International collaborative research is a mechanism for improving the development of disease-specific therapies and for improving health at the population level. However, limited data are available to assess the trends in research output related to orphan diseases.We used bibliometric mapping and clustering methods to illustrate the level of fragmentation in myeloma research and the development of collaborative efforts. Publication data from Thomson Reuters Web of Science were retrieved for 2005–2009 and followed until 2013. We created a database of multiple myeloma publications, and we analysed impact and co-authorship density to identify scientific collaborations, developments, and international key players over time. The global annual publication volume for studies on multiple myeloma increased from 1,144 in 2005 to 1,628 in 2009, which represents a 43% increase. This increase is high compared to the 24% and 14% increases observed for lymphoma and leukaemia. The major proportion (>90% of publications) was from the US and EU over the study period. The output and impact in terms of citations, identified several successful groups with a large number of intra-cluster collaborations in the US and EU. The US-based myeloma clusters clearly stand out as the most productive and highly cited, and the European Myeloma Network members exhibited a doubling of collaborative publications from 2005 to 2009, still increasing up to 2013.Multiple myeloma research output has increased substantially in the past decade. The fragmented European myeloma research activities based on national or regional groups are progressing, but they require a broad range of targeted research investments to improve multiple myeloma health care. Multiple myeloma is an orphan malignant disorder of plasma cells. The incidence of multiple myeloma is 5–6 cases per 100,000 inhabitants. Knowledge of the essential pathogenic mechanisms and therapeutic possibilities has increased substantially over the last decade. In parallel, a broad range of novel technologies has resulted in new diagnostic, prognostic, and predictive procedures.To exploit the clinical benefits of these recent developments, international collaborations have been organised through the European Myeloma Network (EMN), which was founded and legalised in 2003 by leading research groups. EMN is a Pan-European umbrella organisation that unites basic and clinical research groups. It provides a directory for these groups to pursue specific research and clinical goals together , 2.The primary achievement of the EMN to date has been to introduce uniform criteria for diagnostic and prognostic assays in multiple myeloma. This has been accomplished through workshops focused on specific procedures related to biobanking, interphase FISH, multiparametric flow cytometry, and microarray technologies , 4. The The EMN is currently recognised internationally as a key promoter of interactions between researchers, companies, patient groups, and individuals working in different areas of the growing myeloma field. Therefore, the EMN provides a “golden opportunity” for continuing work on multiple myeloma and for preparing a strategy to support translation of basic discoveries into the clinic. In our aim to create an ideal future set-up for the EMN vision, we have used bibliometric mapping and cluster models to address questions related to the previous fragmentation of EU myeloma research. Our goals were to identify collaborative groups and to evaluate their outcomes and development over time. Finally, we relate our findings to other research fields with higher productivity, like lymphoma and leukaemia.The findings of this study will allow us to restructure the EMN organisation and management, based on a strategy with focus on work that has high impact on individualized medicine. Implementation of individualized medicines has been limited but recent policy in EU has addressed central issues including biomarker validation, biobanking, clinical trials, data handling, public-private innovative medicines initiative and funding to personalized medicine. Initiatives, which future EMN work needs to take into consideration to speed up drug development and treatment strategies.All bibliometric data were extracted from the Science Citation Index-Expanded (SCI-E) from Thomson Reuters Web of Science (WoS). The extraction was performed with topic queries for haematological malignancies, including multiple myeloma, lymphoma, and leukaemia. SCI-E is considered one of the largest citation databases in the world; it contains information on paper citation frequency and bibliographic metadata. Thus, it provides information that may not be retrieved from more specialised medical databases, such as PubMed MEDLINE or EMBASE. Citations to a paper can be used as a proxy for the impact a report has made on the research community, and therefore, the citation frequency can serve as an indicator of the importance, quality, or usefulness of the information .Research papers on the disease areas of interest published during the years 2005–09 were identified as shown in In the scientific literature, there are a variety of manuscript types, but in principle, a count of publications should only include peer-reviewed research papers. Articles and reviews are normally peer-reviewed, and these were included in our counts. Letters constitute a heterogeneous category. They include peer-reviewed short communications, but also un-refereed correspondences. It was not algorithmically possible to distinguish between the two types of letters. However, we considered it more important to include the peer-reviewed letters than to exclude non-peer reviewed letters; therefore, we decided to include all letters.To compare the geographical affiliation of collaborating authors, we retrieved the country-element of the addresses registered for the authors of each paper. We defined European countries as the 28 countries of the EU plus Switzerland, Norway, Iceland, Macedonia, and Turkey, based on their central location in the EU and/or their candidacy to become an EU member state. We compared papers from the EU to those from the US and those from the Asian continent, which included Russia. In most cases, these three groups explained close to 100% of the addresses identified.We used both the names and addresses of authors from the SCI-E-data. These data were given in the journal, typically supplied by the authors. Nevertheless, these data may have contained spelling errors, due to a lack of standards or differing standards between journals. We only used the country information of addresses; therefore, this was a minor issue. All country information was easily standardised.Variations and ambiguity in author names were resolved in some systems by canonical or authorised author names. Although WoS used the so-called ResearcherID, this system was not fully incorporated in the entire database, nor was the more recent OrcID system available for cases of retrieval. Thus, cases of two or more authors that used the same name or cases with different spellings of the same name remained problematic. Some attempts have been made to resolve these issues –16, primhttp://pajek.imfm.si/doku.php) for co-author network analysis. For clustering, the Louvain community clustering method [The bibliometric method was based on identifying particularly strong collaborations between authors, based on the number of co-authored papers –19. Tradg method  was usedCC1) and closeness centrality (closeC). While both measures express a variant of density, they differ somewhat in their interpretation. The CC1 indicates for each member of a network how many other members are in the neighbourhood compared to the total potential neighbours [closeC indicates the average (inverse) shortest distance from any member of a network to all other members [Clusters were evaluated using two measures of cluster density: clustering coefficients for immediate neighbours  For l counts  to show Cluster publication counts, cN, or the full count, was defined as the total number of unique papers per cluster, where at least one author from the cluster was listed as an author, regardless of whether it was first, last, or any other place in the author list.Fractional cluster author counts was defined as in was the number of authors from the respective cluster that appeared on a paper ii, a was the total number of authors on paper i, and N was the total number of papers that listed at least one author from the cluster.fcp/cN, or the proportion of co-authorships within a cluster by authors from that cluster.was defined as the ratio Intra-cluster collaboration i, ic, by the mean citations to papers published the same year and for the same disease category. We denote the normalised citations for paper i as is and the mean normalised citation score of all papers for a given group as sµ. These mean normalised citation scores should be interpreted with care, especially for small groups, due to the highly skewed nature of citations [top10PP, inspired by the similar indicator used in the CWTS Leiden ranking system [D10s. All papers in this disease category with si above this score are considered top papers, and the top10PP indicator can subsequently be calculated for any set of papers A as topPP10 = |A ∩ D10|/|A|, where |.| denotes the cardinality of a given set and D10 the set of top decile papers. The expected score would be 0.1, with values above indicating higher than expected performance.2) We used the total citation counts at the date of collection, and standardised these according to year of publication. While some impact indicators use field standardisation to compensate for differing citation densities (e.g. ), the daitations . We counitations . This teg system . For eacA plethora of other metrics exists. However, we believe for comparing the impact of research groups in a given time period for so closely related research areas, the chosen indicators are the best suited. In particular when the mean- and percentile-based indicators are used together, as the latter can compensate for potential skewness of the former , 26–28.A comparison between SCI-E and PubMed MEDLINE databases, based on medical subject headings (MeSH) for publications during the years 2005–09 is given in A follow-up was performed for multiple myeloma specifically, in order to track productivity and impact over a longer period of time. The dataset was thus broadened to all multiple myeloma papers from 2003–2013. This dataset is analysed separately, as the other diseases were not analysed over the same period of time, and impact analyses for recent years are somewhat less stable.> 20 publications during the time period indicated. Each map illustrates the collaborating networks; the vertices (or circles) illustrate one author, the circle size indicates the number of publications in the given time period, the thickness of edges between vertices the degree of collaboration, and common colours show clusters of associated authors. Numbers inside the vertices are IDs of clusters, which in the following tables are used in combination with disease codes  so that my1 is cluster 1 in the multiple myeloma map.Collaborative clusters were successfully identified using the Louvain clustering algorithm. Bibliometric co-author maps were constructed for multiple myeloma , lymphomcN), and the fractional count of publications per cluster (fcp). It should be noted that the clusters did not contain all papers in the datasets, as they were generated from authors with at least 20 publications in the time period. The publication rates differed for multiple myeloma, lymphoma, and leukaemia, with medians of 211 (range 27–794), 341 (range 20–1164), and 328 (range 19–2649), respectively. While the omission of authors with less than 20 papers leads to a reduction in the total data, it was necessary to use a threshold in order to allow interpretation of the maps. The results should thus be seen as representative of the most productive researchers rather than the entirety of multiple myeloma research.The clusters were analysed for productivity and other descriptive data  Table. Pfc/Ncp). The closer this number was to 1, the greater the intra-cluster collaboration; i.e., a larger number of authors on each publication belonged to the same cluster. fc/Ncp) for multiple myeloma, lymphoma, and leukaemia had medians of 0.281 (range 0.122–0.412), 0.256 (range 0.117–1), and 0.258 (range 0.189–1), respectively. The medians for each disease are comparable, indicating similar strengths in collaborations regardless of disease, which should be seen in spite of disease-specific differences, such as the relatively lower incidence rate of multiple myeloma. We thus compared the multiple myeloma clusters to acute myeloid leukaemia (AML) research, another bone marrow disease with the same incidence (fc/Ncp), median 0.195 (range 0.124–0.325), was somewhat lower for AML, which supports the notion that multiple myeloma research has closer intra-cluster collaboration than could be expected.The intercontinental and worldwide collaborations for each cluster were graded by calculating the distribution of EU, US, or Asian partners. The most specific collaboration-indicator was the ratio between the fractional and the full publication counts (ncidence . We founsµ) as shown in sµ values for multiple myeloma, lymphoma, and leukaemia were 1.465 (range 0.67–2.06), 1.42 (range 0–2.28), and 1.075 (range 0–2.49), respectively. These results indicated that the multiple myeloma clusters had a high level of impact. Again, we compared multiple myeloma research with acute myeloid leukaemia research, and found a median sµ = 1.47 (range 0.23–2.17), with highest values for the US clusters  than the identified EU clusters  (The impact of publications was indicated by the mean standardised citation score (clusters . Comparand 0.99) . In otheAn overview of the multiple myeloma-related cluster scores is displayed in Of interest, among the three US clusters, my2 and my3 are institutional members of the Multiple Myeloma Research Consortium (MMRC), founded in 2004. This consortium brought together an extraordinary group of US myeloma researchers and world-renowned institutions to speed up translational and clinical developments in multiple myeloma. During 2005–2009, the three US clusters were well defined, with relatively abundant intra-cluster collaborations .The lymphoma related cluster scores are given in The leukaemia related cluster scores are given in p-values were found from the quantile rank of EMN scores in the random distributions. For the closeness centrality, EMN scores were above any recorded values (p = 0.000), and for the clustering coefficient, the EMN scores were in the upper 0.2% (p = 0.004). This provides evidence that the EMN group collaborates more closely than what could be expected if they had just been a randomly selected group of authors.To analyse the development of the EMN and the three major US-clusters  over time, the multiple myeloma dataset was extended from 2003 to 2013, using the same approach as that used for the main dataset. The cluster density indicators CC1 and closeness centrality are reported in sµ, or the top-10% fraction, it is clear that publications where EMN members collaborate (Multi-EMN) have a higher citation impact than those where only one of the authors is from the EMN (Single-EMN).In top10PP scores per country for multiple myeloma research . Originally, the FP initiated the EMN and united 12 leading European institutions and national cooperative clinical trial groups, including the Haemato Oncology Foundation for Adults in the Netherlands , Central Myeloma Study Group , Deutsche Studiengruppe Multiples Myelom , German Speaking Myeloma Multicenter Group , Nordic Myeloma Study Group , Gruppo Italiano Malattie EMatologiche dell′Adulto , Medical Research Council , and Programa para el Estudio de la Terapéutica en Hemopatía Maligna . In addition, the network included groups from Greece, the Czech Republic, Israel, and Turkey. Unfortunately, this network was unsuccessful in applying for Network of Excellence status and procuring support from the FP6The present report aimed to identify scientific collaborations, output, impact, international key players, and research developments over time by mapping the international research networks for multiple myeloma. The analysis of publication productivity and impact identified several successful groups with a high level of intra-cluster collaboration in the EU and US. However, US-based research clearly stands out as the most highly cited, even though EU research groups have considerable impact and have shown increased activity over time. These findings may guide us in restructuring the EMN organisation and infrastructure to implement a scientific strategy that focuses on specific areas that have potential impact on translational research, drug development and patient care.The new era of ‘omics’ information will allow implementation of individual treatment strategies. A range of recent policy initiatives in EU address this issue and accelerate international projects toward personalized medicine. It is increasingly important to identify individuals who are unlikely to benefit from current treatment, or are at high risk to develop long-term side effects and therefore may benefit from novel or selected treatment regimens. This approach, personalized or precision medicine, is the key to reduction of the burdens of healthcare. Not only will it improve clinical outcomes, but it will ensure an efficient use of healthcare resources when fully developed. Personalized medicine includes diagnostics, biomarkers and drug development making a more complete understanding of the underlying disease mechanisms a prerequisite. Initiatives that facilitate the adoption of personalized medicine are steadily progressing in Europe, including European Medicines Agency (EMA) working parties, Innovative Medicines Initiatives (IMI) and Horizon2020. Personalized medicine will not succeed without grant support to health care professionals with interest in rare diseases, to ensure benefit for health cost-effectiveness. EMN represents such an organisation, in urgent need for EU support.The main infrastructure of the EMN includes the Secretariat, placed in Denmark , the EMN Data and Statistical Centre, placed in Italy (Torino/GIMEMA) and the Netherlands (Rotterdam/HOVON), the EMN Sponsor Offices in Denmark and the Netherlands, the National and Regional Clinical Research Units, and the Network of European Myeloma Biobanks and Laboratories. The EMN has been approved by the European Haematology Association (EHA) as an official scientific working group. The EMN also provides clinical recommendations and organises major clinical phase II-III trials to be carried out across the EU, with financial support from pharmaceutical companies. From unrestricted grants to the organization, the EMN has supported and facilitated the advent of the Myeloma Stem Cell Network (MSCNET), the translational project on Resistance and Targeted Therapy (RESTART), the Clinical Trial Network (TALISMMAN), and the MyelomA Genetics International Consortium (MAGIC).The results from this analysis are retrospective and indicative in nature. However, the most significant observation was the intercontinental difference between the EU and US in outcome and impact. We observed indications that the major performance group in multiple myeloma research, my3, includes awardees of the 2.7 million USD SPORE Grant  and collThere are no differences between the EU and US in the incidence and prevalence of multiple myeloma. It has been estimated that more than 20,000 individuals will be diagnosed with multiple myeloma in the US and in the EU during 2014, and more than 10,000 patients will die annually as a result of resistant disease. Although we cannot draw any direct conclusions from our analyses, it may not be surprising that well-funded, collaborative, focused research projects produce intra-cluster collaborative progress and high-impact research papers. The EU investment in multiple myeloma research is unknown, but the EMN partnership has estimated that the investment is far below the US level.We conclude that the fragmented European multiple myeloma research activities performed by national or regional groups are progressing towards international collaborations. Therefore, our findings can provide the basis for an updated EMN strategy for achieving the content and output expected from future multiple myeloma research. This strategy should be decided by the EMN board and leading partners from the Myeloma Biology and Clinical Trial Groups. A clearly defined “top down” strategy for EMN will give all members a precise description of the achievements needed to apply successfully for Horizon 2020 grant support.S1 FigThis network maps illustrate the collaboration networks of all authors in the datasets. Each vertex on the map illustrates an author, the size of the vertex indicates the number of papers published by this author, on the respective subjects , in the (TIF)Click here for additional data file.S2 FigThis network maps illustrate the collaboration networks of all authors in the datasets. Each vertex on the map illustrates an author, the size of the vertex indicates the number of papers published by this author, on the respective subjects , in the (TIF)Click here for additional data file.S3 FigThis network maps illustrate the collaboration networks of all authors in the datasets. Each vertex on the map illustrates an author, the size of the vertex indicates the number of papers published by this author, on the respective subjects , in the (TIF)Click here for additional data file.S1 TableQueries for multiple myeloma, lymphoma, and leukaemia in Science Citation Index-Expanded (SCI-E) and PubMed MEDLINE, delimited to publication years = 2005–2009. The refined SCI-E query contains only articles, reviews, and letters.(PDF)Click here for additional data file.S2 TablePublication counts in SCI-E distributed by publication year.(PDF)Click here for additional data file.S3 TablecN = total publication count; fcp = fractional publication count; fcp/cN = ratio between fcp and cN, indicating degree of intra-cluster collaboration; sµ = mean standardised citation score; top10PP = proportion of publications from the top decile; coeffC = 1-neighbourhood cluster coefficient; closeC = mean closeness centrality for the cluster; EU, US, Asia = fraction of addresses on papers from the respective areas.Descriptive data for all clusters: (PDF)Click here for additional data file.S4 TablecN = total publication count; fcp = fractional publication count; fcp/cN = ratio between fcp and cN, indicating degree of intra-cluster collaboration; sµ = mean standardised citation score; top10PP = proportion of publications from the top decile; coeffC = 1-neighbourhood cluster coefficient; closeC = mean closeness centrality for the cluster; EU, US, Asia = fraction of addresses on papers from the respective areas.Descriptive data for all clusters: (PDF)Click here for additional data file.S5 TablecN = total publication count; fcp = fractional publication count; fcp/cN = ratio between fcp and cN, indicating degree of intra-cluster collaboration; sµ = mean standardised citation score; top10PP = proportion of publications from the top decile; coeffC = 1-neighbourhood cluster coefficient; closeC = mean closeness centrality for the cluster; EU, US, Asia = fraction of addresses on papers from the respective areas.Descriptive data for all clusters: (PDF)Click here for additional data file.


Detailed data are lacking on influenza burden in the United Kingdom (UK). The objective of this study was to estimate the disease burden associated with influenza-like illness (ILI) in the United Kingdom stratified by age, risk and influenza vaccination status.This retrospective, cross-sectional, exploratory, observational study used linked data from the General Practice Research Database and the Hospital Episode Statistics databases to estimate resource use and cost associated with ILI in the UK.Data were included from 156,193 patients with ≥1 general practitioner visit with ILI. There were 21,518 high-risk patients, of whom 12,514 (58.2%) were vaccinated and 9,004 (41.8%) were not vaccinated, and 134,675 low-risk patients, of whom 17,482 (13.0%) were vaccinated and 117,193 (87.0%) were not vaccinated. High-risk vaccinated patients were older (p<0.001) and had more risk conditions (p<0.001). High-risk (odds ratio [OR] 2.16) or vaccinated (OR 1.19) patients had a higher probability of >1 general practitioner visit compared with low-risk and unvaccinated patients. Patients who were high-risk and vaccinated had a reduced risk of >1 general practitioner visit . High-risk individuals who were also vaccinated had a lower probability of ILI-related hospitalisation than individuals who were high-risk or vaccinated alone (OR 0.59). In people aged ≥65 years, the mortality rate was lower in vaccinated than unvaccinated individuals (OR 0.75). The cost of ILI-related GP visits and hospital admissions in the UK over the study period in low-risk vaccinated patients was £27,391,142 and £141,932,471, respectively. In low-risk unvaccinated patients the corresponding values were £168,318,709 and £112,534,130, respectively.Although vaccination rates in target groups have increased, many people are still not receiving influenza vaccination, and the burden of ILI in the United Kingdom remains substantial. Improving influenza vaccination uptake may have the potential to reduce this burden. Influenza is an acute self-limiting viral disease which, in the majority of cases, is inconvenient but generally not serious. However, seasonal influenza can cause severe illness, hospitalisations and deaths, especially in those who are at ‘high risk’ due to age or underlying chronic health problems.There are three types of influenza virus, Type A, Type B and Type C ; only A Influenza can be prevented by vaccination. Annual vaccination against seasonal influenza is recommended for high-risk groups, including people aged 65 years or more and people with chronic health conditions , and theAlthough several studies have previously estimated the burden of illness attributable to influenza in the UK –9, they To provide a more detailed understanding of the burden of influenza-like illness (ILI) to healthcare resources in the UK, we have conducted a large database analysis using linked hospital and general practice databases to quantify primary and secondary resource use and costs associated with ILI. To our knowledge, this is the first study to use linked hospital and general practice databases to assess the burden of illness in both primary and secondary care in ILI in the UK. The primary results of the study have been published elsewhere . The objective of the present analysis was to examine resource use and costs by vaccination and risk status.This was a retrospective, cross-sectional, observational study using data extracted from UK databases for the period 21 January 2001 to 31 March 2009 inclusive. The study period ended immediately before the 2009 H1N1 influenza pandemic. The data were divided into influenza seasons running from 1 April to 31 March inclusive, e.g. 1 April 2001 to 31 March 2002, etc. The study thus covered nine influenza seasons. The first season (2000–2001) ran from the study start date on 1 January 2001 to 31 March 2001. Influenza circulated from week 4 in 2001 according to surveillance data from the Health Protection Agency (HPA), so the study would have captured the majority of the influenza cases in the 2000–2001 season, although it is possible that there were some cases in the last weeks of 2000 for which data were not collected.Influenza cases are generally not virologically confirmed in routine UK clinical practice , and infst January 2001 and 31st March 2009 inclusive. Consultations coded with any of these READ codes that occurred during periods of peak influenza circulation were attributed to ILI , by risk status , using mid-year estimates for the resident population for 2001–2009 .Surveillance data on circulating influenza and other respiratory infections were obtained from the UK HPA for the period November 2002 to December 2008, which were grouped into flu weeks (periods of approximately 4–5 weeks). Data on the mismatch between the influenza vaccine and circulating influenza virus strains/lineages were obtained from the HPA .The primary outcome measures were mortality, resource use  and cost associated with influenza in primary and secondary care, stratified by age group, complication status, vaccination status and risk status. This paper presents data on vaccination uptake, and resource use, cost and mortality by vaccination status and degree of mismatch. Other results of the study have been published elsewhere . Medications prescribed were limited to include items such as antipyretics, analgesics, antivirals, nasal decongestants, antihistamines and antibiotics. Furthermore, only those encounters related with an episode were included in the analysis any routine visits or unrelated encounters were excluded.Unit costs for hospitalisations, GP consultations and outpatient visits were obtained from the Personal Social Services Research Unit database for 2011 . ResourcRegression analysis was used to estimate the proportion of GP consultations, hospitalisations and deaths potentially attributable to each pathogen, using the same technique as Pitman et al. , previouMycoplasma pneumoniae, parainfluenza, respiratory syncytial virus, and rhinovirus. Laboratory reports were not age stratified as this would have resulted in too few individuals in certain classes.The observed temporal trends in laboratory confirmed reports of agents that could potentially cause influenza/acute respiratory infection/ILI was compared with the number of events under consideration  over the same time period. The latter was used as the dependent variable of a multiple regression. The independent variables were the weekly number of national laboratory reports  for adenovirus, coronavirus, influenza A, influenza B, i in week j, Lij and a background number of national laboratory reports to estimate the regression coefficients αj that fit into the equation: Yj = c + Σiαi* Lij, Yj indicating the independent variable . A multivariable regression, assuming normality of the error terms, was performed. The initial model included all the organisms as explanatory variables. The significance of each organism was assessed, and if the p value was >0.1 or the variable was significant but the resulting coefficient negative  the variable was discarded from the model. The validity of the final model was assessed in terms of the proportion of the variation it explained (R2), the significance of the joint relationship between the observed and independent variables in each model (i.e. the probability that R differed significantly from zero), and the impact of changes in the model specification.This method of linear regression uses the number of laboratory reports for pathogen Regression analysis was used to assess the relationship between burden and the degree of mismatch between the influenza vaccine and the circulating influenza virus strains in each year. Multivariate analysis was used to uncover structure within the data and those factors contributing to excess burden. This was based on knowledge of the source data once it has been obtained and processed. Generalised linear models were fitted to characterise any association between baseline characteristics and burdenVaccinated and unvaccinated patients categorised as high-risk were compared using an independent samples t-test with age and number of risk conditions as the test variables. A similar analysis was undertaken in patients categorised as not high-risk, using age as the test variable.To extrapolate from the database sample to the total UK population, a multiplying factor was calculated. The annual average total UK population during the study period was 60,313,633, using ONS mid-year estimates for the resident population for 2001–2009 . The annThe linked dataset included 156,193 patients with at least one GP consultation for ILI (defined as described in the Methods). The mean age was 42.7 years and 55% were women. The demographic characteristics of the study population have been published elsewhere . In the high-risk group, the mean age of the vaccinated group was 65.1 years (standard deviation [SD] 16.5) compared with 48.2 years (SD 20.4) in the unvaccinated group (p<0.001). The mean number of risk conditions in the vaccinated group was 1.29 (SD 0.60), compared with 1.15 (SD 0.45) in the unvaccinated group (p<0.001). In the patients without risk conditions, vaccinated patients were also older than unvaccinated patients . Vaccinated patients were therefore statistically significantly different from unvaccinated patients, as they were older and had more risk conditions. This should be taken into account when considering outcomes in the different groups.In low-risk patients, unvaccinated patients used more GP and outpatient resources than vaccinated patients, reflecting the large number of unvaccinated low-risk cases in the database. Secondary care resource use was more evenly split, with slightly higher total resource use and cost in the group of vaccinated patients than in the group of unvaccinated patients. This is consistent with the older age of vaccinated patients compared with the unvaccinated group. Extrapolated to the UK, the cost of ILI-related GP visits and hospital admissions over the study period in low-risk vaccinated patients was £27,391,142 and £141,932,471, respectively. In low-risk unvaccinated patients the corresponding values were £168,318,709 and £112,534,130, respectively.Secondary care resource use was concentrated in cases of influenza with complications recorded, regardless of vaccination status.In high-risk patients, the group of vaccinated patients used more resources in primary and secondary care, compared with the group of unvaccinated patients. This is consistent with the older age and higher number of risk conditions in vaccinated than unvaccinated patients. As was the case in low-risk patients, secondary care resource use was concentrated in cases of influenza with complications recorded, regardless of vaccination status. Extrapolated to the UK, the cost of ILI-related GP visits and hospital admissions over the study period in high-risk vaccinated patients was £21,241,118 and £193,730,761, respectively. In high-risk unvaccinated patients the corresponding values were £15,283,283 and £82,189,349, respectively.The season 2005–2006 also had a very high circulation of influenza B, with influenza B accounting for 70% of the circulating influenza that season.There was a trend for influenza B mismatched seasons to be associated with peaks in ILI-related GP visits . The seaHospital admissions were highly correlated with GP visits , and mortality was highly correlated with hospitalisation .High-risk individuals who were also vaccinated had a lower probability of ILI-related hospitalisation than individuals who were high-risk or vaccinated alone . In years with influenza B mismatch, there was a statistically significant increase in the odds of hospital admission . Patients who were high-risk had a higher probability of ILI-related death during the study period , and patients who were vaccinated had a lower probability of death during the study period .The present study builds on previous investigations of the burden of ILI in the UK ,8 in sevInfluenza vaccination uptake increased over the study period, but vaccination still failed to reach 20–25% of people aged 65 years and older. In England, the target rate for influenza vaccination in 2011–2012 was 75% in people aged 65+ years and 60% in other at-risk groups, increasing to 75% in 2013/2014 [Most ILI cases occurred in individuals who were not categorised as high-risk, and who were not vaccinated. Over 117,000 such patients visited a GP and 534 were admitted to hospital in the study population, at an estimated cost of over £4 million and over £3 million, respectively. Scaled up to the whole UK population, this would be equivalent to over £168 million for GP visits and over £112 million for hospital admissions. This raises the possibility that mass annual vaccination could potentially have medical and economic benefits, by reducing the burden of influenza cases in individuals who are not in groups currently targeted for vaccination. Universal influenza vaccination was introduced in Ontario, Canada, in 2000 and has been associated with reductions in influenza-related mortality and healthcare use, compared with targeted vaccination programmes in other provinces . It has Vaccinated patients differed significantly from unvaccinated patients, being older and with more risk conditions. This pattern is well known , and is Multivariate analysis indicated that patients categorised as high-risk had a disproportionate risk of hospitalisation. However, high-risk individuals who had also been vaccinated had a lower risk of hospitalisation than individuals who were high-risk alone. Similarly, patients who were high-risk had a higher probability of >1 GP visit, whereas patients who were high-risk and vaccinated had a lower probability of >1 GP visit. These findings suggest that vaccination may help to reduce the risk of hospitalisation and additional GP visits in high-risk groups. This demonstrates the clear benefit of vaccination of high-risk individuals and the rationale for ensuring that coverage in this group of individuals be reinforced, as coverage in those younger than 65 years is below target. Low vaccination coverage places individuals at risk of serious complications and death because they are not being vaccinated against influenza. However, although our results show clearly that vaccinated high-risk patients in the database had lower rates of additional GP visits and hospitalisations than unvaccinated high-risk patients in the database, there may be potential for confounding by differences in health-seeking behaviour that could not be captured in the database or accounted for in the analysis. For example, surveys in adults with asthma  and pareAs per our assumption that the circulation data from the HPA was reflective of the strain circulation in the community, which is a limitation of our study, influenza B GP visits, hospitalisations and deaths showed peaks in influenza seasons with high influenza B activity and vaccine mismatch. The correlation coefficients show that for influenza B, deaths were more closely correlated with hospitalisations than hospitalisations with GP visits. For influenza A and other respiratory infections, hospitalisations were more closely correlated with GP visits than deaths with hospitalisation. The multivariate analysis also showed a statistically significant increase in the odds of hospitalisation in years with vaccine influenza B mismatch. In seasons with a mismatch between the vaccine lineage and the circulating influenza lineages, individuals may receive less clinical benefit from vaccination than anticipated, because the vaccine provides limited or no protection against the mismatched virus lineage. This suggests that improving vaccine protection against influenza B in mismatched years could be of value. Quadrivalent influenza vaccination provides protection against both influenza B lineages, which have started to co-circulate in recent years, and should therefore improve protection.It should be noted that the mismatch analysis depends on an implicit assumption that the HPA surveillance data are representative of cases of respiratory infection seen in GP practices and hospitals nationally. However, the HPA data are derived from sentinel practices, which may differ from the more general pool of GP practices from which the GPRD data are derived. It is possible that using the HPA data to attribute cases between the various respiratory viruses could over- or under-estimate the proportion of infections due to each pathogen, and this is a limitation of the study.A further limitation of the study is that complication status was assessed according to whether complications were recorded in the database. If any patients had complications that were not recorded, they could potentially have been mis-coded as having influenza without complications. To explore this possibility we investigated the full records of the small number of patients who were admitted to hospital despite having no complications of influenza recorded in the database. This showed that although the patients had no secondary diagnosis codes (and were therefore classed as having no complications), they in fact had complications such as pneumonia or other respiratory manifestations. Coding errors such as these form a natural limitation to any retrospective database study, as even a comprehensive database cannot capture all possible information.Our data are likely to underestimate the true burden of ILI in the UK, because the years included in the study all happened to be years of low influenza activity, as presented in the primary publication . Our data would also not have identified hospital-acquired influenza infections. Furthermore, previous research has indicated that hospitalisation for influenza may be a trigger for long-term health decline in elderly patients . Our stuThis study provides the most detailed quantitative data to date on the ILI burden in the UK. It should help to narrow the considerable uncertainties in modelling the potential impact of interventions .Our results indicate that although vaccination rates in target groups have increased over the study period, a substantial proportion of people are still not receiving influenza vaccination. Improving the uptake of influenza vaccination among elderly people and other high-risk groups has the potential to achieve substantial health benefits.S1 File(DOCX)Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOC)Click here for additional data file.


Chronic renal failure exposes patients to the risk of several complications, which will affect every aspect of patient’s life, and eventually his hope. This study aims to determine the effect of stress management group training on hope in hemodialysis patients.In this quasi-experimental single-blind study, 50 patients with renal failure undergoing hemodialysis at Motahari Hospital in Jahrom were randomly divided into stress management training and control groups. Sampling was purposive, and patients in stress management training group received 60-minute in-person training by the researcher (in groups of 5 to 8 patients) before dialysis, over 5 sessions, lasting 8 weeks, and a researcher-made training booklet was made available to them in the first session. Patients in the control group received routine training given to all patients in hemodialysis department. Patients’ hope was recorded before and after intervention. Data collection tools included demographic details form, checklist of problems of hemodialysis patients and Miller hope scale (MHS). Data were analyzed in SPSS-18, using Chi-square, one-way analysis of variance, and paired t-test.Fifty patients were studied in two groups of 25 each. No significant difference was observed between the two groups in terms of age, gender, or hope before intervention. After 8 weeks of training, hope reduced from 95.92±12.63 to 91.16±11.06 (P=0.404) in the control group, and increased from 97.24±11.16 to 170.96±7.99 (P=0.001) in the stress management training group. Significant differences were observed between the two groups in hope scores after the intervention.Stress management training by nurses significantly increased hope in hemodialysis patients. This low cost intervention can be used to improve hope in hemodialysis patients. As an irreversible and progressive loss of kidney function, chronic renal failure eventually causes the patient to need dialysis or transplantation . The gloEnd-stage renal disease is incurable and patients will require kidney transplantation for survival. Considering limitations of kidney transplant, many patients have to opt for dialysis. Although dialysis saves lives and increases longevity, it entails a wide range physical, mental, and socioeconomic problem for patients, which collectively affect their quality of life . EvidencHope is defined as process of thinking about personal goals, and motivation for achievement of goals , and methods of achieving goals (intrusive thinking) . Hope isPatient training is considered an important nursing role in all areas  . This roSince nurses spend longer time with hemodialysis patients compared to other medical team members . They arDespite all this and planning educational programs, in practice, patient training is less applied . In IranIncreased knowledge of stress management in hemodialysis patients can increase their performance, and increased stress management ability promises increased hope in these patients. Overcrowded hemodialysis department is highly stressful for patients, and inadequate nurse/patient ratio does not lend itself to receiving necessary training. Given all the above, and cultural, social, and economic differences in Iran (compared to other countries), this study aims to assess the effect of stress management training on hope in hemodialysis patients, so that a small step may be taken to abate patient suffering and reduce costs incurred to these patients.This case-control quasi-experimental study was approved by the Ethics Committee of Shiraz University of Medical Sciences, and registered at the Ministry of Health Center for Clinical Trials (code No IRCT2014042617440N1).This study was conducted over 4 months from November 2014 to March 2015 in hemodialysis department of Motahari Hospital in Jahrom, with a sample size of 25 in each group . Study population consisted of patients with advanced chronic renal failure attending hemodialysis department of Motahari Hospital in Jahrom in 2013-2014. Study participants were selected purposively and were then randomly divided into two groups using Random Allocation software. Sampling was conducted after obtaining necessary permissions and coordination with hemodialysis department authorities. Study inclusion criteria were the following: age between 18 and 65 years old, end stage renal disease, constantly receiving hemodialysis treatment for at least 6 months for once to three times per week lasting 3 to 4 hours each time, with no intention to leave Jahrom or to have kidney transplant in the course of intervention, receiving no formal hemodialysis training, no cognitive or psychological disorders, Farsi speaking with minimum literacy, and having a mobile phone. Study exclusion criteria included history of adverse events or experience in the recent 6 months, receiving antidepressants, admission for acute illness, and unwillingness to take part.First, a questionnaire containing inclusion criteria were given to patients, and if they met the inclusion criteria, they were selected as participants, and written consent was obtained from them. Next, data were collected using a demographic questionnaire and Miller hope scale.The QuestionnaireMiller hope scale was first used to assess hope in cardiac patients in America. Miller hope scale contains 48 items on hope and despair. Each item scores from 1 to 5 marks, adding up to a total score of 240, indicating maximum hope. Minimum hope is shown by minimum score of 48. Validity and reliability of this questionnaire and its suitability for assessment of hope in Iranian population were investigated in a study by Content validity method was used to validate the questionnaires. After compilation based on literature, comments from nephrologists, urologists, psychiatrists, psychologists, nurses, and 5 members of study population were received and implemented. Reliability was assured with Cronbach’s alpha 80% found through completion of questionnaires by 10 patients in the study population. Prior to commencement, explanations were given to both groups about how to complete forms and questionnaires.InterventionPatient training group (stress management training) received 60-minute in-person training by the researcher (groups of 5 to 8 patients) before dialysis, over 5 sessions, lasting 8 weeks.Patient training group also received a researcher-made booklet, in which explanations and advice were provided pertaining to the process of disease, the importance of hemodialysis, dietary regimen, limited liquid intake, daily weight control, physical activity, and control of vital signs, introduction to symptoms of underlying diseases, the importance of quitting smoking, stress management, and muscle relaxation. Patients in this group were also able to phone the researchers 24 hours a day in case of questions or problems. The control group received routine training provided in hemodialysis department, and did not participate in training sessions or receive educational booklet. Miller hope scale was again completed by the patients two months after completion of training. Study was performed in a single-blind format, so that participants had no knowledge of the training and control groups.Data were analyzed by SPSS-18 software using one-way analysis of variance and Chi-square tests at significance level of P<0.05.The majority of patients were about 50 years of age or younger. The mean age was 50.92±6.46 years in the stress management group, and 49.4±6.04 years in the control group. According to statistical tests, these showed no significant difference between the two groups. Chi-square test showed that both groups are similar in socio demographic characteristics. Before intervention, mean hope score was (97.24) in training group and (95.92) in control group and Chi-square test showed no significant difference between the two groups in this regard (P=0.404) . After iAfter intervention, mean hope score reduced by 4.76. A significant difference was found in mean hope score before and after intervention in the intervention group (P<0.05), and after intervention, mean hope score increased by 73.72. Independent t-test showed no significant difference between the two groups in mean hope score before intervention (P=0.8). But, after intervention, the difference between the two groups was significant (P=0.001).The present study aimed to assess the effect of stress management training on the level of hope in hemodialysis patients. Descriptive data showed that trial and control groups matched in terms of age, gender, training, and duration of disease. According to the results, intervention was able to increase mean hope score in stress management training group compared to the control. Moreover, there was a significant difference between the two groups in terms of pretest and posttest mean scores (P<0.001). In other words, the difference between the two groups in hope scores was significant. Studies conducted on progressive renal failure in Iran so far have rather focused on patients’ quality of life, stress and coping mechanisms using quantitative or statistical methods, but stress management training and its effect on hope in hemodialysis patients in Iran had not been studied. Stress management training can reduce anxiety and depression, and increase the number of ways to cope with stress. Furthermore, it is a strategy for better control of the disease, reduction and prevention of physical and psychosocial complications. Stress management has been considered effective in many psychological disorders such as anxiety and depression, psychosomatic diseases, and even diseases such as cancer and multiple sclerosis. Studies by Due to the high prevalence of patients requiring hemodialysis, to prevent increased medical costs, and to enhance the process of recovery, it is necessary to use psychological therapies. Stress management and life skills training are considered effective in reducing stress, anxiety and depression in general population . TherefoConsidering chronic nature of the disease in patients undergoing hemodialysis, despair is inevitable in these patients. On the other hand, the role of this internal factor cannot be overlooked in self-care in these patients.The present study results showed that stress management training leads to increased hope in the case group. Finally, this strategy can also be recommended for inspiring hope in patients suffering other chronic diseases.


Nodularia spumigena blooms on aquatic organisms have been mainly attributed to the production of the hepatotoxic nodularin (NOD). In the current work, the accumulation of other N. spumigena metabolites in blue mussels and crustaceans, and their effect on Thamnocephalus platyurus and Artemia franciscana, were examined. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses provided evidence that both blue mussels collected after a cyanobacterial bloom in the Baltic Sea and the crustaceans exposed under laboratory conditions to N. spumigena extract accumulated the cyclic anabaenopeptins (APs). In the crustaceans, the linear peptides, spumigins (SPUs) and aeruginosins (AERs), were additionally detected. Exposure of T. platyurus and A. franciscana to N. spumigena extract confirmed the negative effect of nodularin on the organisms. However, high numbers of dead crustaceans were also recorded in the nodularin-free fraction, which contained protease inhibitors classified to spumigins and aeruginosins. These findings indicate that cyanobacterial toxicity to aquatic organisms is a complex phenomenon and the induced effects can be attributed to diverse metabolites, not only to the known hepatotoxins.Thus far, the negative effects of  In fresh, marine, and brackish waters throughout the world, anthropogenic eutrophication, together with favorable weather conditions, have a stimulating effect on cyanobacterial growth and bloom formation ,2. The eNodularia spumigena, Aphanizomenon flos-aquae and Dolichospermum spp., and the single-celled picocyanobacteria, mainly from the genus Synechococcus  +. The composition of the four fractions is shown in The biological activity of the four fractions obtained from −1), a demethylated form of the toxin, and small amounts of two APs (A. franciscana (37.5%) was in fraction IV in which trace amounts of NOD were found and two anabaenopeptins were detected as the main components , one spumigin (m/z 597) and one aeruginosin (587) were also detected; the additive effect of these peptides on tested organisms should be considered. Accumulation of nodularin in aquatic biota has been studied by many research groups. In the Baltic, during a bloom event, NOD concentrations in zooplankton and blue mussels reached 0.62 μg∙g−1 d.w. and 2.15 μg∙g−1 d.w., respectively  NOD . To confirm the structure of the peptides detected in the invertebrates, their enhanced ion product (EIP) spectra were acquired at a collision energy (CE) of 50 V. EIP mode was also used in the analyses of N. spumigena peptides in cell extracts, fractions, and the culture medium. Data acquisition and processing were accomplished using Analyst QS® 1.5.1 software.The content of cyanopeptides in the cyanobacterial bloom sample, in the fractions obtained from the Statistical analysis was performed using Microsoft Excel 2013 (v15.0). The results of assays performed with Thamnotoxkit F™ and Artoxkit M™ were considered to be significant when the crustaceans’ mortality did not exceed 10% in control variants, and was higher than 20% in the tested samples.N. spumigena metabolites might be active against A. franciscana. These results indicate that cyanobacterial toxicity to aquatic organisms is a complex phenomenon and the induced effects can be attributed to the activity of diverse metabolites, not only to the known toxins. As there are significant inter- and intraspecies differences in the metabolite profile and in the reaction to their exposure, the type and strength of the interactions between organisms are also expected to be strain-specific, with respect to both the cyanobacteria and the grazers.Our studies proved the accumulation of different classes of cyanobacterial peptides in two representatives of aquatic invertebrates: the crustaceans and blue mussels. We also showed that apart from nodularin, other


Few studies have been carried out in low- middle-income countries assessing contextual characteristics associated with bullying. This study aimed to assess the relative importance of contextual (school and city) and individual-level factors to explain the variance in verbal bullying among a nationally representative sample of Brazilian adolescents.59,348 students from 1,453 schools and 26 state capitals and the Federal District participated in the National Survey of School Health among 9th Grade Students . We performed multilevel logistic regression in a three level model .The 30-day prevalence of verbal bullying among these students was 14.2%. We found that 1.8% and 0.3% of the total variance in bullying occurred at school-level and city-level, respectively, and 97.9% at individual-level. At city-level, all factors included failed to demonstrate a significant association with bullying (p <0.05) whereas at school-level, private schools presented more bullying than public schools . At individual-level, male gender, younger age, not living with both parents, exposed to domestic violence, under or overweight were all associated with bullying.All socioeconomic indicators assessed contributed little to explain the variance in bullying at individual, school or city-level. Population subgroups at risk identified according to their individual profile could be targeted in future interventions in Brazil. Bullying is a common form of aggression among adolescents worldwide. School-based surveys in high-income countries (HIC) have found average prevalence rates among adolescents ranging from 2% among girls aged 13 years in Italy to 32% within boys aged 11 years in Lithuania ,5.Bullying behavior is of concern to both education and health systems, because of its deleterious consequences to victims. Bullying victims have higher risks of psychosocial problems, like low self-esteem, anxiety, depression  and suicThere has been research suggesting that school bullying tends to cluster in classes, schools, cities and countries -15. HoweAt the individual-level the following variables have been associated with bullying: male gender , youngerThe association of macroeconomic and social indicators with bullying has also been explored at a higher level . For instance it is argued that income inequality, is responsible for reducing social cohesion across communities and this is considered a preventive factor to reduce violence in general ,29 incluAt school-level, studies in HIC have found that poverty -33 or hia had increased prevalence of bullying in schools, among 5th grade students [Violence is another characteristic that has been linked to bullying. The connection between violence and bullying in cities may be explained based on the social learning perspective that postulates that aggression is a behavior that may be learned from the environment in which individuals live. In other words, those who are exposed to violence in their communities learn that aggression, including bullying, may be an acceptable way to achieve goals, consequently developing normative beliefs, which may condone or legitimize aggression ,36. A ststudents . On the students  found noBullying may take different forms, such as physical, verbal, relational/social or electronic (cyberbullying) ,38. In BThe associations previously described came from studies that analyzed factors associated with bullying as a whole, but may also be important to explore specific predictors of each form of bullying. At the individual-level, some gender differences were found, for example in associations with verbal and physical bullying . Thus, iBrazil has the largest population in Latin America: 198.7 million people , with abUsing a dataset from a Brazilian surveillance, which assessed verbal bullying among adolescents, we hypothesize that: schools and cities may contribute to explain some of the variance in verbal bullying among young people in Brazil. We also intend to explore associations between verbal bullying and individual characteristics, considering that previous research have shown that individual features are more strongly correlated with bullying.The present study is based on data supplied by the National Survey of School Health among 9th Grade Students - PeNSE, which was carried out between March and July of 2009 .The mainThe expected age range in 9th grade in Brazil is between 14 and 15 years old , but theThe sample was selected from the 2007 School Census database using a complex design that included stratification per cluster and two-stage selection. The sampling strata considered each of the 26 state capitals and the Federal District. The primary sampling units (PSUs) were schools, and the secondary sampling units (SSUs) were school classes. The odds for school selection were proportional to the school size , while the classes in each school were chosen by simple random selection. Two classes were selected from the schools with three or more ninth-year classes, and one class was selected from the schools with one or two ninth-year classes. All of the students enrolled in the selected classes were invited to participate in the study .b device, which included the following thematic modules: socio-demographic characteristics, diet, body image, physical activity, smoking, use of alcohol and other drugs, support network (family and friends), sexual behavior, situations at home and school (including bullying), violence and accidents, and anthropometric measures (weight and height). The questionnaire was based on the Global School-based Student Health Survey/World Health Organization-GSHS/WHO and Youth Risk Behavior Surveillance System/Centers for Disease Control and Prevention- YRBSS/CDC.PeNSE 2009 used a self-reported structured questionnaire available in a Personal Digital AssistantFrom the total number of students selected for the sample , 501 refused to participate, 1,937 did not report their gender and 1,625 did not answer the bullying question and thus were excluded from analysis (response rate 93.6%). The sample was re-weighted  to represent students enrolled in the ninth year of schooling who attended regularly. Therefore, the analysis uses data corresponding to 59,348 students from 1,453 schools and 26 cities and the Federal District. Further details on the sampling procedures are available in the PeNSE report [Verbal victimization was measured using the question “In the past 30 days, how often have you been mocked, teased, called names or intimidated by one of your schoolmates so much that you were hurt/annoyed/upset/offended/ashamed?” Response options were “not at all”, “rarely”, “sometimes”, “most of the time”, and “always”. Students were categorized as victims of bullying if they reported being verbally bullied “sometimes” or more frequently. We assumed that the answer “sometimes” implies more than once, which is equivalent to the frequency of “two or more times within the last month”, a threshold recommended in previous literature ,50.The following socio-demographic variables were considered in the analysis: gender; age range ; ethnicity/skin colour ; mother’s educational level . The socioeconomic-status was assessed as tertiles of the total scores of the Goods and Service index (GS score) . The GS The assessment of weight and height was performed by trained researchers and is described elsewhere . After cLiving arrangements were also evaluated and categorized into three groups: living with two parents, living with one parent (mother or father) or other arrangements. There was no differentiation between biological or adoptive parents. Domestic violence against the adolescent was evaluated from the question “in the past 30 days, how many times were you physically assaulted by an adult in your family”, categorized as “none”, “once”, or “two or more times”.Schools were classified as either public or private. We estimated a school’s socioeconomic level as the mean GS score of the children supplying data from each school. The GS score was distributed into tertiles. We used the coefficient of variation of mean GS score as a measure of a school’s socioeconomic disparity . The coefficient of variation was also divided into tertiles.http://www.ibge.gov.br/home/estatistica/populacao/censo2010/indicadores_sociais_municipais/tabelas_pdf/tab16.pdf), divided in tertiles. It was used as an indicator of overall city income. In addition we obtained GINI indices for each capital, also from IBGE system (2010=http://tabnet.datasus.gov.br/cgi/idb2011/b09capc.htm), which were subsequently divided into tertiles. A GINI index of zero represents perfect income equality and a score of 1 maximum inequality. Violence in the capital was assessed by homicide rate (2009) obtained from the Brazilian Department of Public Health Information [The 2010 per capita income of each city obtained from the Brazilian Institute of Geography and Statistics – IBGE  with the corresponding 95% confidence intervals were obtained. The cut-off point for statistical significance was arbitrarily established as p < 0.05.We performed multilevel analysis at different levels taking into consideration the data hierarchy (students nested in schools and schools nested in cities) to analyze the proportion of the variance explained at different levels using regression models .Initially we calculated the crude variance coefficients representing between-city and between-school variance in exposure to bullying victimization without considering any individual, school, or city variables (empty model). This model indicates the crude amount of clustering of bullying by school and city. We used the ‘latent variable method’ to obtain intraclass correlation coefficients (ICC), assuming that an individual’s risk of bullying follows a logistic distribution, with individual-level variance equals to 3.29 ,57.In a second step, we analyzed the association between each covariate with bullying, without additional adjustments for other variables (Unadjusted model). Then, the influence of all the individual-level covariates on the outcome was examined (model 1). In Model 2 we simultaneously examined the influence of all covariates, student, school and city-level. We also verified the proportional change in variance of bullying across schools and cities for models 1 and 2 .All the analyses were performed using Stata SE version 13 .PeNSE 2009 was approved by the National Commission of Research Ethics , record no. 11.537. It was performed in accordance with the Declaration of Helsinki and all participants gave their informed consent. Database was made publicly available on an IBGE website without any information that could identify subjects.The descriptive analysis of individual, school and city-level characteristics are presented in Table There was wide variation in the prevalence of bullying among schools, ranging from 1.8% to 40.0%, and between cities ranged from 10.9% (Cuiabá) to 16.3% (Curitiba). In the empty model, the ICC showed that 1.8% and 0.3% of the total variance in verbal bullying occurred at school-level and city-level, respectively, and 97.9% at individual-level. These variances were statistically significant, showing clustering of bullying at these levels. The inclusion of covariates at individual-level in model 1 were able to explain 33.3% of the school-level variance. The inclusion of covariates at school and city-level in model 2 were not able to explain the school and city-level variance (Table In the unadjusted model schools with higher mean of GS scores (third tertile) presented a higher likelihood of victimization and private schools were also more likely to report bullying. In the adjusted model, there were no associations between bullying and the school-level mean of GS scores or the coefficient of variation . However private schools remained associated with more bullying victimization in the fully adjusted model , younger age , native ethnic groups , not living with both parents , victim of violence within the family at least once in the last month , overweight , obesity  and underweight  , may be perceived as different for a number of reasons, including different cultural and social norms .Individuals who reported violence at home were much more likely to report verbal bullying victimization. Although we cannot establish the causal direction of this association, it has been reported that domestic violence increases anxiety and depressive symptoms, low self-esteem and social isolation, which might interfere with the social skills of these adolescents who could become easy targets for bullies ,65.Underweight, overweight and obese adolescents reported more bullying than their eutrophic counterparts, something that had been previously reported in the literature ,66. ThisThis study has some limitations. First, the measure of bullying based on a single-item is rather limiting but other studies have also had a similar problem. This question seeks to capture those individuals who had experienced negative feelings as a result of bullying. Students classified as victims in this study might be more severe cases of bullying or those who were unable to cope well with the situation. Therefore it is possible that the prevalence of verbal bullying as measure in this study may have been underestimated. Additionally, the associations found or not found, can only be stated for verbal bullying and might differ for other forms of bullying or for bullying measured as a summary of its different forms. However, the lack of these measures in the surveillance used prevented us from exploring other associations.The second limitation is the use of aggregated measures to assess school characteristics instead of using proper contextual level measures . Unfortuth grade and the good response rate. The direct measurement of height and weight of students rather than self-reported measures also reduced potential measurement bias [The major strength of this study is the large random sample, representative of Brazilian schoolchildren of 9ent bias .This study provided evidence that verbal bullying variance at school and city-level was small, and most of the variance was accounted for at the individual level. This does not mean school or city-level lacks importance, but may suggest that city boundaries comparing only state capitals do not capture differences that shape the relevant environment for bullying occurrence . Those cThose individual variables strongly associated with verbal bullying might allow the identification of possible higher risk sub-groups that could be targeted for interventions in the future and denote the role of family arrangements and violence in verbal bullying victimization. The profile of vulnerable adolescents to verbal bullying in Brazil can guide policy makers, teachers and school staff on bullying prevention.Finally studies exploring associations between other forms of bullying and other contextual variables, measured at rural/urban or central/peripheral neighborhoods; or comparing state capitals with small towns; including other family and school characteristics, which are more proximal to individuals, may provide a more accurate picture of the possible influence of contextual-level variables on bullying in Brazil.aDecades-old-armed conflict has happened among left-wing guerrilla groups, right-wing para-militaries and the national-armed forces in Colombia.bavailable at: http://www.ibge.gov.br/home/estatistica/populacao/pense_avaliacao_nutricional_2009/questionario.pdf.


To assess the impact of respiratory therapy with the expiratory flow increase technique on cerebral hemodynamics of premature newborns.This is an intervention study, which included 40 preterm infants (≤34 weeks) aged 8-15 days of life, clinically stable in ambient air or oxygen catheter use. Children with heart defects, diagnosis of brain lesion and/or those using vasoactive drugs were excluded. Ultrasonographic assessments with transcranial Doppler flowmetry were performed before, during and after the increase in expiratory flow session, which lasted 5min. Cerebral blood flow velocity and resistance and pulsatility indices in the pericallosal artery were assessed.p=0.50), the end diastolic flow velocity (p=0.17), the mean flow velocity (p=0.07), the resistance index (p=0.41) and the pulsatility index (p=0.67) over time.Respiratory physical therapy did not significantly alter flow velocity at the systolic peak (The expiratory flow increase technique did not affect cerebral blood flow in clinically-stable preterm infants. These neurological diseases may cause permanent motor sequelae of varying degrees, depending on the lesion extent, as well as cognitive, behavioral and intellectual disorders.-CBF alterations are commonly associated with upper airway obstruction, severe respiratory diseases, apnea, hypoxia, hypercapnia, hypocapnia, ventilation with intermittent positive pressure, asynchrony with the ventilator, tracheal aspiration and expansion of circulating volume, as well as care routine, such as diaper changing and repositioning of the endotracheal tube, excessive manipulation and agitated sleep.,In this context, respiratory physiotherapy has become necessary and a routine in most neonatal intensive care units (NICU) worldwide.-Few studies have investigated the influence of respiratory physiotherapy on brain injuries in preterm newborns regarding CBF alterations.The objective of this study was to assess the influence of physiotherapy on the CBF in clinically-stable preterm newborns.This is an intervention study, carried out in intensive care and neonatal intermediate care units at Hospital da Mulher Prof. Dr. José Aristodemo Pinotti, Centro de Atenção Integral à Saúde da Mulher (Caism) of Universidade Estadual de Campinas (Unicamp), from October 2013 to June 2014. The sample consisted of clinically-stable preterm newborns with gestational age ≤34 weeks, between 8 and 15 days of postnatal age, spontaneously breathing room air or receiving oxygen with the aid of a nasal cannula and with no contraindications for respiratory physiotherapy and the supine position. In our service, all preterm newborns, even without pulmonary involvement, have indication for respiratory physiotherapy; however, in the ones that require oxygen and/or who have pulmonary and/or nasal secretions, respiratory physiotherapy is intensified. We excluded all newborns with cardiac and/or neurological malformations, diagnosis of brain lesion (hemorrhagic or ischemic) during any period of hospitalization and/or receiving vasoactive drugs. Written informed consent was obtained from the parents/tutors of each subject.To calculate the sample size, a pilot study was performed, in which 10 preterm newborns underwent identical assessments to those used for the data collection in this study (described later). Considering a type I error of 5% and a type II error of 20%, the sample size was determined by the difference between the means of paired measurements for all studied variables. Thus, a sample size of 40 newborns was determined.Gestational age (GA) was obtained from the date of the last menstrual period. If this date was unknown or uncertain, the GA estimated at an early ultrasound  and/or clinical and neurological examination of the newborn by New Ballard method was considered.CBF assessment of was carried out by transfontanellar Doppler ultrasonography, performed by the same neonatologist, in order to avoid observer-related variations. The Sono Site™ system, M-Turbo model, with a 5MHz transducer was used. The pericallosal artery, a branch of the anterior cerebral artery, adjacent to the knee of the corpus callosum was evaluated. This artery was chosen because it is widely used in scientific studies for similar tests,T0) was performed. After that, the expiratory flow increase (EFI) maneuvers were performed for 5min. The examination was repeated on the second (T1) and fifth (T2) minutes of respiratory physiotherapy and 10min after completion of the maneuvers (T3). After the tests, the newborns received nursing care, according to the service routine. The examinations were performed one hour before the following feeding to prevent vomiting and bonchoaspiration. Fasting patients and those fed by continuous infusion through infusion pump or parenteral nutrition were assessed one hour before the subsequent nursing care in order to not interrupt the newborn's resting and sleep time. Newborns that were restless or tearful during the physiotherapy session were calmed with a 25% sucrose solution and/or non-nutritive sucking with pacifier or a gloved finger. All routine brain ultrasonographic examinations, performed after the tests carried out for this study, were systematically followed by the researchers.The examinations were carried out with the newborn in the supine position with the head in midline position, and kept at rest or reduced motor activity for approximately 10min, after which the brain ultrasound was performed to exclude brain lesions and, subsequently, the first Doppler ultrasound examination , starting at the end of the inspiratory plateau and ending at the end of expiration, which is prolonged. The hand must be positioned between the sternal notch and the xiphoid process of the newborn's sternum. The other hand of the therapist is placed on the last ribs (without applying pressure) as a bridge, of which columns are the thumb and forefinger (or middle finger) . Thus, cMaternal and neonatal sociodemographic variables were collected from medical records to characterize the sample. The absolute frequency and percentage of qualitative variables and descriptive statistics of quantitative variables, with measures of central tendency, position and dispersion  were computed.Heart rate and oxygen saturation were continuously monitored in a multi-parameter monitor. Respiratory frequency was assessed by visual count. Blood pressure (BP) was measured non-invasively using the automated oscillometric method with a multi-parameter monitor, preferably in the right upper limb.p<0.05. The statistical analysis was carried out using The SAS System for Windows, version 9.2 (2002-2008).To investigate whether respiratory physiotherapy promoted alterations in CBF, analysis of variance for repeated measures was used, with the response variables transformed into ranks. Each child served as his/her own control. The twinning variable was used to adjust the models in order to avoid statistical bias, since newborn twins do not have independent obstetric history. The statistical significance level was set at The Protocol for this study was approved by our hospital's Institutional Research Committee and by the University's local Ehtics Committee, under protocols no. 24/2013 and 421.237, respectively.n=28) were considered adequate for gestational age, while 27.5% (n=11) were small for gestational age and only one (2.5%) was considered large for gestational age. On examination, the patients weighed on average 1617±519g, ranging from 840 to 3900g. Of the newborns, 10 (25%) were twins. Regarding the maternal history, 12 (30%), four (10%) and seven (17.5) were born to hypertensive, smoker and diabetic mothers, respectively. Eight (20%) patients were born to mothers that had used magnesium sulfate and 33 (82.5%) to mothers who received antenatal corticosteroids. The most frequently observed neonatal morbidities were risk of ovular infection , respiratory distress , use of surfactant  and patent ductus arteriosus .Forty-two newborns were enrolled in this study, of which two were excluded due to the presence of periventricular leukomalacia (PVL), observed in pre-discharge transfontanellar ultrasound. Thus, 40 newborns were included, of which most of them (95%) were breathing room air, were males (52.5%) and born via Cesarean section (67.5%). The mean gestational and postnatal age was 31.8±1.6 weeks (range: 28-34) and 10.9±1.9 days (range: 8-15), respectively. The newborns had a mean birth weight of 1658±539g, ranging from 830 to 3840g. Fifteen newborns (37.5%) had birth weight<1500g. Most patients   was significantly altered by the respiratory physiotherapy maneuvers over time (and T3) .p=0.99) and heart rate (p=0.07) did not change significantly with the respiratory physiotherapy over time and were within normal limits .Hemoglobin oxygen saturation (l limits . Systoli-This study showed, in an unprecedented manner, that respiratory physiotherapy using the EFI technique did not significantly change the CBF velocities, and did not seem to modify cerebral vascular resistance in clinically-stable preterm newborns. Some studies investigated the association between respiratory therapy and the occurrence of cerebrovascular lesions.-,In the late 1990s, Harding et al.Cerqueira-Neto et al.-,As currently the EFI technique is widely used in the NICU, we consider of great importance to quantitatively assess its effects on the CBF in premature newborns, as this maneuver involves compression, even slight and slow, of a more compliant chest. It is not known whether this situation could change the intrathoracic pressure enough to affect venous return and, thus, change CBF. We also emphasize that the technique used in premature newborns does not involve the use of abdominal pressure, which, in the original technical description, should be applied in the opposite direction to that of thoracic pressure.Not all patients in this study had an absolute indication for respiratory physiotherapy, as the majority was in a clinically-stable situation and with no oxygen support. On the other hand, the therapy was indicated for oxygen-dependent patients and for those with pulmonary and/or nasal secretion. It is worth mentioning that no subject had contraindications for such intervention, which would not bring any harm to the patient. Therefore, the study population was heterogeneous regarding the indication of pulmonary therapy, but stable considering the clinical point of view.Furthermore, it is important to mention that the children were not followed after hospital discharge. Some patients were discharged right after the assessment for this study. Early discharges were due to favorable clinical outcome or inter-hospital transfer, which was the case for 18 of the 40 studied children. Therefore, we have no information about the possible development of subsequent brain lesions.The knowledge of factors that could change the CBF of preterm newborns is important for the prevention and control of complications related to prematurity, such as cerebrovascular lesions. As the vast majority of premature newborns need respiratory physiotherapy, it is important to know the pattern of cerebral hemodynamics in these patients during the application of the most often used physiotherapy techniques. This information can contribute to better care for the newborns, as well as better prevention, treatment and control of cerebral disorders and complications that affect them. Additionally, it may help physiotherapists for a more adequate and safer indication of respiratory therapy.It can be said that the EFI is a safe physiotherapy technique when applied in clinically-stable preterm newborns, as it did not result in significant changes in CBF. In this study, we analyzed clinically-stable newborns as a first step toward the assessment of the technique safety. The extrapolation of these results in clinically-unstable infants and on the first days of life should be viewed with caution and becomes an interesting field for further studies addressing critically-ill preterm newborns.


To the best of our knowledge, the association of nasopharyngeal and laryngeal tuberculosis has never been described before in the literature. We report here a first observation.We report the case of a 38-year-old Arab man who presented with an isolated hoarseness. Radiological and endoscopic examinations showed a thickening of the left lateral wall of his nasopharynx and the left vocal cord. Pathology revealed the diagnosis of tuberculosis of both localizations. He received a 6-month antituberculous chemotherapy with a satisfying uneventful evolution.Tuberculosis should be considered in the differential diagnosis of soft tissue masses of the head and neck, particularly when the imaging findings and clinical presentation are atypical. The diagnosis of tuberculosis is mainly based on histopathological and/or bacteriological examination. Mycobacterium tuberculosis. The main site involved is commonly the lung. However, there is a marked increase in head and neck infections especially in developing countries [Tuberculosis (TB) is an infectious disease caused by ountries , 2. Laryountries . Nasophaountries .Clinical, radiological and endoscopic features of head and neck TB are not specific; they are often confused with neoplastic lesions or even incidentally discovered . PositivTo the best of our knowledge, the association of NPTB and LTB has never been described in the literature. We report here a first observation.A 38-year-old Arab man, a heavy cigarette smoker , who never worked in the wood or leather industries, with no history of diabetes, allergic rhinitis or immunodepression and with no medical history of familial or personal TB, presented with an isolated hoarseness that appeared a month prior without dyspnea or dysphagia. He did not present any nasal symptom such as obstruction or epistaxis. Moreover, he reported a non-estimated weight loss without fever or night sweats. A nasofibroscopy showed a slight thickening of the posterior wall of his nasopharynx with adenoid appearance, a budding process of the anterior commissure of the glottis and a granulomatous thickening of the left vocal cord whose mobility was reduced. His nasal cavity, oropharynx and laryngopharynx were intact. Examination showed no lymphadenopathy.A cervical and thoracic computed tomography scan showed a budding thickening of the left lateral wall of his nasopharynx and a thickening of the left vocal cord Figure , with fiHe underwent laryngoscopy; three biopsies of the posterior wall of his nasopharynx, a biopsy of the anterior commissure and two biopsies of the left vocal cord were performed.Histology showed on a vocal cord and nasopharynx specimen, an epithelioid and gigantocellular granulomatous process with caseous necrosis without any malignancy sign Figures  and 3.FiHuman immunodeficiency virus (HIV) serology was negative. His complete cell blood count was normal. He was given a 6-month antituberculous treatment 2RHZE/4RH where R is rifampicin 10mg/kg/day, H is isoniazid 5mg/kg/day, Z is pyrazinamide 30mg/kg/day, and E is ethambutol 20mg/kg/day, with a satisfying uneventful evolution.TB is widespread in the world with an incidence of 8.7 million in 2011 and a mortality of 1.4 million. Virtually all the organs can be affected. There has been a significant decrease in the disease in the last decades thanks to the advent of the antituberculous regimen. However, we notice a resurgence of extrapulmonary involvement partly due to HIV infection. The prevalence of HIV infection in patients with tuberculosis is about 8.8%. Up to 10% of extrapulmonary TB involves the head and neck region  with 95%Currently, LTB is rare, but prior to antibiotics, it was associated with 37% of pulmonary TB and a high mortality rate . In freqWhen exposed to respiratory epithelium, the bacteria are phagocytized by alveolar macrophages, which are unable to digest them, subsequently allowing the unchecked multiplication of the bacteria and manifestation of disease by direct infection/extension, as well as hematogenous and lymphatic spread .The larynx is rarely the primary site involved, it is rather usually infected via expectoration of sputum from tracheobronchial tree, hematogenous spread from other sites or less frequently via lymphatic spread , 9. MoreIn the past, clinical manifestations of LTB were not specific, due to the frequent association with lung disease  . CurrentLTB is classified into four types according to its macroscopic appearance: granulomatous (like in our case), polypoid, ulcerative and nonspecific. Lesions can be unique or multiple. Granulomatous lesions are more common in patients with pulmonary TB . EndoscoInfection by HIV should be ruled out in all patients with TB, especially if the TB is extrapulmonary and there is no apparent immunodeficiency .In LTB, the four predominant patterns described based on imaging appearances include superficial ulcerative lesions, nonspecific mucosal enhancement due to inflammatory change, polypoid masses, and ulcerative/fungating lesions . In NPTBMycobacterial smear and culture are difficult in these locations due to low concentrations of the bacilli. Histopathology seems to be more useful to make an early diagnosis. A biopsy must be performed in any space-occupying lesion. Sample analysis includes histology and mycobacterial culture. Histology shows granulomas with giant cells, with or without caseous necrosis. Cultures come afterward to confirm diagnosis. Quick and accurate diagnosis can also be made by polymerase chain reaction from oral samples with a high sensitivity rate (89 to 100%) .TB may mimic or coexist with other conditions in the head and neck, especially tumors; therefore, tissue confirmation is mandatory . It is oMedical treatment consists of the combination of powerful antituberculous drugs according to the regimen: 2RHZE/4RH where R is rifampicin 10mg/kg/day, H is isoniazid 5mg/kg/day, Z is pyrazinamide 30mg/kg/day, and E is ethambutol 20mg/kg/day. A 6-month treatment is usually sufficient and results in complete recovery , 13. SurHead and neck TB although uncommon in developed countries, must be kept in mind in case of cervical swelling or infectious condition resistant to classical antibiotics. Given the frequency of carcinomas in this region, biopsies must be performed as much as necessary to make the right diagnosis .TB should be considered in the differential diagnosis of soft tissue masses of the head and neck, particularly when the imaging findings and clinical presentation are atypical. The diagnosis of TB is mainly based on histopathological and/or bacteriological examination , 12, 13.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.