The staggering diversity of angiosperms and their flowers has fascinated scientists for centuries. However, the quantitative distribution of floral morphological diversity (disparity) among lineages and the relative contribution of functional modules  to total floral disparity have rarely been addressed. Focusing on a major angiosperm order , we compiled a dataset of 37 floral traits scored for 381 extant species and nine fossils. We conducted morphospace analyses to explore phylogenetic, temporal and functional patterns of disparity. We found that the floral morphospace is organized as a continuous cloud in which most clades occupy distinct regions in a mosaic pattern, that disparity increases with clade size rather than age, and that fossils fall in a narrow portion of the space. Surprisingly, our study also revealed that among functional modules, it is the androecium that contributes most to total floral disparity in Ericales. We discuss our findings in the light of clade history, selective regimes as well as developmental and functional constraints acting on the evolution of the flower and thereby demonstrate that quantitative analyses such as the ones used here are a powerful tool to gain novel insights into the evolution and diversity of flowers. This diversity is mirrored in the high variability of breeding systems and reproductive strategies across angiosperms. Hence, it is hypothesized that floral form and function have important effects on diversification –4. ThereMorphospace analyses are used to study macro-evolutionary patterns and trends in disparity within and among clades. While disparity analyses are traditionally conducted on large numbers of traits capturing the overall morphology of particular organisms –21, someMost flowers are composed of three main functional modules. From the periphery to the centre, a flower usually comprises one or two sets of sterile organs (perianth), a set of male reproductive organs (androecium) and a set of female reproductive organs . In the perianth, sepals commonly protect younger organs during pre-anthetic stages, while petals mainly attract and guide pollinators at anthesis . The funca 112 million years ago [a), 346 genera, and approximately 11 550 species [We addressed these issues in the Ericales, a speciose order of angiosperms nested in the asterid clade of core eudicots. Ericales diverged from their sister group in the Early Cretaceous, ears ago  and encoears ago ; figure  species  displayi species . In many species . The ord species ,44. This species –47. Impo species ,38,40. A species ), most o species .Figure For this study, we compiled an extensive dataset of extant and fossil ericalean species and built a floral morphospace based on 37 traits capturing the morphology of their flowers. Our first goal was to quantify patterns of morphospace occupation within and among ericalean families and suprafamilial clades. We tested the hypothesis (i) that various suprafamilial clades do not overlap or only overlap partly in the floral morphospace. This hypothesis derives from the fact that several clades such as, for instance, the ericoid and the primuloid clade, were not considered to be closely related in pre-molecular, largely morphology-based classifications (e.g. ), sugges2.(a)We sampled 381 species belonging to 275 genera (accepted in ). For ea(b)We used original species descriptions or, when available, recent taxonomic revisions, online floras, and other scientific literature, as well as personal observations from living and alcohol collections of the Botanical Garden of the University of Vienna. We scored 37 floral characters describing: general features , the perianth (12 characters), the androecium (13 characters) and the gynoecium (six characters) of the anthetic flower. These characters were chosen for their capacity to characterize the number and position of organs, organ union (organs of the same type), organ fusion (organs of different types) and organ form (for staminodes). Using taxonomic keys as our primary source, we selected all the characters that described the flower and that were applicable throughout the whole order of Ericales.For species producing unisexual flowers, characters of androecium and gynoecium organs were only scored for functional organs and not for sterile organs, such as staminodes and pistillodes.Some characters, such as organ number and size, were frequently described as polymorphic in the literature. As the frequencies of these variations were rarely detailed, we choose to code the most common state, when it was documented. For instance, ‘(4-) 5 (-6) petals’ in a description was coded ‘5’ in our dataset. The remaining polymorphic characters  were coded as such, which represents 274 data entries . As most of our analyses do not support polymorphisms, we randomly sampled a matrix , in which each of the polymorphic cells was replaced by a value comprised of the cell range  or by one of the possible states . Given the low amount of polymorphic data entries, this matrix sampling had no effect on the statistics calculated nor on data visualization (data not shown).Data were entered and are stored in the online database PROTEUS . Each da(c)All our analyses were performed using the software R v. 3.0.0 . Scriptsmean character difference (here noted D) [A and B described by N morphological characters. For a character i, the difference ABdi between A and B was calculated in different ways depending on the type of character:ABdi was calculated as the absolute value of the difference between the values of the character for A and B, divided by the range of the character in the dataset;— for numerical characters, ABdi was calculated as the number of steps between the values of the character for A and B, divided by the maximum possible step difference for the character in the dataset;— for ordered categorical characters, ABdi took the value {1} if A and B shared the same state, {0} if not;— for binary and unordered categorical characters, A or/and B, this character was removed from the calculation of D. N was thus reduced to the number N' of characters with no missing data for A or B.— if the value of a character was missing for We calculated pairwise dissimilarities between taxa using the noted D) . Let us ABD between taxa A and B was finally computed asD was calculated for each pair of taxa to create the dissimilarity matrix. Note that characters ‘19. Number of stamens’ and ‘36. Number of ovules per carpel’ were log transformed to reduce the weight of extremely high (and rare) values on the analyses, observed in the distributions of these two characters only.The mean character difference (d)To illustrate morphological differences between the 22 Ericales families, we visualized the morphospace of Ericales with a principal coordinate analysis  taking D per family .Calculation and analyses of the morphological diversity (disparity) were carried out from the original dissimilarity matrix, and not from the ordination scores. Disparity within each family was calculated as the mean pairwise dissimilarity, i.e. the mean  noted ; ), and as family; ). Contraple size . We thusPDiv, the additive contribution of each family to the disparity of the whole order) was calculated following [Partial disparity (ollowing . It is t(e)vegan package in R [F ratio under the null hypothesis. We used the same analysis as post hoc, with a Bonferroni correction.Two groups falling in different parts of the morphospace are morphologically different, whereas they are similar if their distributions in the space overlap. We assessed morphological differences among ericalean families with non-parametric analyses of variance  using the function adonis from the age in R . We used(f)R) and the number of species per family as reported in [R) and the stem age of families as estimated in [Spearman correlation tests were performed to investigate the links between disparity dAB, i.e. the differences between taxa, for each character. The resulting values, here noted Dchar, increase with the variation of a character in the dataset.To compare variation among the 37 morphological traits, we averaged (h)D for each taxa pair) calculated for each of the modules' character sets, respectively, and the disparity matrix calculated for the whole character set. Taxa pairs for which D could not be computed for one of the functional modules, due to missing data, were pruned from the matrices before performing the test.In our dataset, the perianth morphospace is based on 12 characters, the androecium space on 13 characters, and the gynoecium space on seven characters. Because these three morphospaces differ in character composition and in size, their respective disparities cannot satisfactorily be compared directly. We first investigated if the disparity for each of the functional modules increased with total disparity in Ericales. To do so, we performed a Mantel test, to test for a correlation between the disparity matrices  to match the usual 0.05 threshold value.To assess if the perianth, androecium and gynoecium of Ericales are more or less variable than the rest of the flower, we then compared the disparity (posed in  for asse(i)Actinocalyx bohrii , Glanduhraceae; ), Parasadiaceae; ), Paleoeicaceae; ), Paradiheaceae; ), Raritaricales; ). Morpho3.(a)Our dataset contains 12 512 data entries. In total, 1927 (13.4%) data are missing. The average percentage of missing data is 13.4 ± 10.3 (mean ± s.d.) per taxon and 13.4 ± 12.2 per character.c; electronic supplementary material, interactive three-dimensional figure S3). The first three principal coordinate axes of the space representation summarized 31.5% of the original variance , the first two, 24.2% (figure 1c). Both three-dimensional and two-dimensional representations gave a fair approximation of the relative dissimilarity among taxa . In this space, most of the seven suprafamilial clades, plus the families Theaceae, Lecythidaceae and Mitrastemonaceae, occupy distinct neighbouring regions arranged in a mosaic pattern . The only exception is the balsaminoid clade, which does not significantly differ from most of the other suprafamilial clades, mainly because two of its three families, Tetrameristaceae and Marcgraviaceae, overlap with most clades in the order .The floral morphospace of Ericales is organized in a continuous cloud . For instance, Ericaceae significantly differ from only 11 of the 21 other families and distinctly overlap with, e.g. Cyrillaceae and Marcgraviaceae .Finally, each family cluster overlaps with at least two other families from its own and other suprafamilial clades (PERMANOVA: (b)R = 0.007 in Mitrastemonaceae to R = 0.27 in Lecythidaceae.The disparity of ericalean families ranged from PDiv = 16.1%), Sapotaceae (PDiv = 14.3%), Primulaceae (PDiv = 14%) and Ericaceae .Four ericalean families together contribute 50% of the Ericales disparity: Lecythidaceae ((c)rho = 0.49, p = 0.02; R: rho = 0.64, p = 0.001; figure 2a). We found no significant correlation between disparity . With few exceptions , partial disparity significantly increased with species number .We found a positive, but nonlinear, correlation between disparity ((d)e). Their distribution in the space overlaps with the balsaminoids, the ericoids, the Pentaphylacaceae-Sladeniaceae clade and Mitrastemonaceae  and they contribute 1.8% to the total disparity of Ericales. Note that the percentage of missing data in the fossil dataset was 10.51% .The nine fossils of Ericales included in our dataset group together near the centre of the morphospace e. Their (e)Dchar ≥ 0.5) stem from the androecium  whereas the least variable characters  describe the perianth .The most variable characters : Mantel test for the perianth (71 631 taxa pairs): p < 0.001; for the androecium (72 390 taxa pairs): p < 0.001; for the gynoecium (70 876 taxa pairs): p < 0.001.Disparity for each of the three modules significantly increases with disparity of the whole character set a–c: Mantp = 0.040; figure 3a,d), the androecium varies marginally more than the rest of the flower , and the gynoecium shows neither less nor more variation than the rest of the flower .The perianth varies significantly less than the rest of the flower The floral morphospace of Ericales is organized in a continuous cloud, where most of the suprafamilial clades occupy distinct neighbouring regions arranged in a mosaic pattern. In other words, each of these lineages evolved towards a distinct combination of floral morphological traits. Our analysis also reveals two contrasting patterns of trait variation. On the one hand, ericalean species from across the order share recurrent combinations of character states: for instance, 75.1% of the 381 sampled species share structurally bisexual flowers with a differentiated perianth, a single whorl of sepals, and a single whorl of five petals . Many of these common traits are likely plesiomorphic and evolutionarily constrained within the order. On the other hand, some floral traits, such as petal union and stamen and integument numbers, are highly variable in Ericales , although they have traditionally been considered stable within major angiosperm clades . These tWithin each suprafamilial clade, our analysis showed that there are two main patterns of space occupation by families. The balsaminoid, styracoid, sarracenioid and ericoid clades are all morphologically homogeneous, with the families overlapping . For instance, the sarracenioids  are all characterized by, e.g. free petals to which stamens are not  attached. The recovery of sarracenioids based on morphology is consistent with their phylogenetic relationships and illustrates a case where floral traits typically have a higher diagnostic value than vegetative traits . In cont(b)In Ericales, the most variable family, Lecythidaceae, is a pantropical family of trees (340 species). The least variable family, Mitrastemonaceae, is a root-parasitic family composed of only one Asian and one Central American species . The positive correlation between disparity and the species richness of families can be explained by the fact that family size is highly variable in Ericales, ranging from two species in Mitrastemonaceae to 4010 in Ericaceae. Although disparity measured as mean pairwise distances is generally robust against differences in group sizes , a groupIn a study on the disparity of Neotropical pollen morphotypes, Mander  found a b), in spite of the fact that it is extremely speciose. Balsaminaceae is composed of two genera: Impatiens (1100 spp.) and Hydrocera (1 sp.). The high taxonomic diversity in Impatiens may result from rapid radiation during the Pliocene and Pleistocene, triggered by climatic fluctuations resulting in refuge areas [Only four ericalean families together  contribute 50% of the Ericales disparity. Some families, like Ericaceae and Pentaphylacaceae, display high partial disparity because they are widely spread in the space; i.e. are themselves highly variable. Alternatively, some families, like Sapotaceae and Balsaminaceae, display high partial disparity because they are distributed in the periphery of the space, i.e. they increase the overall disparity by adding new traits or trait combinations. Such traits are, e.g. two whorls of sepals in Sapotaceae, and distally united filaments, nectar spur and zygomorphic flowers in Balsaminaceae . Zygomorphy and the presence of nectar spurs might explain the peculiar pattern found in Balsaminaceae: the family displays very low morphological disparity in the investigated organizational floral traits b, in spige areas . This rege areas ). Zygomoge areas ,78, and ge areas .a). They are close in age (72–94 Ma) to the Ericales' initial diversification  and thea 104 Ma . The ava(c)Our results indicate that, in Ericales, morphological variation differs considerably among the flowers' three functional modules, probably because of the different selective regimes they are submitted to. The perianth varied significantly less than the rest of the flower, as expected. Contrastingly, the androecium varied marginally more than the rest of the flower, and the gynoecium showed neither less nor more variation than the rest of the flower, although we expected it to show more variation, due to its complex organization.In our dataset, most species are characterized by actinomorphic, whorled, and pentamerous flowers . In Finally, the gynoecium, with its multiple functions and complex morphogenesis, is often considered the most complex module of the flower ,32. All Overall, variability occurs less at the level of floral organization , than at the level of floral construction  and mode (traits like organ shape and colour). Floral mode often directly concerns interactions with pollinators and is generally highly variable, even at low taxonomic ranks ,84. Such


Biosimilars could be a promising option to help decrease healthcare costs and expand access to treatment. There is no previous evidence of a global bibliometric analysis on biosimilars. Therefore, we aimed to assess the quantity and quality of worldwide biosimilars research.We performed a bibliometric analysis using documents about biosimilars published until December 2016 in journals indexed in Scopus. We extracted the annual research, languages, countries, journals, authors, institutions, citation frequency, and the metrics of journals. The data were quantitatively and qualitatively analyzed using Microsoft Excel 2013. Additional information about authors' participation was obtained using the R-package Bibliometrix. Publication activity was adjusted for the countries by population size. Also, author co-citation analysis and a term co-occurrence analysis with the terms included in the title and abstract of publications was presented as network visualization maps using VOSviewer.p < 0.001). The United States was the country with the highest production with 685 (29.40%) documents followed by Germany and UK with 293 (12.58%) and 248 (10.64%), respectively. Switzerland (11.05), Netherlands (5.85) and UK (3.83) showed the highest per capita ratio. The highest citation/article ratio were for the Netherlands (28.06), Spain (24.23), and France (20.11). Gabi Journal published 73 (3.13%) documents; both Biopharm International and Pharmaceutical Technology and Mabs, 41 (1.76%). Three out of top ten journals were Trade publications. Amgen Incorporated from the USA was the most prolific institution with 51 documents followed by Pfizer Inc. with 48. Terms about specific diseases and drugs were found in recent years, compared with terms such as legislation, structure, protein, dose and generic in the early years.A total of 2330 biosimilar-related documents identified in the Scopus database, most of them were articles . The number of documents published had an exponential increased between 2004 and 2016  contains supplementary material, which is available to authorized users. A biosimilar, or “similar biological product”, is a highly similar product to an already approved biological product regarding structure, function, potency, quality, clinical efficacy and safety . CurrentThe development of biological products represented a significant advance in the therapy of many diseases that did not have effective treatments. Nonetheless, these products require a vast expenditure of money and resources to develop, leading to an increase in the cost of these therapies for both patients and the health sector , 6. The Few studies had evaluated the clinical evidence in support of different biosimilars: there are only three cancer related-biosimilars products whose safety/efficacy have been published , while fBibliometric analysis is a useful method to objectively measure current research of a certain subject and its international scientific influence as an aspect of scientific quality . Howeverhttps://www.scopus.com/). While there are a variety of document types, only articles, reviews, editorials and letters were included.We performed a bibliometric analysis using documents published until December 2016 in journals indexed in Scopus  is the largest abstract and citation database of scientific peer-review literature including more than 22,000 titles from international publishers. We decided to use this database because it includes all MEDLINE documents and includes further characteristics such as country of all the authors and citations per document, information that is relevant for this study –17.A literature search was conducted by a research librarian in Scopus for publications on a single day, October 18, 2017, and used the following MeSH and free terms in the title and abstract field: biosimilar pharmaceutical OR biosimilar*. The validity of the search strategy was tested by manually reviewing retrieved articles.All data were collected by two authors and downloaded in csv format . To describe more information about author participation in research production about biosimilars, we use the open-source Bibliometrix R-package (http://www.bibliometrix.org/) to obtain the mean of articles per author, the mean of authors per article, the mean of articles’ citation and the number of articles with only one or more than one author.Bibliometric indicators were extracted from the data and with the option “Analyze Results” in Scopus, including annual research, languages, countries, journals, authors, institutions, and citation frequency. Scopus Journal Metrics was used to extract the metrics of journals. The contributions of countries were evaluated based on paper and citation numbers, and the research output of each country was adjusted according to population size  to analyze the relations among highly cited references and productive authors, and a term co-occurrence analysis with the terms included in the title and abstract of publications was presented as network visualization maps using VOSviewer version 1.6.6  techniques .The data were downloaded from Scopus and as secondary data, did not involve any interactions with human subjects. There were no ethical questions about the data. Approval of an ethics committee was not necessary.p < 0.001). In general, 83 countries contributed to research articles about biosimilars. Table A total number of 2330 documents indexed on Scopus were retrieved from 2004 to 2016. The majority of papers were articles  followed by reviews , editorials , and letters . In 2004, three publications were identified compared to 521 in 2016  documents, followed by Biopharm International and Pharmaceutical Technology and Mabs both with 41 (1.76%). Three out of ten titles were Trade publications. Mabs journal had the greatest SJR 2016 (1.62).The total of documents retrieved were published in 803 journals, but top ten journals account for 18.82% of the total . This could be explained because three biosimilars are available to treat rheumatoid arthritis and others are in the way to approval , and theWords included in the title and abstracts of biosimilars research papers and their main year when they were published were: Legislation (2011), enzyme (2012), structure, protein, dose, antibody, interchangeability (2013), glycosylation, receptor, phase, adverse event (2014), and rheumatoid arthritis, ulcerative colitis, extrapolation, rituximab, etanercept (2015). This suggests that the emphasis of biosimilars research responds to a subject that is very new to researchers and should follow the law of the development of a new discipline. This find is similar to a report in a previous bibliometric analysis on exomes . In the The present research shows an overall view about biosimilars research and their distribution mostly in high-income countries where they have policies to their approval. Although markets like BRICS , MIST  , and LatIn summary, the results of the present study showed that documents published in journals about biosimilars are increasing. The majority of publications came from high-income countries, being the US the most productive country in biosimilars followed by European countries. To the best of our knowledge, this is the first study conducted in the analysis of research production and citations in biosimilars. The trends in terminology use are according to state of the art in the topic that comes from issues of safety and efficacy to the study of new biosimilar products in specific diseases.Additional file 1:Dataset 1: Data obtained from Scopus, a .CSV that contain list of studies included. (CSV 6323 kb)


P > 0.05). However, magnification may be related to the source of heterogeneity (P = 0.0065). Therefore, NBI may be a promising endoscopic tool in the diagnosis of head and neck cancer.Head and neck cancer is difficult to diagnose early. We aimed to estimate the diagnosis value of narrow band imaging(NBI) in head and neck cancers. We identified relevant studies through a search of PubMed, Embase and the Cochrane Library. We used a random effect model. Subgroup analysis and meta-regression analysis were performed to estimate the factors which may influence the sensitivity and specificity of the NBI. We included 25 studies with total 6187 lesions. The pooled sensitivity, specificity, positive likelihood rate, negative likelihood rate and diagnostic odds ratios of NBI were 88.5%, 95.6%, 12.33, 0.11 and 121.26, respectively. The overall area under the curve of SROC was 96.94%. The location, type of assessment, type of endoscope system and high definition were not significant sources of heterogeneity ( According to the globocan 2012, the incidence of head and neck cancer every year is 683235/1000,000, the mortality is 375665/1000,000. And it is the sixth cause of cancer death throughout the world3. Because of the difficulty in early diagnosis, the five-year survival rate of head and neck cancer is lower than other cancers like breast, cervix and colorectal cancers4. Therefore, early diagnosis of head and neck cancer is extremely important.Head and neck cancer include oral cavity and oropharyngeal cancers, nasopharyngeal cancers (NPC), laryngeal and hypopharyngeal cancers, 5. PET/CT identified primary tumors of non-squamous origin that infiltrated the middle or deep submucosal layer, including nonkeratinizing and undifferentiated carcinomas. Small or superficial lesions can easily be missed, because they are too small to take up sufficient FDG for detection on PET, this is the limited resolution of the PET scanner7. Therefore, endoscopy may be the prime method to early diagnose head and neck cancer. Among them, narrow band imaging (NBI) is a novel optical digital method of image-enhanced endoscopy which combined with the electronic laryngoscope. The thin capillary network on the mucosal surface shows as brownish and thick blood vessels show as cyan, on the NBI image. To identify suspicious lesions, especially in the colon, stomach, and esophagus, NBI has been applied as the standard endoscopic examination. Besides there were many meta-analysis studies to evaluate the diagnostic performance of NBI in these cancers15.There are many kinds of methods to detect head and neck cancer, including radiologic examinations and endoscopy. Radiologic examinations include CT, MRI, PET/CT and so on. CT or MRI provides cross sectional imaging, if the tumors are too small, they can’t be visualized by CT or MRI. The time and cost may be also problem for patients. Additionally, CT or MRI may be beneficial in staging laryngeal carcinoma and planning the most appropriate surgical procedure16, to our knowledge, and there was another meta-analysis to assess the diagnostic performance of NBI for second primary lesions in patients with esophageal and head and neck cancer17. Therefore, we aimed to establish the sensitivity, specificity of NBI for differentiation between benign and malignant head and neck lesions.However, there was only one meta-analysis to systematically evaluate the value of NBI in diagnosing head and neck cancerWe included 25 studies with total 6187 lesions. The search process and articles eligible for this meta-analysis are shown in Fig. 42. All included studies were published in English except one which was published in Chinese42. The year of publication of studies ranged from 2008 to 2016. These studies were from 6 different countries, most of them were done in Asia Twenty (80%) studies were prospective, only five (20%) were retrospective. Four (16%) studies were performed with magnification system, other twenty-one (84%) studies were without magnification. And eight (32%) studies were assessed with high definition system, twenty (80%) studies were without it, three (12%) studies consisted of both high definition and no high definition. Six studies (24%) were done with Exera series endoscopy systems, three (12%) with Lucera spectrum endoscopy systems, and sixteen (64%) with unknown systems. Sensitivity for differentiation of lesions in all studies varied from 43.2% to 100%, and specificity from 74.5% to 100%. The numbers of patients and lesions, mean age the ratio of male and female, the numbers of pathologists and endoscopists also can be seen in the Table The characteristics of the 25 included studies are summarized in Table 1P > 0.05). However, magnification may be related to the source of heterogeneity, diagnostic accuracy of NBI with magnification was 0.1 times higher than NBI without magnification .Analyzed by meta-regression, the location, type of assessment, type of endoscope system and high definition were not significant sources of heterogeneity . The overall area under the curve (AUC) of SROC was 96.94%, Q statistic was 91.98%. .A total of 6187 lesions were detected. The pooled sensitivity and specificity of NBI were 88.5% . The specificity in head and neck cancers, nasopharyngeal carcinoma were higher than in oral and oropharyngeal cancers, laryngeal and hypopharyngeal cancers (97.5% and 97.4% vs 92.0% and 91.5%). Besides, the PLR of NBI in head and neck cancers, nasopharyngeal carcinoma were higher than in oral and oropharyngeal cancers, laryngeal and hypopharyngeal cancers. The NLR in head and neck cancers, nasopharyngeal carcinoma were lower than in oral and oropharyngeal cancers, laryngeal and hypopharyngeal cancers. The DOR and SROC also can be seen in Table A total of 5073 lesions with real-time assessment and 1114 lesions with post-procedure were detected in retrospective assessment. The sensitivity with real-time was lower than post-procedure (81.5% vs 91.7%). The specificity was higher in real-time (96.4% vs 91.9%). The PLR of NBI in real time was higher than in post-procedure. The NLR, DOR and SROC also can be seen in Table A total of 482 lesions with magnification and 5705 lesions without magnification were detected. The sensitivity and specificity with magnification were both lower than without magnification . The PLR of NBI with magnification was lower than without magnification. The NLR, DOR and SROC also can be seen in Table Three studies used both high definition technology and no high definition technology. A total of 1627 lesions with high definition and 5446 lesions without high definition were detected. The sensitivity with high definition was higher than without high definition (91.6% vs 88.6%). However, the specificity with high definition was lower than without high definition (93.8% vs 96.3%). The NLR of NBI with high definition was lower than without high definition. The PLR, DOR and SROC also can be seen in Table A total of 282 lesions were detected by the type of Lucera and 950 lesions were detected by the type of Exera. The sensitivity in Lucera system was higher than in Exera system (92.5% vs 85.5%). However, the specificity in Lucera system was lower than in Exera (90.6% vs 92.8%). The NLR of NBI in Lucera was lower than in Exera. The PLR, DOR and SROC also can be seen in Table P = 0.447), representing no striking publication bias.Based on QUADAS, the quality assessment of included studies is presented in the Supplementary Table P > 0.05). However, diagnostic accuracy of NBI was different in magnification (P = 0.0065).We analyzed the overall diagnostic accuracy of NBI, and found that NBI could be a considerable tool for differentiating benign and malignant lesions in head and neck cancer . Additionally, we found that diagnostic accuracy of NBI was similar in the location, type of assessment, type of endoscope system and high definition  showed high diagnostic accuracies for primary, recurrent, and nasopharyngeal lesions16. This article only included 17 studies and emphasized more on the identification of primary tumors, recurrent tumors, cancers of unknown primary(CUP), and nasopharyngeal tumors. This meta-analysis included 25 studies with 6187 lesions. Meanwhile, we paid more attention on the locations of lesions and the methods of using NBI. In addition, one previous study showed that the sensitivity of NBI in detecting second primary neoplasm of head and neck cancer in patients with esophagus cancer was 87%17, similar with the sensitivity in this study. However the previous meta-analysis included only 3 studies to evaluate diagnostic performance of NBI for detecting head and neck cancer.To the best of our knowledge, Cosway, B. et al.13, but there is rare study to explore the diagnostic value of NBI in the head and neck cancer17. Meanwhile, the difficulty of observing lesions of different locations in head and neck is different, thus the diagnostic accuracy may be also different. However, in this study, we didn’t find the difference. The sensitivity and specificity were both high. Additionally, the PLR of NBI were all more than 10 and the NLR were all less than 0.1 except in oral and oropharynx. Besides, the AUC of SROC were all more than 90%. The results indicated that NBI is a considerable tool to differentiate between benign and malignant lesions in head and neck cancer.There are many studies investigating the performance of NBI in colon, gastric and esophagus cancer, in-vivo optical diagnosis. However, real time assessment sometimes can not acquire the timely histological examinations. Thus, we analyzed the type of assessment to investigate the difference. The PLR and AUC of NBI in real time were higher than in post-procedure. However, we didn’t find the difference, which was consistent with the results of the previous study8. The small number of included studies may lead to this result. Therefore, a meta-analysis including more studies is needed to explain the reason.The type of included studies were RCT, prospective and retrospective, and we considered RCT and prospective as real time, the retrospective as post-procedure. Real-time assessment is the optimum selection to evaluate performance, because it avoids bias of photographic selection and performs an 44. This meta-analysis showed that NBI with magnification had a lower specificity (79.6%) than NBI without magnification (96.4%). Besides, the PLR and AUC of NBI with magnification were lower than without magnification. The results were not consistent with the previous study which indicated no significant difference between NBI with or without magnification46. This may because that the number of included studies of with or without magnification is extremely different. Additionally, the location is also different between this study which is in the head and neck and the previous studies which are in esophagus, stomach or colon. There are more polyps in stomach or colon cancer, while there is more squamous cell carcinoma in head and neck cancer. One study reported that high definition endoscopy could improve the detection and diagnosis of early gastric cancer47. However, this study showed that there was no difference between NBI with or without high definition. This is consistent with the previous study48. It may be related to the small number of studies including NBI with high definition. One previous study found that high definition significantly decreased the performance of NBI12. This previous study reported that this may because of the lack of experiences of endoscopists. More studies need be performed to explore the accuracy of NBI with or without high definition.With the development of optical technology, NBI can detect lesions with magnification or high definition system. Thus, this may influence the sensitivity and specificity of NBI. The utility of NBI is enhanced when it is employed with a magnifying endoscope49. This indicated that the LUCERA and EXERA series provided the same clinical benefit in detecting head and neck cancer.Different types of endoscope system may have different performance. The NBI technique developed by Olympus Medical Systems is now available in the most recent models of video-endoscopes that use the non-sequential system of illumination (Lucera Spectrum) or the sequential R/G/B system of illumination (Exera II). The two systems use different technology and improvements over time in the successive versions series endoscopes. Result in this study didn’t show the difference between the two systems, which is consistent with the previous studyet al.37. Additionally, some studies used visualize intrapapillary capillary loops (IPCLs) pattern and a color change in the area between IPCLs. Several different classification systems used in the included studies also can reduce the generalizability of the overall performance. Because of the limitation of the numbers, we didn’t analyze this factor. Third, some studies included patients after treatment, while some studies included patients without treatment. This may influence the morphology of lesions, and influence the diagnosis Fourth, the heterogeneity of this study was relatively high. We showed that the NBI with or without magnification was the possible source. However, the time of detecting, the lesion size, the sample size, the pathological type and the bias of selection of patients can also reduce the generalizability of the overall performance and increase the heterogeneity of this study. Finally, our study only included studies written by English or Chinese.There were several limitations in this study. First, we didn’t know exactly the standard of experts and non-experts. In some studies, experts were experienced persons, and in other studies, experts were got trained persons, and another studies had no clear explanation of expert. Uneven standard greatly reduced the generalizability. Second, the diagnostic criteria were different. In some studies, they regarded a well-demarcated brownish area with scattered brown spots as susceptible lesions. Some studies used Ni’s classification, the classification of the microvascular endoscopic patterns of Ni, P > 0.05). The NBI with magnification should have better diagnosis accuracy. However, our article was not consistent with the hypothesis. More articles are needed to estimate the diagnosis value of NBI. Moreover, further studies should be focused on the diagnostic criteria, whether real-time and whether training will help improve the diagnostic performance of narrow band imaging.In conclusion, narrow band imaging could be used by appropriately trained endoscopists to make a reliable optical diagnosis for head and neck lesions in daily practice. The location, type of assessment, type of endoscope system and high definition were not significant sources of heterogeneity  guidelinesStudies were in English or Chinese.Studies included populations who were suspected to have oral cancers, oropharyngeal cancers, nasopharyngeal cancers, hypopharyngeal cancers, laryngeal cancers or head and neck cancers.Studies investigated detection of narrow band imaging.Studies took pathology as gold standard.Studies provided data of true-positive (TP), false-positive (FP), true-negative (TN), and false-negative (FN); or reported data of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and numbers of patients or lesions.Studies were prospective, randomized controlled trails (RCTs) or retrospective.In accordance with PICOS , the inclusion criteria were as follows:The abstracts were also included when they contained available data.Studies were in other languages.Studies focused on other lesions, such as oral leukoplakia, ulcers.Studies didn’t use narrow band imaging or had no pathological results.Studies did not have available data.Studies were other research types, such as reviews, case reports, letters.The exclusion criteria were as follows:Two authors independently extracted the following data: the name of first author, year of publication, country, publication (full text or abstract), number of patients, number of lesions, patients’ characteristics , characteristics of narrow band imaging , endoscopists, pathologists, outcome data , and study design . Extracted data were imported to a standard Excel (Microsoft Office). If there were any disagreements, the two authors would discuss and reach a consensus.3. Each of the 14 items included in the original QUADAS tool is rated as “yes”, “no”, or “unclear”, with “yes” representing a positive outcome. The majority of the items  is related to bias, with only two items related to variability (items 1 and 2) and the quality of reporting , respectively1. Two independent authors performed and crosschecked the quality assessment.We used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool to assess risk of bias, applicability and reporting quality51. Besides, the summary receiver operating characteristic (SROC) curve was constructed as described by Moses et al.18 to show the results. The areas under the curve (AUC) were calculated to assess the diagnostic accuracy of NBI for the benign and malignant tumors.We estimated the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic OR with corresponding 95%CI by a fixed effect model (Mantel-Haenszel method) when homogeneity was fine or a random effect model (DerSimonian-Laird method) when heterogeneity was significant, to indicate the accuracy of NBI in the diagnosis of benign and malignant tumors2) to manifest the percentage variability attributable to heterogeneity. If the I2 value >50%, it demonstrates substantial heterogeneity. To investigate the potential sources, we performed subgroup analysis and meta-regression analysis to assess the effects of different locations, type of assessment , magnification, high definition, and type of endoscope system.We calculated Spearman correlation coefficient to analyze diagnostic threshold. If there was no threshold effect, we pooled these sample statistics directly. If there was threshold effect, we employed fit SROC curve and calculated the AUC and Q statistic. Besides, we used the inconsistency index (Ip > 0.05 representing no significant publication bias52. All statistical analysis were performed by using Meta-DiSc statistical software version 1.4 and STATA version 12.0.Publication bias was assessed by Deeks’ funnel plot asymmetry test, with All the data we get was from public sources.Supplementary Information


P = 0.015 and P<0.001). And the concentration of hemoglobin (HB) was significant lower in bone metastatic patients compared with non bone metastatic patients (P = 0.009). Multivariate logistic regression analysis indicated that ALP, HB and calcium were independent risk factors for bone metastases in patients with BC. The cut off values of ALP, HB and calcium were 116 U/L, 37.5g/L and 2.54 mmol/L according to the receiver operating characteristic (ROC) curves analysis. And combined ALP, HB with calcium had the highest diagnostic accuracy for predicting bone metastases in BC patients . Therefore, for newly diagnosed patients with BC, the concentrations of ALP >116 U/L, HB <37.5 g/Land calcium >2.54 mmol/L were the risk factors for developing bone metastases. Combined ALP, HB with calcium was more useful to diagnose the bone metastases.Early detection of bone metastases is helpful for the treatment of bladder cancer (BC). In this study, we investigated the potential risk factors for bone metastasis in newly diagnosed patients with BC. A total of 902 patients diagnosed with BC between January 2000 and August 2016 were retrospectively reviewed. Of these patient, 50 (5.5%) were identified with bone metastasis. The serum levels of alkaline phosphatase (ALP) and calcium were significantly higher in patients with bone metastases than those without bone metastases ( Bone is a relatively frequent site of symptomatic metastasis in patients with solid tumors, such as lung, prostate, breast and renal cancers , but notDiagnosis of patients with bone metastases primarily relies on imaging study. And bone scintigraphy is routinely used for the detection of bone metastases. However, it lacks specificity on detection of skeletal lesions, and the value of bone scintigraphy for detecting cancer progression was questionable on the basis of cost-effectiveness .Since routinely used tumor markers in BC can’t accurately predict the risk of metastasizing to bone , other rThe present study was performed to investigate the correlation between clinical parameters and bone metastases in patients with BC, and to identify the independent risk factors for detecting bone metastases.This study was approved by the ethics committee of the First Affiliated Hospital of Nanchang University, and informed consents were harvested from all patients. A retrospective study, including 1229 patients with BC admitted to our hospital between January 2000 and September 2016, was carried out. For the diagnosis, the confirmation as primary BC was based on the histopathologic analysis of specimens. Bone metastases were diagnosed by bone scan. If necessary, local computed tomography (CT) scan and magnetic resonance imaging (MRI) would be used to make sure of the diagnosis. Patients who presented with a history of bone metabolic disorders, significant hematologic disorders, hyperparathyroidism, severe liver and/or renal insufficiency, and other malignant tumors were excluded from this study. In addition, patients who had other distant metastases, such as liver and lung, were not included in the study.Patients’ demographics and clinical-pathological parameters, including age at diagnosis of the primary tumor, gender, histopathologic types, laboratory findings, such as alkaline phosphate (ALP), hemoglobin (HB) and serum calcium levels were retrospectively reviewed. The biomarkers were measured in sera obtained from peripheral venous blood. The measurement of serum ALP is total ALP and serum calcium is ionized calcium in this study. All the measurement was conducted by the Department of Nuclear Medicine of the hospital. All of the data were collected at the time of patients firstly diagnosis at our hospital before giving any treatment. The concentrations of ALP, HB and calcium were measured in serum samples from patients with BC.Chi-square test. Quantitative variables were reported as means ± standard deviation and analyzed by Student’s t test. Multivariate logistic regression model was used to identify the independent risk factors for bone metastasis in BC. Receiver operating characteristic (ROC) curve was used to assess the predictive power of risk factors for bone metastases. Statistical significance was set as P value less than 0.05.All analysis was performed by SPSS Version 22 (SPSS Inc. Chicago IL). Qualitative variables were expressed as numbers and percentages, and were analyzed by the Table 1showed the demographics of patients with BC. Of these patients, 81.6% were males and 18.4% were females. The majority of histopathologic types were transitional cell carcinoma, which accounts for 91.2% (823 cases) of the patients. A total of 50 cases (5.5%) developed bone metastases in this group, and 82% (41 cases) of them were males. Of the 50 patients with bone metastases, 31 (62%) were osteolytic lesion, 14 (28%) were osteoblastic lesion and 5 (10%) were mixed bone lesion.A total of 902 patients were included in this study and 327 patients were excluded according to the inclusion and exclusion criteria. Table 2).For the patients with bone metastases, the most commonly affected sites were the pelvis (68%), followed by the spine  and ribs (24%). The humerus was the least metastatic sites in these patients . Also, no statistical differences were noted for the biomarkers of AFP, CEA, CA125, CA153, CA199 and CA724 between the two groups . However, the serum concentrations of ALP and calcium were significantly higher in patients with bone metastases compared to those without bone lesions (P = 0.015 and P<0.001). And the HB level was significantly lower in bone metastatic patients than those in non bone metastatic patients (P = 0.009) (Table 3). Multivariate logistic regression analysis indicated that ALP , HB  and calcium  were the independent risk factors correlated with bone metastases in patients with BC (Table 4).Based on the analysis, there were no statistically significant differences on age, gender and histopathologic type between BC patients with and without bone metastasis  = 0.691, P<0.001], with a sensitivity of 38% and specificity of 92.7%. The cut-off values of ALP, HB and calcium were 116U/L, 37.5g/L and 2.535mmol/L, respectively (Table 5). In order to identify the accuracy of combined factors for diagnosing bone metastases, we analyzed the ROC curves for different combinations of risk factors. The results indicated that combined ALP, HB with calcium had the highest diagnostic accuracy for predicting bone metastases in BC  .Bone metastasis is a common feature of advanced genitourinary malignancies and a prominent cause of morbidity and mortality. Clinical manifestations of bone metastasis include pain, pathologic fractures and spinal cord compression , which wFor the rate of bone metastases from BC, previous study reported that 4–14.5% of patients with BC developed bone metastases , 11. In Based on the analysis of this study, high concentrations of ALP and calcium, and low HB level were found to be the independent risk factors for predicting bone metastases in patients with BC. ALP is synthesized in the liver and osteoblasts, and has been used as a specific biomarker for liver and bone. Previous studies revealed that ALP was a biomarker for the presence of bone metastases before their appearance on the bone scintigraphy , 12, 13.Kawai et al  revealedFor human body, the majority of calcium is stored in bone, and the concentration of it is under strictly hormonal regulation at the level of resorption in the kidney, mobilization from the skeleton and intestinal absorption . Study sIn the present study, we also analyzed the diagnostic accuracy of combined risk factors for predicting bone metastases in patient with BC. Compared to the single factor of ALP, HB and calcium, combined ALP, HB with calcium had a higher accuracy for predicting bone metastases in BC. It suggested that combination of risk factors appeared to be more accurate for predicting bone metastasis and may provide important information for patients with BC.Although the results of this study were interesting, there were still some limitations in it. First of all, this is a retrospective study and we just collected the data at the time of primary diagnosis. Some follow-uped information, such as time to bone metastasis and survival duration, were insufficient and not reported in this study. Second, the study was conducted in a single medical center with a relative small sample, which may not present the characteristics of the whole population with BC. Also, we were failed to perform the analysis based on tumor categories. Third, most of the patients didn’t report the stage of tumor due to the retrospective methodology. And we couldn’t make clear of the risk factors for bone metastases according to the tumor stage. Fourth, the sensitivities and specificities of these risk factors for predicting bone metastases in BC were not high. Further study with large sample and multi-center investigation is necessary to make sure the efficacy of these risk factors for predicting bone metastases in BC.In conclusion, based on a large population analysis, the present study suggested that the serum concentrations of ALP, HB and calcium were independent risk factors for bone metastases in patients with BC. For newly diagnosed patients, the values of ALP >116U/L, HB <37.5g/L and calcium >2.535mmol/L could be used as additional factors for determining the risk of developing bone metastases. And combined ALP, HB with calcium had the highest diagnostic accuracy for predicting bone metastases. However, the validation of these factors in clinical practice need further study to confirm.S1 File(XLSX)Click here for additional data file.


Insulin resistance is characterized by the failure of target cells to respond to normal levels of circulating insulin, and this condition is related to cardiovascular disease. This study sought to evaluate the prevalence of insulin resistance and its association with markers of metabolic abnormalities and metabolic syndrome in bank employees.A cross-sectional study was performed on 498 working men and women aged ≥20 years old. The Homeostasis Model Assessment (HOMA-IR) was used to determine the presence of insulin resistance based on cut-off values of ≤2.71 for normal insulin levels and >2.71 for insulin resistance, as established for the adult Brazilian population.p=0.001), respectively. The levels of insulin, ultrasensitive C-reactive protein and uric acid were also associated with insulin resistance.It was observed that the 52 (10.4%) overweight individuals with insulin resistance were 4.97 times (95%CI 1.31-18.83) more likely to have high HOMA-IR values than the normal-weight participants; among those who were obese, the likelihood increased to 17.87 (95%CI 4.36-73.21). Individuals with large waist circumferences were 3.27 times (95%CI 1.03-10.38) more likely to develop insulin resistance than those who were within normal parameters. The HOMA-IR values differed between subjects with and without metabolic syndrome, with values of 2.83±2.5 and 1.10±0.81 (The prevalence of insulin resistance among bank employees is high, and insulin resistance is associated with and serves as a marker of metabolic syndrome. Cardiovascular disease and metabolic syndrome-associated metabolic abnormalities were observed, and insulin resistance may be a risk factor in this group of professionals. Insulin resistance (IR) is characterized by the failure of target cells, including adipose, pancreas, skeletal muscle and liver tissues, to respond to normal levels of circulating insulin. IR occurs because of genetic, nutritional and metabolic disorders The metabolic disorders that occur in IR are involved in the pathogenesis of type 2 diabetes mellitus (type 2 DM), and when associated with dyslipidaemia, obesity and hypertension (AH), these conditions constitute metabolic syndrome (MS) MS has been the subject of increasing concern worldwide because it is related to an increased risk of cardiovascular disease (CVD) Classically, the gold standard for measuring IR is the euglycaemic hyperinsulinaemic clamp; however, its use in large populations is limited because it is invasive, costly and complex As IR is a multifactorial condition that includes an increase in inflammatory markers, changes in lipid metabolism and changes in the intestinal microbiota, which are all interconnected to different degrees, early identification of this metabolic change presents the possibility of disease prevention and improved quality of life Bank employees are a group of workers with high occupational stress This study aimed to assess the prevalence of IR and its association with markers of metabolic abnormalities and MS in bank employees.This study was approved by the Research Ethics Committee (number 059/08) of the Centre for Health Sciences, Federal University of Espírito Santo, and written informed consent was obtained from all participants.We conducted an observational cross-sectional study of employees, aged 20 to 64 years old, at a state-owned banking network located in southeastern Brazil. Data were collected from August 2008 to August 2009.The sample size was calculated to estimate the prevalence of MS in a population of 1,410 bank employees. We used simple random sampling for a prevalence of 20% with a 3% error and a significance level of 95%. The 1.5 design effect was considered to offset the correlations among individuals at the same agency. Quotas were established for the type of work , sex and age. Therefore, the minimum sample size was 461 bank employees. Because of a possible low response rate, 525 bank employees were invited to participate. Data collection was performed at the workplace, and the employee was relieved of his or her duties during data collection. Socioeconomic status was determined according to the Brazilian Economic Classification. Ethnicity was determined by self-classification as black, brown, white, yellow or indigenous, according to the Brazilian Institute of Geography and Statistics ethnicity categories.OMRON Healthcare Inc., Shanghai, People's Republic of China), which was calibrated and validated by the National Institute of Metrology, Quality and Technology (Inmetro), was used. The individual's blood pressure levels were measured according to the criteria of the VII Joint National Committee Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured three times during the interview for each participant, and the first measurement was discarded. Blood pressure was measured an additional time if the difference between readings was higher than 4 mmHg. For the blood pressure measurement, the OMRON 742 digital® (2) as recommended by the World Health Organization 2): underweight, BMI<18; normal, ≥18.5 and <25; pre-obese, ≥25 and <30; and obese ≥30. The types of obesity, including grades I to III, were pooled in the analysis so that the group could be more representative. Waist measurements were obtained using a metal tape measure. To measure the waist circumference (WC), the tape measure was placed at the midpoint between the last rib and iliac crest. WC measurements were also classified according to the WHO All anthropometric measurements were taken by trained researchers. Body weight was obtained using a Tanita® electronic scale that was accurate to 0.1 kg , and the individual was asked to be weighed with an empty bladder and wearing only underwear. Height was measured in metres using the Sanny® stadiometer, which was accurate to 0.1 cm , while the subjects were barefoot and standing with their arms along their bodies and eyes fixed on a spot on the horizon. Body mass index was calculated , high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), very-low-density lipoprotein cholesterol (VLDL-c), triglycerides, uric acid, ultrasensitive CRP (us-CRP) and insulin. The insulin levels were determined using chemiluminescence with a COBAS E601 machine . The concentration of LDL-c was calculated using the Friedewald formula The presence of MS was classified according to the National Cholesterol Education Program's Adult Treatment Panel III IR quantification was assessed using the HOMA-IR index calculated according to the formula developed by Matthews et al. 2). The level of significance for all tests was set at 5%. After the bivariate analysis, logistic regression analysis was performed using the presence of MS as a dependent variable, according to the NCEP-ATP III. The crude and adjusted odds ratios (ORs) of the variables that entered the logistic regression model were calculated. All variables with p<0.20 in the bivariate analysis were included in the regression model. In the final model, only the variables with p<0.05 are shown.Statistical analyses were conducted using SPSS for Windows, version 15.0 . The mean values were compared using the Student's t-test for independent samples. When the normality was not verified by the Kolmogorov-Smirnov test, we performed the nonparametric Mann-Whitney test. To analyse differences in proportions, we used the chi-square test (XOf the subjects in this study (n=498), 52 (10.4%) presented with IR according to the HOMA-IR index. Of these, most were in the 41-50-year age group, belonged to classes B and C, completed or were enrolled in third grade, were white and were married.p=0.028), BMI (p=0.001), WC (p=0.001) and BP (p=0.001).Biochemical, anthropometric and haemodynamic markers in individuals with and without IR are shown in Regarding the relationship between the HOMA-IR value and the presence or absence of conditions related to MS among bank employees, according to the NCEP-ATP III criteria, we observed values of 83±2.5 for subjects with MS and 1.10±0.81 (p=0.001) for those without MS. The index was significantly higher among subjects with low HDL-c , elevated blood pressure , abdominal obesity , high triglycerides  and increased glucose levels  for both measurement systems.IR is closely related to cardiovascular risk factors In recent decades, there have been profound changes in work processes, particularly at banks, which were the subject of this study. Among these changes, corporations, mergers, privatization and outsourcing have led to a sharp reduction in the market for banking, which has led to job elimination, agency overlap, management restructuring, job mergers, and the intensive use of information technology Therefore, the organizational changes in the banking field have resulted in the accumulation of physical and cognitive overload, unemployment, precariousness in labour relations, and illness. These factors have led to a substantial increase in the risk of acute and chronic disorders of the cardiovascular system in this population, including IR, DM, MS and other cardiovascular diseases Regarding the presence of these risk factors in the study population, IR was present in 52 (10.4%) individuals, a proportion lower than that identified in rural populations The present study showed an association between BMI and WC with IR; there was also a high number of bank employees who were overweight or obese. Obesity is consistently associated with a set of metabolic diseases, including hypertension, atherosclerosis, dyslipidaemia, and type 2 DM, which commonly occur with MS Both weight gain and the distribution of body fat seem to greatly influence the abnormalities associated with obesity, IR and the glucose and lipid profiles; in particular, free fatty acids and their metabolites are more commonly detected in individuals who have central obesity In addition to the excess body fat identified in the present study, there was an association between blood pressure and IR. Insulin promotes renal sodium reabsorption, and hyperinsulinaemia is expected to exacerbate that action. In the IR state, this retention effect is maintained in the kidneys, and insulin sensitivity of the proximal tubular cells is preserved. Comparisons of subjects with and without MS have shown that patients with MS have significantly increased proximal sodium reabsorption When comparing subjects with and without MS, which does not require a direct measurement of IR, the HOMA-IR values were significantly higher among individuals with MS, which has also been reported by other authors In addition to the diagnostic criteria for MS, other metabolic biomarkers that were altered in the study population, such as uric acid and us-CRP, were associated with IR and MS. Similar results were previously found for uric acid Uric acid and high us-CRP are risk factors for the onset of type 2 DM and obesity Self-reported health conditions are not merely impressions related to actual health, and studies in this field in Brazil have verified the high reliability and validity of such reports There are limitations to this study associated with the cross-sectional model, which may interfere with causal evaluations; however, there was sufficient information to observe associations and ORs for the data. The euglycaemic clamp method is considered the most reliable method for assessing IR; however, because it is expensive and invasive, we used the HOMA-IR as a simple, minimally invasive and inexpensive method that has been demonstrated as a useful tool for epidemiological studies The main strength of this study was the identification of the prevalence of IR in bank clerks, who share similar challenges and occupational hazards with millions of other workers because the service sector employs approximately 70% of the country's workforce. Epidemiological studies involving insulin dosing and HOMA-IR calculation are rare and costly; therefore, such studies may advance knowledge in this area.Our results show that the prevalence of IR among bank employees is high and that IR is associated with MS. CVD- and MS-associated metabolic abnormalities were also observed, which suggests that IR may serve as a risk factor in this group of professionals because IR precedes the development of type 2 DM and other metabolic changes. Considering the overall health status of these workers, our findings support the need to improve health promotion in banking workplaces, and the results may offer a significant contribution to occupational health.Salaroli LB participated in the study and product design, data acquisition, analysis and interpretation of the data, and drafting and revising of the manuscript. Cattafesta M participated in the article design, data acquisition, analysis and interpretation of the data, and drafting and revising of the manuscript. Molina MC participated in the data acquisition, data interpretation, and drafting and revising of the manuscript. Zandonade E participated in the analysis and interpretation of the data and drafting and revising of the manuscript. Bissoli NS participated in the study and product design, data acquisition, analysis and interpretation of the data, and drafting and revising of the manuscript.


Electronic Healthcare Records (EHRs) are created to capture summaries of care and contact made to healthcare services. EHRs offer a means to analyse admissions to hospitals for epidemiological research. In the United Kingdom (UK), England, Scotland and Wales maintain separate data stores, which are administered and managed exclusively by devolved Government. This independence results in harmonisation challenges, not least lack of uniformity, making it difficult to evaluate care, diagnoses and treatment across the UK. To overcome this lack of uniformity, it is important to develop methods to integrate EHRs to provide a multi-nation dataset of health.To develop and describe a method which integrates the EHRs of Armed Forces personnel in England, Scotland and Wales based on variable commonality to produce a multi-nation dataset of secondary health care.An Armed Forces cohort was used to extract and integrate three EHR datasets, using commonality as the linkage point. This was achieved by evaluating and combining variables which shared the same characteristics. EHRs representing Accident and Emergency (A&E), Admitted Patient Care (APC) and Outpatient care were combined to create a patient-level history spanning three nations. Patient-level EHRs were examined to ascertain admission differences, common diagnoses and record completeness.Unknown/unspecified cause of morbidity”. In addition, A&E records were sporadically coded; we found five coding systems for identifying reason for admission.A total of 6,336 Armed Forces personnel were matched, of which 5,460 personnel had 7,510 A&E visits, 9,316 APC episodes and 45,005 Outpatient appointments. We observed full completeness for diagnoses in APC, whereas Outpatient admissions were sparsely coded; with 88% of diagnoses coded as “currently suited to epidemiological research. However, only small changes may be needed to take advantage of what should be a highly cost-effective means of delivering important research for the benefit of the NHS.At present, EHRs are designed to monitor the cost of treatment, enable administrative oversight, and are not  Standare.g. unique ID number for each citizen) across public services such as welfare, housing, education and health [There are multiple challenges in integrating EHRs in the UK. Firstly, there is no system or framework which uniquely identifies a person  and outcomes [Current research efforts have been directed towards modelling and predicting single conditions  they frequently move/relocate, so it is important to capture EHRs from across the nations and 2) they may have different health needs due to being exposed to a high level of physical and mental strain. This study used the KCMHR cohort, which is a longitudinal cohort of the UK Armed Forces (full details of the methods and sample description were previously reported in ), to dev2.2e.g. similar in content and type) between data providers were requested. Where available, data was requested for the financial years 2003/04 to 2013/14 or closest available.EHRs are managed by NHS Digital in England , Secure 2.3e.g. first name, last name); to enable identification the authors supplied a unique identifier to represent each participant. For clarity, the extraction process is described hereafter, data extraction had no impact on the creation of the framework or integrated datasets.Data extraction was performed independently of the authors through the data providers to preserve privacy. Providers were supplied a set of demographic variables; 10-digit NHS number (where available), first name, middle name, surname, gender and date of birth (DOB). When providing extracted data, providers removed all demographic identifiers  EHR data. Valid NHS numbers were mapped with an internal identifier, the HES ID. EHRs were extracted if any of the following conditions were met: (1) match on NHS number, gender and DOB; (2) match on NHS number, partial match for gender or DOB; (3) match on NHS number only.SAIL operated a two-stage extraction process to preserve privacy. First, demographic variables were supplied by the Data Provider to NHS Wales Informatics Service  where thISD did not require a NHS/CHI number for matching. Participant demographics were cross-matched using probabilistic linking to identify a) valid NHS/CHI number; b) to confirm the NHS/CHI number is valid. EHRs which belonged to a valid CHI number were identified and extracted.Data from each provider was supplied in financial year using a comma separate file format.2.4e.g. method of admission). Discussions were held within the research team to discuss variable categorisation, matching and development of coding schemes.The datasets contain many variables ; howeverNHS Digital (HES datasets), the largest data provider of EHRs in the UK, was selected as the anchor for comparison to other datasets.individually for each data provider; A&E, APC and Outpatient variables were grouped using the categories defined in e.g. admission date, discharge date, diagnoses and treatment). Finally, variables that were similar in nature were identified and a common coding scheme was developed to reflect coding schemes used by data providers  with the objective of having a single coding scheme. Supplement 1 outlines variables linked for each dataset and data provider.Variable commonality was undertaken in three stages. First, Admitted Patient Care EHRs across the data providers, include details of the patient, when they were treated, where they were treated and what they were treated for. As illustrated in Outpatient appointments were recorded across the data providers, including appointment date, appointment treatment, care provider and outcomes. Variables differed widely across the data providers due to service provision and method of recording the visit. Variables identified for joining included appointment date, status of appointment attendance, diagnosis and speciality. For variables such as attendance type and appointment source, a common coding scheme was developed bringing together individual nation coding schemes. Codes which were ambiguous (without a suitable definition) or not an identical match were retained separately. Diagnoses, interventions and procedures were coded using ICD-10 and OPCS across the data providers.Accident and Emergency attendance was recorded differently across the data providers, and for NHS Digital HES data were different between hospital trusts. Variables such as admission date, treatment time, conclusion time and discharge time/location were linked based on commonality. Major differences were observed when coding the reason for the visit to A&E; unlike APC, which utilises the ICD-10 coding system across the combined dataset, A&E does not use a national standard. For example, within England, care providers utilise a local coding system, ICD-10 coding or a NHS England coding standard [standard .2.5First, Continuous Inpatient spells were computed for APC in HES, ISD and SAIL separately. A Continuous Inpatient spell is considered as a continuous period of care within the NHS, regardless of any transfers between care providers that may take place [e.g. A&E, Outpatient) as a patient can have multiple episodes of care relating to a single admission into hospital. Second, admission and discharge date  were checked to ensure consistency and that a valid date was present. Third, duplicate records  relating to the same period of care or admission were identified and excluded. Fourth, EHR  for the same individual were brought together within HES, SAIL and ISD to create a personal admission history for England, Wales and Scotland respectively using the unique identifier. Finally, admission history across the nations was merged to the KCMHR Armed Forces cohort to create a patient-level history for A&E, APC and Outpatient care.A patient-level EHR dataset was constructed using a five-stage integration process. ke place ; it can 2.6•Linkage rate overall and by nation were computed using record matching information supplied by national data providers. The analyses were undertaken using those who gave consent for their medical records to be accessed . Results were presented as frequency and percentage values. Students’ t-test was performed to identify significance in the matching.•Departmental utilisation was calculated based on the number of visits a patient made to the department. Gender frequencies and percentages were computed to provide a breakdown of departmental admissions.•Common conditions were calculated by summing the number of events for each 3-digit ICD-10 code and represented as a frequency. Gender frequencies and percentages were computed for each common condition.•The total numbers of hospital visits were calculated by summing the number of events per participant matched for each department. The frequency, median and inter-quartile range (IQR) were computed at the patient-level as the data was not normally distributed.•Variable completeness was calculated as the number of valid variable entries compared to missing or null entries . Valid variable entries were represented by records which have a value which is not null or missing. Results were presented as percentages.This work compared the matched sample  with the non-matched sample  to assess differences on a range of demographic factors. Analyses including median and frequencies were computed in Stata 12 . In addiIt should be noted that the unit of analysis is the patient, rather than hospital, geographical region or nation.33.1The completeness of demographic variables, which may impact data extraction, contained within the KCMHR Armed Forces cohort is presented in 3.2The highest proportion of hospital visits recorded for England was 5,221 participants compared to Scotland with 1,233 participants or Wales with 699 participants . The ove3.3A total of 3,192 participants had 7,510 admissions to A&E  males and 379 (11.87%) females). 253 variables were available for linkage, we derived 102 common variables. Out of the admissions to A&E, 90.32% were discharged or transferred to a ward on the day of admission, with 9.62% spending at least 24 h within A&E. There were five methods identified for recording reason for an admission; for England: ICD-10, local coding and regional coding schemes, Wales: ICD-10 and regional coding schemes, finally Scotland: ICD-10 and free-text input. The most common mode of attendance was self-presentation (75.50%) followed-by road ambulance (7.49%) and then hospital transfer (6.52%).Variable completeness of the original data providers , measure3.4A total of 3,324 participants had 9,316 episodes, 2,842 were male (85.50%) and 482 were female (14.50%); 416 variables were present from the nations, with 89 common variables identified to represent a single episode. Overall, variable completeness across the derived dataset, in terms of a value being present was 78.06% . All epiZ51 representing “Other medical care” was the most common (Outcome of Delivery” which relates to child birth); this is not unexpected, as the cohort is largely male. The most common source of an admission was the residential home of the patient (90.07%) and other NHS hospitals was the second most common source (8.08%). Five participants died during a hospital episode.Unlike A&E or Outpatient EHR, each record was accompanied by a diagnosis; completeness was 100%. In this population, 17,541 individual ICD-10 diagnoses, representing 963 ICD-10 (3-digit) disease groups including primary and secondary diagnoses were recorded. Aggregating the ICD-10 code t common . Predomi3.5Unknown and unspecified causes of morbidity” assigned to 87.57% of all appointments. Only 5.16% of appointments were not coded with any type of diagnosis. England had the largest number of visits with a proportion of 91.34% compared to Scotland 4.72% and Wales 3.94%.A total of 4,810 participants had 45,005 appointments, with 4,178 (86.86%) male and 632 (13.14%) female. Multiple coding systems were employed to encode diagnoses of an outpatient visit, including ICD-10 and free text. The most common ICD-10 code is R69, defined as “In total, 174 variables, which represent all three nations, were grouped resulting in 46 common variables being defined. Overall completeness of the derived variables, in terms of a value being present was an average of 57.11% . Appoint4Our work introduces a framework to integrate data from national providers to produce a combined dataset of secondary health for serving and ex-serving Armed Forces personnel. This work can also be applied to other settings and populations. We have shown that a linked dataset containing national EHRs can be created and used to evaluate healthcare utilisation across England, Scotland and Wales. However, it is important to acknowledge that we do not know how many persons with an admission were not detected due to the matching and extraction methodology employed by data providers. Using linked EHRs, clinicians and researchers can monitor and improve admissions, quality of care, improve clinical decision making, and to influence patient outcomes and care. We have been able to use the data to show the frequency of APC, Outpatient and A&E visits, diagnosis and arrival mode for Armed Forces personnel. Conversely, we have identified disparities between data providers and their methods of recording, validating and storing of data which has been shown to impact data quality and reliability. Similarly, data completeness and accuracy in assigning presentation or diagnoses code values are of concern in A&E and Outpatient data across the nations. For Outpatient EHRs, diagnoses and main procedure variables were not a mandatory requirement, however recording is increasing over time . NeverthThe ability to obtain EHR from multiple national providers and integrate to an existing cohort allows greater insight into patient admission patterns and history . However4.1For our methodology to be a functional resource it is important to be aware of the limits of health data and integration. Personal identifiers were obtained via the KCMHR cohort study, with permission from participants, and included participants’ first name, last name, date of birth gender, and National Health Number which can be difficult to obtain and record correctly. NHS number was not available for 20.05% of participants. The matching process undertaken by NHS Digital set NHS number as a mandatory variable, resulting in a lower success rate. However, ISD in Scotland and SAIL in Wales did not place this same requirement. We did not request data from Northern Ireland. This was because of the complex structures surrounding EHRs in Northern Ireland. No central organisation is responsible, instead it is delegated to the local trust. In addition, there are security concerns surrounding former Armed Forces personnel.There are several problems with using national EHR datasets such as HES, ISD or SAIL when integrating these datasets. The complexity of gathering data at data centres and the large number of organisations and institutions which can provide submissions can give rise to reduced accuracy of the EHR including diagnoses, outcomes and patient management . FurtherWe were limited to the variables requested and provided by national data providers, to enable linkage. We undertook a pragmatic approach to matching variables based on commonality using variable definitions provided by the data providers. This is a time-consuming exercise, and might prove an obstacle in even larger datasets. Further, national coding schemes, may have been interpreted differently by hospital trust and coder leading to additional confusion and coding bias. It is important to be aware that though EHRs are widely used in research, offering a broad range of information about treatment, diagnoses and care, there are issues relating to determining data quality, completeness of data and drawing conclusions from the data .4.2Our initial examination of the dataset has proved useful in identifying the most common diagnoses, types of A&E admissions and number of Outpatient appointments for Armed Forces personnel. Further analysis of the dataset is required to evaluate clinical practices, common diagnoses stratified by patient characteristics and variable coding accuracy to improve dataset recording and retention. This could include assessing A&E trends in admission, prevalence of A&E admissions resulting in an APC episode and waiting times. Alternately, further data linkage to primary healthcare records might make it possible to identify pre and post follow-up health of individuals who have had a contact with secondary care. This could improve the quality of analysis and enable refinement of queries used on the dataset to improve the quality of the dataset.In the future, there is potential to develop a more responsive, real-time and useful linked dataset based on the framework and methodologies presented in this work. This would require more regular and frequent updates from data providers, including more efficient data linkage of cohort users.5It was possible to integrate secondary health records to create a combined dataset of attendances to NHS hospitals in England, Scotland and Wales. This is the first to combine and present analyses of EHRs from Armed Forces personnel in the UK (excluding Northern Ireland). The dataset was developed using variable commonality and included both serving and ex-serving Armed Forces personnel, enabling evaluation of healthcare utilisation. The NHS of England, Scotland and Wales obtain, store and process EHRs using different methodologies. Scotland and Wales utilise participant demographics without the need of a NHS number whereas matching in England requires an NHS number. Future work should seek to harmonise the protocols for national linkage and seek a uniform UK-wide policy on EHRs for research. The increasing shift towards the use of EHR by health trusts presents an opportunity to monitor admissions, diagnoses and outcomes to inform public health policy and service provision.Ethical approval was obtained from the London-Dulwich NHS Research Ethics Committee in November 2014 (REC no: 07/Q0703/36). Further, a Section 251 of the National Health Service Act 2006 (Ref no: 15/CAG/0136) was obtained.None required.Coding schemes and syntax used to perform data linkage are available upon request from the corresponding author.Economic and Social Research Council (grant number ES/L014521/1), DL and ZC were funded by the grant. Over the course of this work RDH was funded by a Medical Research Council Population Health Scientist Fellowship (grant number MR/J01219X/1). RDH and SL have received salary support from the National Institute for Health Research Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.This work is funded by the RDH has received research funding from Roche, Pfizer, Janssen, Lundbeck and In-Silico-Bioscience. SW is advisor to the British Army in psychiatry and a trustee of Combat Stress. This work was undertaken prior to NTF’s appointment to the Independent Group Advising on the Release of Data. NTF is a trustee of The Warrior Programme. DL, ZC, SL, PM, MJ and LG declare that they have no competing interests.What was already known?•Electronic Healthcare Records are used to capture summaries of care and contact to healthcare services; in the United Kingdom they are intended to financially reimburse hospital trusts for care provided.•In the United Kingdom; England, Scotland and Wales maintain separate data stores for Electronic Healthcare Records with responsibility being devolved to National Governments. This has introduced a lack of uniformity, making it difficult to evaluate care, diagnosis and treatment across the entire United Kingdom.•Propriety systems are used by England, Scotland and Wales National Health Services which makes it challenging to perform analyses across England, Scotland and Wales.What has this study added to the body of knowledge?•This paper presents the first framework to integrate national Electronic Health Records. It has been developed with collaboration from health professional and could be rolled out nationally to assist in United Kingdom wide research.•This paper found that variable completeness across the nations was varied, with Outpatient care being sparsely coded making it challenging for use in epidemiological research.•This paper highlights the types of analyses which can be performed when undertaking United Kingdom wide linkage, with the potential of combing additional data modalities.DL conducted the data linkage, data analysis and wrote all drafts of the manuscript. ZC provided advice on the data linkage, commented on drafts of the paper. MJ has provided guidance during the work and commented on drafts of the paper. SL, PM, RDH, SW and NTF participated in design of the work and commented on drafts of the paper. LG designed the work, sought and obtained funding, oversaw data collection, analysis, linkage and commented on all drafts of the paper. All authors have read and approved the final manuscript.


To evaluate bone mass by quantitative ultrasound of the phalanges in young karate practitioners compared to a control group. p≤0.05. Sample composed of 162 karate practitioners  and 326 healthy controls  aged 6 to 16 years old, in Western Paraná (Southern Brazil). Weight, height, BMI, amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT) were evaluated. BMI, AD-SoS and BTT values were converted to Z scores. Mann-Whitney, chi-square or Fisher Exact tests and multiple linear regression were applied, with significance level set at 2=0.42) and BTT (R2=0.45), respectively. Among male karate practitioners, age was related to 26% of AD-SoS variances and height was responsible for 36% of BTT variances. Both genders showed higher values of BTT as Z scores when compared to control group. Females from the control group had higher AD-SoS values (m/s and Z score) compared to female karate practitioners. When relative and absolute frequencies were assessed according to BTT Z score in both groups, male karate practitioners’ bone mass was shown to be adequate more frequently. In female practitioners, age and weight were independent predictors of AD-SoS (R Children and adolescents who practice karate were shown to have more bone mass in comparison to the control group, regardless of gender. BTT was more sensitive for this evaluation. The case group (karate practitioners) was composed of students enrolled in Karate in 2014 at selected gym centers of all seven cities of western Paraná , totaling 258 , of which 162 (63%)  participated in the study. The control group was assembled from a database of our laboratory with healthy students enrolled in municipal schools of Cascavel (Paraná), all being evaluated by the same methodThe informed consent was granted by the gym center management, parents and/or caregivers of karate practitioners, school principals, parents and/or caregivers of subjects in control groups. This research was approved by the Research Ethics Committees of Universidade Federal de Santa Catarina (control group: 131/2006) and Faculdade Assis Gurgacz . Data were collected at the gym center or at the schools.® graduated with 100 g; height (cm), was measured with a Seca® wall-mounted stadiometer graduated with 1 mm. From these data, BMI (kg/m2) was calculated. The BMI values were transformed in Z score and sorted according to the International Obesity Task Force (IOTF):The weight (kg) was evaluated with a digital scale of the brand Tanita®, Capri, Italy). Evaluations complied with the manufacturer’s standard protocol, being performed on the proximal phalange distal metaphysis of the non-dominant hand, from the second to the fifth finger. Parameters evaluated were AD-SoS (m/s) and BTT (µs). AD-SoS is the measure of range between the first signal transmitted and the last one received, influencing soft tissue; BTT reflects bone properties regardless of effects on soft tissue, thus being considered more accurate for this evaluation. The absolute values of AD-SoS and BTT measures were converted to Z scores, as in the reference study by Barkmann et al.Bone parameters were assessed by QUS of the phalanges . After data transformation, stepwise multiple linear regression was applied to evaluate the effects of each independent variable on bone parameters. P-value ≤0.05 was adopted as significance level. Afterwards, sample effect was studies based on the power of each test and using the Standard Power Calculation method and the R test, with level of significance set at α = 0.05 for all tests. SPSS program version 20.0 was used to process statistics.When it comes to correlations between bone and anthropometric parameters, none was found between BMI and AD-SoS of males practicing karate. All other variables had moderate to high/significant correlations, usually above 0.40. Exceptions were BMI and AD-SoS in females practicing karate, weight and AD-SoS in males practicing karate; BMI and BTT in males practicing karate, BMI and AD-SoS and MTB in male subjects in control group; although positive, such correlations were low .2 = 0.45 for karate group, r2 = 0.51 for control groups) and height for males .In our study, young karate practitioners of both genders had more bone mass, adjusted for age and gender (BTT Z-score) and compared to the control group. Females’ weight and males’ height were the best prediction anthropometric data.et al.In the literature, only a study by Drozdzowska Although the results of our study indicate higher AD-SoS among karate practitioners as opposed to control group, one must note that BTT is more sensitive for bone mass evaluation when assessed by QUS in relation to AD-SoS and, for this reason, this parameter was included in the study. Such variables show the ultrasound velocity in the bone, but AD-SoS is the interval measured between the first signal transmitted and the last one received with influence on soft tissues. BTT, on its turn, shows bone properties regardless of the confounding effect of soft tissue.et al. established that upper limb techniques are often predominant (89.1%) compared to lower limb techniques (8.4%).Karate engages several muscle groups with complex movements and rapid acceleration and deceleration movements by displacement techniques and different postures.et al.,et al.Recently, Nasri et al.,,,In 2011, Tenforde and Fredericsonet al.Löfgren ,,,et al.In Brazil, studies using QUS of phalange in healthy children and adolescents of both genders showed the influence of age, weight and height on the increase of bone mass.et al.Consequently, increase in bone mass in children and adolescents related to age and puberty is expected and has been well documented by Lappe However, some of the limitations of our study are worth mentioning, non-evaluation of puberty stages and of duration and intensity of karate practice included. It is, though, a pioneering study on bone mass assessed by QUS, with a significant number of children and adolescents practicing karate in relation to a control group.Bone mass evaluation-in karate practitioners initially when performing basic techniques and, later on, during classes and progress of bands-can help maintain the health of the practitioner and, therefore, to improve their quality of life, confirming the importance and benefits of combat sports in pediatric age. In this study, BTT was shown to be the most adequate and useful parameter to conduct evaluations with karate practitioners due to its greater sensitivity for bone tissue assessment. Considering the lack of evidence on this matter in the scientific literature, this study may be used as example for further research on combat sports (high impact), to elucidate their benefits for bone health. Conclusion is that karate practitioners in this group of children and adolescents, regardless of gender, were shown to present higher bone mass index compared to the control group.