show that standard program-analysis techniques can be adapted to linear hybrid systems. In particular, we consider symbolic model-checking and minimization procedures that are based on the reachability analysis of an infinite state space. The procedures iteratively compute state sets that are definable as unions of convex polyhedra in multidimensional real space. We also present approximation techniques for dealing with systems for which the iterative procedures do not converge.

Humans express a wide array of ideal mate preferences. Around the world, people desire romantic partners who are intelligent, healthy, kind, physically attractive, wealthy, and more. In order for these ideal preferences to guide the choice of actual romantic partners, human mating psychology must possess a means to integrate information across these many preference dimensions into summaries of the overall mate value of their potential mates. Here we explore the computational design of this mate preference integration process using a large sample of n = 14,487 people from 45 countries around the world. We combine this large cross-cultural sample with agent-based models to compare eight hypothesized models of human mating markets. Across cultures, people higher in mate value appear to experience greater power of choice on the mating market in that they set higher ideal standards, better fulfill their preferences in choice, and pair with higher mate value partners. Furthermore, we find that this cross-culturally universal pattern of mate choice is most consistent with a Euclidean model of mate preference integration.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. In the European Union, COPD and asthma, together with pneumonia, are the third most common cause of death. In North America, COPD is the fourth leading cause of death, and mortality rates and prevalence are increasing. The major characteristic of COPD is the presence of chronic airflow limitation that progresses slowly over a period of years and is, by definition, largely irreversible. Most patients with COPD are, or were, cigarette smokers. Prevention by reducing the prevalence of smoking remains a priority. Although much of the damage is irreversible at the time of clinical presentation, treatments are available to improve the quality of life, the life expectancy, and perhaps the functional ability of patients with COPD. Several national and international consensus statements on optimal assessment and management of asthma have been published in recent years. These consensus statements have led to international standardization of diagnosis and management and to better care. They also form a basis for clinical audits and suggest areas of future research. However, there have been few attempts to develop consensus guidelines on management of COPD [1, 2]. The European Respiratory Society (ERS) has taken the initiative of producing a consensus statement on COPD. A Task Force of scientists and clinicians was invited to provide this European consensus. The guidelines are intended for use by physicians involved in the care of patients with COPD, and their main goals are to inform health professionals and to reverse a widespread nihilistic approach to the management of these patients. This Task Force firmly believes that treatment can significantly improve the quality and length of life of patients suffering from this chronic, progressive condition. Subcommittees of the Task Force focused on the five main sections of this project: Pathology/Pathophysiology, Epidemiology, Assessment, Treatment, and Management. Experts produced papers within each section, and these papers were brought together by the subcommittee heads. At a plenary meeting held in Wiesbaden, Germany on November 11–13, 1993, all contributions were extensively discussed, and additional working group meetings were arranged. Flowcharts for management in common clinical situations were produced. However, at all stages, members of the Task Force found themselves confronted by unresolved questions and regional differences in management across Europe. A practical approach was adopted, combining established scientific evidence and a consensus view when current data were inadequate. This approach identified more clearly those areas where further research is needed. Comments on drafts of the consensus statement were invited from participants of the original meeting, which included colleagues from North America. The edited document was sent to independent experts for external review. All members had an opportunity to comment on the document at the ERS meeting in Nice on October 2, 1994. As chairmen of the Task Force, we hope that the final document will promote better management of COPD in Europe. We would like to thank all who contributed to it. On behalf of the ERS, we also gratefully acknowledge a generous educational grant from Boehringer Ingelheim and the organizational assistance provided by M.T. Lopez-Vidriero.

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.

1. Wu JT, Leung K, Leung GM. Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study. Lancet. 2020;395(10225):689-697. doi:10.1016/S0140-6736(20)30260-9. CrossRef Google Scholar

Acute exacerbation of idiopathic pulmonary fibrosis has been defined as an acute, clinically significant, respiratory deterioration of unidentifiable cause. The objective of this international working group report on acute exacerbation of idiopathic pulmonary fibrosis was to provide a comprehensive update on the topic. A literature review was conducted to identify all relevant English text publications and abstracts. Evidence-based updates on the epidemiology, etiology, risk factors, prognosis, and management of acute exacerbations of idiopathic pulmonary fibrosis are provided. Finally, to better reflect the current state of knowledge and improve the feasibility of future research into its etiology and treatment, the working group proposes a new conceptual framework for acute respiratory deterioration in idiopathic pulmonary fibrosis and a revised definition and diagnostic criteria for acute exacerbation of idiopathic pulmonary fibrosis.

EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. no immunosuppressants IV D no nasal saline irrigation Ib, no data in single use D yes for symptomatic relief topical antibiotics no data D no anti-IL-5 no data D unclear phytotherapy no data D no decongestant topical / oral no data in single use D no mucolytics no data D no oral antihistamine in allergic patients no data D no antimycotics -topical Ia (-) ** A(-) no antimycotics -systemic Ib (-)# A(-) $ no anti leukotrienes Ib (-) A(-) no anti-IgE Ib (-) A(-) no * Some of these studies also included patients with CRS with nasal polyps. % short term antibiotics shows one positive and one negative study. Therefore recommendation C. oral antibiotic short term <4 weeks Ib(-) # A(-)* no intravenous antibiotics III(-) ## C(-) ** no # Ib (-): Ib study with a negative outcome.

Land Use Regression (LUR) models have been used increasingly for modeling small-scale spatial variation in air pollution concentrations and estimating individual exposure for participants of cohort studies. Within the ESCAPE project, concentrations of PM(2.5), PM(2.5) absorbance, PM(10), and PM(coarse) were measured in 20 European study areas at 20 sites per area. GIS-derived predictor variables (e.g., traffic intensity, population, and land-use) were evaluated to model spatial variation of annual average concentrations for each study area. The median model explained variance (R(2)) was 71% for PM(2.5) (range across study areas 35-94%). Model R(2) was higher for PM(2.5) absorbance (median 89%, range 56-97%) and lower for PM(coarse) (median 68%, range 32- 81%). Models included between two and five predictor variables, with various traffic indicators as the most common predictors. Lower R(2) was related to small concentration variability or limited availability of predictor variables, especially traffic intensity. Cross validation R(2) results were on average 8-11% lower than model R(2). Careful selection of monitoring sites, examination of influential observations and skewed variable distributions were essential for developing stable LUR models. The final LUR models are used to estimate air pollution concentrations at the home addresses of participants in the health studies involved in ESCAPE.

Traffic congestion in urban road and freeway networks leads to a strong degradation of the network infrastructure and accordingly reduced throughput, which can be countered via suitable control measures and strategies. After illustrating the main reasons for infrastructure deterioration due to traffic congestion, a comprehensive overview of proposed and implemented control strategies is provided for three areas: urban road networks, freeway networks, and route guidance. Selected application results, obtained from either simulation studies or field implementations, are briefly outlined to illustrate the impact of various control actions and strategies. The paper concludes with a brief discussion of future needs in this important technical area.

Abstract. On board the four Cluster spacecraft, the Cluster Ion Spectrometry (CIS) experiment measures the full, three-dimensional ion distribution of the major magnetospheric ions (H+, He+, He++, and O+) from the thermal energies to about 40 keV/e. The experiment consists of two different instruments: a COmposition and DIstribution Function analyser (CIS1/CODIF), giving the mass per charge composition with medium (22.5°) angular resolution, and a Hot Ion Analyser (CIS2/HIA), which does not offer mass resolution but has a better angular resolution (5.6°) that is adequate for ion beam and solar wind measurements. Each analyser has two different sensitivities in order to increase the dynamic range. First tests of the instruments (commissioning activities) were achieved from early September 2000 to mid January 2001, and the operation phase began on 1 February 2001. In this paper, first results of the CIS instruments are presented showing the high level performances and capabilities of the instruments. Good examples of data were obtained in the central plasma sheet, magnetopause crossings, magnetosheath, solar wind and cusp measurements. Observations in the auroral regions could also be obtained with the Cluster spacecraft at radial distances of 4–6 Earth radii. These results show the tremendous interest of multispacecraft measurements with identical instruments and open a new area in magnetospheric and solar wind-magnetosphere interaction physics.Key words. Magnetospheric physics (magnetopause, cusp and boundary layers; magnetopheric configuration and dynamics; solar wind - magnetosphere interactions)