The current labour market is becoming more flexible and informal, with job insecurity selectively affecting young workers. However, the role of these increasing adverse psychosocial working conditions on health outcomes remains little known among newly employed workers.To estimate the associations between psychosocial work environment and musculoskeletal outcomes  in a population-based sample of young workers.Cross-sectional data from workers aged 21 years were collected during the third wave of the EPITeen cohort study . The Job Content Questionnaire was used to characterize the psychosocial work environment according to the demand-control-support model. Data on pain and non-pain dimensions of the widespread pain syndrome  as well as on regional musculoskeletal pain  were also collected. Crude and adjusted odds ratios (OR) with 95% confidence intervals (95% CI) were computed using logistic regression and all estimates were adjusted for sex, education and occupational biomechanical demands.Job insecurity was significantly associated to the non-pain dimension of the widespread pain syndrome . Young workers with strain jobs were significantly more likely to report high levels of non-pain symptoms when compared with those with no-strain jobs and this effect was even stronger when social support was added to the main exposure: workers with strain jobs and low social support had twice the odds of reporting high levels of non-pain features than those with high strain but high social support jobs . These significant associations were not observed when widespread pain or multisite regional pain were the outcomes.In the beginning of professional life, high strain jobs were associated to non-pain complaints, especially when the work environment provided also low social support. Occupation is an important determinant of health in general and its overall positive or negative effect on well-being results from the interaction between individual characteristics and work-related features, the latter comprising biomechanical, psychosocial and sociological axes , 2.The impact of psychosocial work environment on health is particularly relevant under the current change of the labour market , 4, wherClassic biomedical approaches to the aetiology of musculoskeletal conditions have shown that mechanical exposures at work are among the main causes of muscle and joint complaints  and thatMost existing evidence of the impact of psychosocial work environment on musculoskeletal health has originated from long-term workers , where tTherefore, using data collected in a population-based sample of newly employed young workers with a wide spectrum of jobs (2011–2013), we aimed to estimate the associations between psychosocial work environment and musculoskeletal outcomes .The study protocol was approved by the Ethics Committee of University Hospital de São João (Porto) and by the Portuguese Authority of Data Protection and was carried out in accordance with the principles of the 1964 Declaration of Helsinki. Written informed consent was obtained from all participants.This investigation uses cross-sectional data collected in the period of 2011–2013 from young adults of the Epidemiological Health Investigation of Teenagers in Porto (EPITeen). This cohort was first assembled during the 2003/2004 school year, when all the public and private schools in Porto  that provided teaching to adolescents born in 1990 were approached. We identified 2787 eligible adolescents, of whom 2159 (77.5%) agreed to participate. In 2007/2008, the initially recruited sample was re-evaluated and 783 students born in the same year but who moved to Porto after 2003/2004 were additionally recruited to the cohort. Sampling procedures and detailed methods have already been described elsewhere .Between 2011 and 2013, 1761 (of the 2942 eligible) individuals attended the 21 years old follow-up. These were similar to participants lost to follow-up regarding a wide spectrum of characteristics such as sex, body mass index and smoking behaviour at 13 years of age. However, subjects attending follow-up had higher parental education .Among the 1761 young adults assessed at 21 years of age, 650 (36.9%) had worked during at least one month in the preceding year  and constituted the final sample for this investigation . NeitherWorkers with incomplete responses in some of the exposure variables were considered in the analyses. Our methodological option of not excluding these subjects was supported by the absence of significant differences between workers with complete and incomplete responses in crucial characteristics such as sex distribution, education and occupational biomechanical demands .As educational level has been the most accurate indicator to assess the effect of socioeconomic position on health outcomes in the Portuguese population , formal Jobs were classified according to the International Standard Classification of Occupations-88  and grouTen different occupational biomechanical factors  were also collected. Four patterns of exposure to occupational biomechanical factors were obtained in our sample of workers (n = 650) using the latent class analysis: low, sitting, repetitive and asymmetric and high and vibrational demands. A more detailed description on methods used to obtain the patterns of occupational biomechanical demands has been described elsewhere .Psychosocial work environment of the job performed for the longest period of time in the past 12 months was assessed using the self-administered Job Content Questionnaire , 29, whiTaking into account the demand-control-(support) model , two difWidespread pain syndrome features were assessed using the Fibromyalgia Survey Questionnaire which allows for the quantification of the severity of a wide range of pain and non-pain symptoms . Non-paiRegional musculoskeletal pain was assessed using the Nordic Musculoskeletal Questionnaire  which evSample characteristics are presented as counts and proportions for all the categorical variables.a priori. Crude and adjusted odds ratios (OR) with 95% confidence intervals (95% CI) were computed and all estimates were adjusted for sex, education and occupational biomechanical demands.In order to estimate the associations between psychosocial work environment  and musculoskeletal outcomes , logistic regression models were fitted using as reference the category with the expected lowest risk for the outcomes considered. Regarding the demand-control-(support) model analyses, logistic regression models were fitted using as reference workers with no-strain jobs (demand-control) or those with no-strain & high social support jobs (demand-control-support). Based on previous evidence, confounders of the associations between psychosocial work environment and musculoskeletal outcomes were defined Because manual workers are expected to be different from clerical workers in relation to psychosocial work environment exposure , a sensiStatistical analyses were performed using Stata version 11.2 for Windows .Among all workers, jobs characterized by low decision latitude or high job insecurity were significantly associated to high levels of non-pain symptoms (adjusted OR (95% CI) = 1.50  and 1.51 , respectively) but not related to high levels of widespread pain or multisite regional pain. Similar results were found when analysis was restricted to clerical workers, but with a slight increase in the magnitude of estimates .Regarding non-pain symptoms, workers with strain jobs were significantly more likely to report high levels of this dimension of the widespread pain syndrome when compared with those with no-strain jobs. Although the statistical significance was borderline, this association was observed among all workers  as well as among clericals only . When social support was added to the main exposure, workers with strain jobs together with low social support were significantly more likely to score high in the non-pain dimension of the widespread pain syndrome when compared with those with no-strain jobs and high social support . This association was even stronger when only clerical workers were considered: adjusted OR = 2.12, 95% CI: 1.07, 4.24.None of the factors included in the models of job strain (demand-control or demand-control-support) significantly predicted widespread pain or multisite regional pain.In this population-based sample of young workers, jobs characterized by high strain were significantly associated with the non-pain dimension of the widespread pain syndrome and this association was strongly modified by social support. Nevertheless, these psychosocial work environment factors did not statistically predict widespread pain or multisite regional pain.As a framework for the relation between work-related psychosocial factors and musculoskeletal health outcomes we used the demand-control-support model of job strain development . This apPresently, it is unequivocal that job strain is a major risk factor for the onset of work-related musculoskeletal complaints and that job social support may play an important role as an aggravator (low support) or attenuator (high support) of the impact of high-strain jobs on the musculoskeletal health of workers –40. HoweIn the EPITeen workers, we found increased non-pain complaints among those shortly exposed to high-strain and low social support jobs, which is in agreement with previous evidence on the negative impact of adverse psychosocial work environment on the health of workers . NeverthTo interpret the pattern of associations observed, we find three most likely explanations. First, the fact that we found statistical significant relations between psychosocial work environment and non-pain symptoms but not with pain complaints may be due to a true differential effect of the work exposure on different health outcomes. This is in line with the current understanding of the pathophysiology of the widespread pain syndrome, whereby it is expected that non-pain symptoms precede both multisite regional pain and widespread pain , 41, 42.A second explanation is that subjective constructs such as self-reported symptoms and work-related psychosocial factors are both influenced by individual psychological traits , 45. ThiEven though a plausible effect of psychosocial work environment on the onset of the widespread pain syndrome may be hypothesized since early stages of employment, the cross-sectional design of our study did not allow us to empirically confirm this model. The prospective follow-up of workers of the EPITeen cohort throughout their professional life will be fundamental for empirically confirming the etiological hypothesis regarding the effect of early exposures to work-related psychosocial stress on musculoskeletal outcomes.Beyond what was already known on the impact of job strain on health outcomes, probably the most interesting finding of our work was that social support was an important modifier of the association between job strain and non-pain symptoms: young workers with strain jobs and low social support had twice the odds of reporting high levels of non-pain features than those with high-strain but high social support jobs. In such early stages of professional life, a supportive work environment may be especially important, since the need to share experiences, acquire new skills, and discuss difficulties is expected to be high . TherefoAnother important result was that job insecurity was related to high levels of the non-pain dimension of the widespread pain syndrome. The current flexibility and informality of occupations  have beeTo the best of our knowledge, this is the first study estimating the associations between high-strain and low social support jobs and the widespread pain syndrome dimensions in the beginning of professional life. These workers had the same chronological age, which eliminates confounding by birth cohort or calendar period. Moreover, the sample was population-based which adds a scenario of a wide range of real-world jobs performed in early career stages in a decade where the typology of employment has changed dramatically . This isa priori defined confounders such as sex, education and occupational biomechanical demands. Data on contextual features such as ethnic background and cultural beliefs or interpersonal relationships and social capital were not collected in our study due to legal and logistic reasons, respectively. Although workers enrolled in our investigation were reasonably homogeneous regarding age and geographical origin (the proportion of immigrants in the metropolitan area of Porto was only 1.1% when the EPITeen cohort was assembled), residual confounding related to the surrounding context cannot be excluded.Some methodological issues need nevertheless to be addressed. Both psychosocial work environment and musculoskeletal symptoms may be influenced by several individual, social and cultural characteristics. Accordingly, all estimates were adjusted for a set of In line with this, the presence of a chronic health condition among workers is also likely to influence both the perception of psychosocial work environment and the report of musculoskeletal symptoms. However, sensitivity analyses were performed by restricting estimates to workers without any chronic disease and similar conclusions to those found in the whole sample were supported by the results (results not shown).Mental health status and related psychosocial problems may have changed the perception of the psychosocial work environment of workers. Nevertheless, in our sample, we did not observe significant associations between depressive symptoms  and psychosocial work environment characteristics. Therefore, we believe that the mental dimension of health did not majorly impair the interpretation of our findings.Since only 13.2% of workers (n = 77) had manual jobs, we did not have enough statistical power to conduct a stratified analysis in this group alone. Our option was to conduct a sensitivity analysis restricted to clerical workers (from whom we did have a larger sample size) in order to assess the potential impact of considering manual and clerical workers as a whole. As findings remained reasonably similar between the two approaches , we believe that the inclusion of manual workers in our study did not largely affect the estimates. We cannot however exclude that our estimates may be indicating mainly what happens in clerical workers than in workers representing all types of jobs.Health status may have conditioned the beginning of professional life of young adults, with healthier subjects entering in the labour market differentially. As workers were part of the EPITeen cohort, we were able to compare them with non-workers from the same source population regarding health conditions. We observed that the prevalence of chronic health conditions  was reasonably similar between workers and non-workers, which suggests that selection bias for work due to health status did not occur. This was additionally supported by the fact that workers were more likely to report musculoskeletal complaints when compared with non-workers, which was not expected if the healthier young adults were overrepresented among workers.In addition, the healthy worker effect, through which musculoskeletal symptoms may themselves determine the choice or persistence in a specific less strain job, cannot be excluded. Nevertheless, since most workers were recently employed (near 70% of them had been working for 12 months or less), it seems unlikely that musculoskeletal complaints had led to a substantial proportion of individuals to radically change their exposure status before the 21-year-old follow-up. Furthermore, the selection of a certain job depending on its level of strain is unlikely because psychosocial work environment features are particularly difficult to anticipate before starting on the job.A reasonable fraction of workers enrolled in this study were unemployed. Although employed and unemployed workers were not significantly different regarding the main exposures and outcomes, a sensitivity analysis restricted to employed participants was conducted and the magnitude, direction and significance of the estimates remained similar to those found when all workers were considered (data not shown). Thus, we believe that work status did not represent a relevant source of bias to our findings.As exposures and outcomes were collected cross-sectionally, it is not possible to discern the temporal sequence between the exposure to adverse work-related psychosocial factors and the manifestation of musculoskeletal complaints. Moreover, individuals with pain symptoms may have recalled psychosocial work environment exposure as more adverse and/or strained than those who did not present such complaints. However, data have been collected as part of an extensive protocol that assessed a wide spectrum of health-related information and subjects were not expected to be particularly aware of the main hypothesis addressed in this particular study.in loco. Nevertheless, we believe that the impact of adverse psychosocial work environment characteristics on health outcomes might be more dependent on the individual perception and self-evaluation of the work-related psychosocial context than on the objectively-measured features of occupation [Data on main exposures were collected using a single and self-reported source of information—the Job Content Questionnaire. Due to the fact that data were collected as part of the EPITeen population-based cohort , we were not able to objectively assess the psychosocial work environment cupation . Additiocupation .The extent to which any cohort represents the source population throughout follow-up is likely to decrease over time because of differential losses to follow-up. Participants reassessed at 21 years old were reasonably similar to those lost to follow-up in a wide number of characteristics measured in the baseline evaluation, but attrition was significantly higher in individuals with low social position. Despite that, we do not believe that the underrepresentation of young adults with social disadvantage has substantially biased our estimates since we found no associations between parental education and musculoskeletal outcomes  at 21 years of age.a priori according to the Karasek’s Job Strain Model [Finally, as we were testing the associations between a wide spectrum of psychosocial work environment characteristics and musculoskeletal outcomes, multiple testing issues and consequent random effects may have occurred. However, the probability of random findings was expected to be low since all hypotheses were defined in Model . OverallIn conclusion, high-strain psychosocial work environments and job insecurity were significantly associated with the non-pain dimension of the widespread pain syndrome in the beginning of professional life. The potential effect of high strain was strongly modified by social support: workers who perceived their job as low socially supportive had twice the risk of reporting non-pain complaints.


The personal genomics era has attracted a large amount of attention for anti-cancer therapy by patient-specific analysis. Patient-specific analysis enables discovery of individual genomic characteristics for each patient, and thus we can effectively predict individual genetic risk of disease and perform personalized anti-cancer therapy. Although the existing methods for patient-specific analysis have successfully uncovered crucial biomarkers, their performance takes a sudden turn for the worst in the presence of outliers, since the methods are based on non-robust manners. In practice, clinical and genomic alterations datasets usually contain outliers from various sources  and the outliers may significantly affect the result of patient-specific analysis. We propose a robust methodology for patient-specific analysis in line with the NetwrokProfiler. In the proposed method, outliers in high dimensional gene expression levels and drug response datasets are simultaneously controlled by robust Mahalanobis distance in robust principal component space. Thus, we can effectively perform for predicting anti-cancer drug sensitivity and identifying sensitivity-specific biomarkers for individual patients. We observe through Monte Carlo simulations that the proposed robust method produces outstanding performances for predicting response variable in the presence of outliers. We also apply the proposed methodology to the Sanger dataset in order to uncover cancer biomarkers and predict anti-cancer drug sensitivity, and show the effectiveness of our method. Recently, numerous studies have attempted to personalized therapy and medicine based on advanced biomedical technologies Wang et al. Although the issue is critically important, relatively little attention has been paid to the robustness of patient-specific analysis. We consider a robust method to uncover patient-specific genomic features and predict anti-cancer drug response in line with the NetworkProfiler. The genomic alterations dataset is usually constructed with a large number of features for a small number of samples , and detecting and controlling outliers in a high dimensional dataset are difficult tasks. We refer to the method for controlling outliers by using the robust Mahalanobis distance based on principal component analysis (PCA) We propose a robust modeling strategy for patient-specific analysis, which infers patient-specific biomarkers associated with anti-cancer drug response. The proposed strategy is based on kernel-based elastic net-type regularization, and thus can perform patient-specific analysis through neighborhood samples around a target patient. Furthermore, our method can perform effectively for predicting anti-cancer drug sensitivity and identifying drug response-specific biomarkers for each patient even in the presence of outliers, since the method is based on a robust regularized regression by using a weight through the Mahalanobis distance in principal component space http://www.cancerrxgene.org/). Our methodology uncovers biomarkers for individual patients and predicts anti-cancer drug response given as IC50 values based on gene expression levels. Though Monte Carlo simulations and application to the Sanger dataset, we can see that our method performs effectively for patient-specific feature selection and prediction of interesting response variable, even in the presence of outliers.We conduct Monte Carlo simulations to examine the effectiveness of the proposed method, and show the outstanding performance of our method in the view point of prediction accuracy. We also apply the proposed modeling strategy to the publicly available Sanger Genomic of Drug Sensitivity in Cancer dataset from the Cancer Genome Project . Consider the linear regression model, p-dimensional vector of regression coefficients and Suppose we have To uncover a biomarker, the elastic net-type regularization methods  have been widely applied, and used successfully to identify crucial genes based on the following optimization problem, The elastic net-type penalties enable us to simultaneously identify crucial biomarkers and predict drug response. Furthermore, we can effectively perform regression modeling in the high dimensional genomic alterations dataset and in the presence of multicollinearity by imposing the penalty on the least squares loss function. Although the existing methodologies successfully identify crucial biomarkers and show remarkable performance for predicting drug response, they have been used to identify averaged biomarkers for all patients. In other words, the existing method cannot identify patient-specific characteristics in a disease.Shimamura et al. The Gaussian kernel function It is, however, well known that the genomic alterations datasets usually contain outliers from various sources . It implies that the existing method would not perform well for uncovering biomarkers and predicting anti-cancer drug response, because the existing method in (5) is based on a penalized least squares loss function. It was previously shown that the elastic net-type regularization methods that are based on least square loss function perform poorly in the presence of outliers, and several robust methodologies have been proposed to overcome the drawbacks of a least square loss function in regularized regression modeling We propose a robust method for patient-specific analysis in line with the NetworkProfiler.We first show how outliers could affect the estimation process when using the penalized least squares methodology. We propose a robust method to effectively uncover patient-specific cancer biomarkers and predict anti-cancer drug sensitivity in line with the NetworkProfiler. The genomic features dataset is constructed with a large number of features and a relatively small number of samples , and detecting and controlling outliers in a high dimensional dataset are generally difficult tasks. To resolve the issue, we consider the weight for controlling outliers based on robust Mahalanobis distance calculated in robust principal component space, as previously demonstrated by Park and Konishi We refer to the weight in (8) for outlier-resistant patient-specific analysis, and propose a robust method for uncovering biomarkers and predicting drug sensitivity for an individual patient as follows, The proposed modeling strategy is effectively conducted by using the coordinate descent algorithm based on the weighted update We examine the effectiveness of the proposed modeling strategy as a robust method for patient-specific analysis through Monte Carlo simulations and application to cancer genomics data. To evaluate the proposed method, we compare the prediction accuracy and variable selection results of our method, the NetworkProfiler and elastic net. In our study, the NetworkProfiler is used to uncover individual biomarkers instead of gene networks. For the numerical studies, we use the adaptive elastic net penalty We simulated 100 datasets consisting of Two types of coefficient functions in the above varying coefficient model are considered, as shown in We consider a training dataset with 75 samples and a test dataset with 25 samples in each 100 simulations. The hyperparameters are selected by 3-fold cross validation in the training dataset, and the prediction errors are calculated in test dataset based on the selected parameters. We then compare the prediction accuracy given as average of the median squared error, and the variable selection accuracy given as true positive  and true negative  for each of the 100 generated datasets.A large number of predictor variables leads to time consuming analysis, and thus increases the overall computational cost of a method. Furthermore, it has been exposed that a large number of predictor variables with noisy genes may disturb the modeling procedure, and thus leads to poor prediction results Thus, we compare the proposed robust method to the NetworkProfiler and elastic net based on model with http://www.cancerrxgene.org/). The main goal of the project is to identify the molecular features of various cancers and to predict sensitivity of anti-cancer drugs. The dataset consists of gene expression levels, copy number and mutation status for 654 cell lines. The IC50 values  of 138 drugs are given as the natural log of drug sensitivity value. The IC50 values from the Sanger dataset contain not a few of missing values, and thus we perform biomarkers discovery and anti-cancer drug response prediction based on 200 randomly selected samples, of which 150 cell lines were used as a training data and 50 cell lines were used as a test data for each of the 138 drugs.We apply the proposed modeling strategy to the publicly available Sanger Genomics of Drug Sensitivity in Cancer dataset from the Cancer Genome Project  corresponding 138 drugs, we find a first principal component of the dataset, and then decide based on the following criterion, We consider the datasets with As mentioned previously, a large number of features not only leads to inefficient modeling, but may also produce poor results compared with modeling based on a pre-selected small number of features. We first compare the prediction accuracy  of anti-cancer drug response based on expression levels of 133  genes and the 500 genes that have the highest variance based on the NetworkProfiler in In short, our method is a useful tool for predicting anti-cancer drug sensitivity and uncovering patient-specific cancer biomarkers.We have proposed a novel outlier-resistant method for uncovering patient-specific biomarkers and predicting anti-cancer drug response. By using the robust Mahalanobis distance calculated in robust principal component space, the proposed method effectively detects and controls outliers in high dimensional genomic alterations datasets. Thus, the proposed robust method can effectively perform to uncover cancer biomarkers and predict drug sensitivity, even in the presence of outliers. From the Monte Carlo simulations, we have found that our method shows outstanding prediction accuracy as compared to the existing NetworkProfiler and elastic net. We have also applied the proposed method to the Sanger dataset from the Cancer Genome Project. By using our method, we have uncovered cancer biomarkers and predicted anti-cancer drug response. It can be seen from the results that the proposed method is a useful tool for predicting anti-cancer drug response. Furthermore, the biomarkers uncovered by our method had been previously identified as cancer biomarkers. The results implies that our method provides not only reliable feature selection, but also accurate prediction results.There is currently much discussion about patient-specific analysis and personalized medicine based on high dimensional genomic datasets. We expect that our methodology will be useful for the fields, since genomic data usually contains outliers.Although the patient-specific method based on a varying coefficient model is an efficient tool, it controls the effects of observations in order to provide sample-specific results. In other words, it reduces the effect of observations far from a target patient, and thus leads to a high dimensional data frame. Building models based on a large number of features with a small number of samples can lead to overfitting in feature selection, and can produce inefficient prediction results. In order to improve modeling performance, future work can involve extending the patient-specific analysis based on the bootstrap technique.The Sanger dataset from the Cancer Genome Project provides comprehensive information about the molecular features of a cancer  and response of various anti-cancer drugs. Thus, analysis of the dataset may provide informative results about the systems biology of cancer and valuable information for personalized treatment and anti-cancer therapy. The IC50 values of 138 drugs given as drug sensitivity, however, contain many missing values . In order to effectively use the Sanger dataset to reveal the mechanism of cancer, rather than ignoring the incomplete fields, a proper treatment of the missing values is required.Furthermore, we have also identified through numerical studies that a large number of noisy features may disturb modeling performance, and thus strategies for pre-selecting a candidate set will be required to improve modeling performance.


The aim of this study was to evaluate the effect of axial length (AL) on the thickness of intraretinal layers in the macula using optical coherence tomography (OCT) image analysis.Fifty three randomly selected eyes of 53 healthy subjects were recruited for this study. The median age of the participants was 29 years (range: 6 to 67 years). AL was measured for each eye using a Lenstar LS 900 device. OCT imaging of the macula was also performed by Stratus OCT. OCTRIMA software was used to process the raw OCT scans and to determine the weighted mean thickness of 6 intraretinal layers and the total retina. Partial correlation test was performed to assess the correlation between the AL and the thickness values.Total retinal thickness showed moderate negative correlation with AL , while no correlation was observed between the thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCC), retinal pigment epithelium (RPE) and AL. Moderate negative correlation was observed also between the thickness of the ganglion cell layer and inner plexiform layer complex (GCL+IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL) and AL which were more pronounced in the peripheral ring .Our results have shown that the thickness of the nuclear layers and the total retina is correlated with AL. The reason underlying this could be the lateral stretching capability of these layers; however, further research is warranted to prove this theory. Our results suggest that the effect of AL on retinal layers should be taken into account in future studies. Since its first ophthalmic application in the 1950s, ultrasound (US) has become a standard diagnostic method in ophthalmology. The main advantage of this non-invasive modality, when compared with existing ophthalmological examination techniques was that it allowed not only qualitative but also quantitative evaluation of the eyeball; i.e. it enabled the measurement of the axial length (AL) of the eye and the thickness of the ocular wall. As a result of continuous improvement, high-resolution imaging and investigation of the ocular and orbital blood flow characteristics can also be performed using US .The first paper describing the measurement of the ocular coat dimensions using US and the correlation between the thickness of the ocular wall and AL was published in 1984 . Eight yIn the early 1990s, the development of optical coherence tomography (OCT) enabled high-resolution cross-sectional imaging of the retina in vivo along with the quantitative analysis of retinal thickness, enabling accurate diagnosis and follow-up of various retinal pathologies. OCT rapidly became one of the most frequently used imaging tools in ophthalmological practice and nowadays it plays an essential role in the diagnosis and follow-up of several retinal diseases and also in the guiding of therapeutic decisions .Due to the high resolution of OCT images and the different optical properties of the intraretinal structures, various layers of the retina can be detected on OCT images. Several softwares have been developed in the last few years in order to allow the separate measurement of the thickness of the retinal layers, facilitating the localization of structural changes of the retina and the detection of even small changes –9. One oPrevious studies suggested that there is a correlation between retinal thickness and AL, age, OCT image quality, gender or race in healthy eyes –16. ThisThis cross-sectional study was performed at the Department of Ophthalmology, Semmelweis University, Budapest, Hungary. Eighty randomly selected eyes of 70 randomly selected healthy Caucasian subjects  were enrolled consecutively as they presented at the Optometry outpatient unit of the Department of Ophthalmology, Semmelweis University, between January 2010 and March 2010. All patients were referring either for spectacle prescription, a general ophthalmic follow-up or for a sports activity certification or driving license certification. The eligibility criteria for the participants were best-corrected Snellen visual acuity (BCVA) of 20/20 and the lack of any ocular or systemic diseases, except for controlled hypertension. After the exclusion of subjects with cooperation problems during axial length measurements (mostly children) and eyes where scans were not obtained with proper signal strength enabling the visualization of all layers  we had 53 eyes enrolled in the study.All participants were treated in accordance with the tenets of the Declaration of Helsinki. Institutional Review Board approval was obtained for all study protocols . Written informed consent was obtained from all participants in this study. In case of subjects under 18 years of age, written informed consent was obtained from a parent or a legal guardian.® Haag-Streit AG, Koeniz, Switzerland), which based on the principles of optical low-coherence reflectometry. The instrument uses a broadband superluminescent diode light source (peak wavelength 820 nm) to provide a series of axial biometric dimensions along the line of sight with a clinical accuracy of 12 μm [All volunteers underwent an ophthalmic examination including BCVA , manifest spherical equivalent refraction , assessment of intraocular pressure, slit lamp biomicroscopy and binocular ophthalmoscopy with pupil dilation. AL was measured in each eye using a LenStar LS 900 device . The raw macular OCT data were exported from the OCT device and further processed using a computer-aided grading methodology for OCT retinal image analysis (OCTRIMA) described in detail previously by Cabrera et al. . In shorThe thickness of the total retina and the intraretinal layers were measured in nine macular regions, defined by the Early Treatment Diabetic Retinopathy Study (ETDRS)  Fig 2)..Fig 2). The WMT values for the retinal nerve fiber layer (RNFL), ganglion cell layer and inner plexiform layer complex (GCL+IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), retinal pigment epithelium layer (RPE) and the total retina were obtained for each eye. We also calculated the mean thickness values in the central region and the pericentral and peripheral rings for statistical analyses. Because of anatomical considerations only the ONL and RPE thickness data were used in the central region.The circumpapillary RNFL thickness was measured by the software of the Stratus OCT device based on the slow “RNFL Thickness Map” protocol.Statistical analyses were performed using SPSS 16.0 software  software while power analyses were carried out by the SAS Software version 9.22 . The partial correlation test was used to determine the effect of AL on individual layer thickness with age , image qThe STROBE guidelines were followed for the interpretation of the study design and study data.  A p valuDemographic and ocular features of the study population are presented in Total retinal thickness showed a moderate negative correlation with AL . There was no correlation between AL and the thickness of the RNFL, GCC and RPE  using spectral domain OCT (SD-OCT) . They foOur results showed that the weighted mean thickness of the nuclear layers  correlated with AL after adjustment for age, sex and image quality, the correlation getting stronger towards the outer layers. Compared to the above mentioned studies, in the present study the AL of the eyes was relatively in a wide range which could also contribute to our results.According to two previous studies using OCT, the total thickness of the central, 1 mm diameter wide area of the macula  and total macular volume also correlate with AL, although with relatively low coefficients of correlation  . Our resIt remains unknown whether thinning in axial myopia occurs equally in all retinal layers. Abott et al studied the changes in retinal thickness  in a mammalian animal model  of high axial myopia using OCT and histological sections from the same retinal tissue. Analysis of retinal layers revealed that the inner plexiform, inner nuclear and outer plexiform layers are showing the most thinning.  From theAreal cell density measurements (cells/mm2) showed all neuronal cell types  were involved in retinal thinning.  Our resuWolsley et al. showed retinal thinning measured by OCT in human myopes compared to emmetropes along a line from 16° superior temporal to the fovea to 16° inferior nasal. The thinning appeared to slowly increase from 4° to 16° nasally and temporally, but regional differences were not analyzed in detail. Their possible explanation is the retinal laminar thickness change due to the shearing between retinal cell layers and cone packing.  The factThe introduction of the latest SD-OCT devices led not only to a dramatic increase in mapping speed and also some increase in axial resolution, but the examination of the choroid became also possible. In the past years, promising results have been obtained by the manual segmentation and measurement of choroidal thickness on OCT images. Li et al. and Sogawa et al. demonstrated strong negative correlation between AL and choroidal thickness measured in the subfoveal area of young and healthy eyes  , 39. UnfAs the growth of the eyeball is stipulated to continue until the age of 20 years , it is iIn conclusion, our study reveals the inverse correlation between the AL of the eyeball and the thickness of the intraretinal layers. However, there are some potential shortcomings of the study. Due to the limited retinal area of OCT imaging we could not assess whether the total volume of intraretinal layers remains constant despite variability in axial length. This could be achieved by enhanced and extended peripheral scanning of retinal tissue around the macula, which is not yet available technically. Another limitation is the lower resolution of the TD-OCT system and the number of interpolations used due to the six radial scans covering the macular area. First, we examined healthy eyes where no pathological retinal changes were anticipated that could negatively influence the precision of thickness measurements. Second, we have previously shown the high reliability of OCTRIMA measurements along with their comparability to SD-OCT thickness measurements –44. TherBased on our present results we suggest that the effect of AL should be taken into consideration when using OCT image segmentation techniques in future clinical studies involving adults while further studies are warranted to verify our observations in young subjects.S1 Table(XLS)Click here for additional data file.S2 TableThe results organized by study regions. .(XLS)Click here for additional data file.


Adenomyosis is a widespread disease affecting the reproductive period of women’s life. In the last ten years, different pathogenetic hypotheses have been proposed to explain the initiation and development of the disease. This article aims to present and discuss the most important pathophysiologic mechanisms underlying adenomyosis development in order to clarify the relationship between adenomyosis and infertility. A PubMed search was undertaken for English language literature using the MeSH terms ‘adenomyosis’, ‘infertility’, ‘treatment’, and ‘pathogenesis’. Although the exact etiology of adenomyosis is unknown, many theories have been proposed. We analysed the most important pathogenic theories expressed and evaluated the potential consequences on women fertility. A better comprehension of the adenomyosis pathogenesis has allowed realizing that adenomyosis may affect young women and may have a great impact on their fertility through different mechanisms. The understanding of these mechanisms helps to clarify the potential usefulness of current therapies. Adenomyosis is a widespread disease, that affects the reproductive period of life. Its prevalence is estimated in literature from 5-70%, and it is difficult to be precisely determined for many reasons. In one third of the cases, adenomyosis is an asymptomatic disease and consequently can be occasionally diagnosed by pelvic ultrasound or it is found in hysterectomy specimens performed for other medical reasons . In thesThe affection often coexists with other benign disorders, such as endometriosis (70%), leiomyomas 50%), endometrial hyperplasia 35%), endometrial polyps 2%) and endometrial carcinomas  or uterine junction zone (JZ) as a new anatomical and functional entity in uterus wall is mostly likely involved in its development .This article aims to present and discuss the most important pathophysiologic mechanisms underlying adenomyosis development in order to clarify the relationship between adenomyosis and infertility. Novel ideas and aspects might derive from this detailed analysis. A PubMed search was undertaken for English language literature using the MeSH terms ‘adenomyosis’, 'infertility', 'treatment', and 'pathogenesis'.Histogenetic hypothesis of adenomyosis originAlthough the exact etiology of adenomyosis is unknown, many theories have been proposed.1) Adenomyosis may develop de novo from a metaplastic transformation of the embryologic pluripotent mullerian remnants. Extra uterine sites of adenomyosis such as those observed in the rectovaginal septum support the concept that some cases of adenomyosis may result from this etiologic cause. In addition, studies on the proliferative and biological properties of ectopic and eutopic endometrium has shown that adenomyosis did not respond to the same hormonal changes found in its eutopic endometrium .et al defines ademyosis as an invagination of the basal endometrium into myometrium through an alternated or absent JZ (2) The second hypothesis, expressed by Bergeron bsent JZ . The endThe process of invagination and intramyometrial spreading may be facilitated by the non-cyclic, anti-apoptotic activity of the basalis associated with relative hyper-estrogenic states. Estradiol receptor (ER) expression in the adenomyosis foci is greater than in normal endometrium and it is associated with the expression of the apoptosis-suppressing gene product, Bcl-2, throughout the menstrual cycle. The co-expression of Bcl-2 and ER and the hyper-oestrogenic metabolic states may promote both the invagination process and overall ‘spreading’ of adenomyosis into the myometrium. They may also promote other benign disorders: endometriosis, polyps, endometrial hyperplasia and uterine leiomyomas and this is probably the reason for which these conditions are frequently associated with adenomyosis .et al considers hyper-estrogenic as the leading factor and adenomyosis as a consequence of the mechanism of tissue injury and repair (TIAR) (3) Another hypothesis, expressed by Leyendecker r (TIAR) . The uter (TIAR) .2) levels are within the normal range . IL-1-induced activation of the cyclooxygenase-2 enzyme (COX-2) results in the production of prostaglandin E2 (PGE2), which in turn activates the steroidogenic acute regulatory protein (STAR) and the P450 aromatase. Thus, testosterone can be formed and aromatized into E2 that exerts its proliferative and healing effects via the ER2  Another factor that might favour adenomyosis development is represented by the iatrogenic trauma. Surgical interventions might result in extended lesions with an enhanced TIAR reaction . The rapAlterations in adenomyosisHormonal alterations2  of class II in adenomyosis  are distributed throughout the body and modulate concentrations of free radicals at an optimal level to maintain the homeostasis -31. The Oxygen tension in the fallopian tube or uterus must be markedly lower than that in the atmosphere  and embryo can physiologically grow under a reduced-oxygen atmosphere. In this context, many scavenger enzymes in uterus are increased in order to eliminate the excess of free radicals and of nitric oxide (NO), but their hyper activation can produce in turn other free radicals saturating the system. Oxygen free radicals can cause the embryonic arrest and cell death . Nitric et al conducted a study in order to evaluate the expression of endothelial nitric oxide synthase in the surface and glandular epithelia of endometrium during the menstrual cycle in endometriosis and adenomyosis and demonstrated that its expression was persistently greater than in control endometrium throughout the menstrual cycle (Ota al cycle . NO is aal cycle . It has al cycle -40.Hyper vascularizationVascular distribution of the endometrium in adenomyosis has been shown to be different from that of the endometrium of fertile patients without adenomyosis. Hysteroscopy revealed that approximately half of the patients with adenomyosis have an abnormal vascularization: vascular distribution is generally irregular, and vessels were thick, dilated, and/or reticular. Moreover, morphometric analysis of the endometrium revealed that in fertile women, the mean surface area, total surface area, and total number of capillaries are all increased significantly in the secretory phase compared to the proliferative phase .In contrast, the above parameters are increased in the adenomyosis group in both the proliferative phase and secretory phase compared to the fertile women. These findings suggest that regulatory factors involved in the vascular proliferation are diversely exaggerated. Estrogens are supposed to be the most noteworthy factor associated with vascularization acting indirectly on vascular proliferation via growth factors . In adenVEGF gene with the consequence that its trascription levels are influenced by estrogens. Indeed, addition of estrogens to human granulosa cells during culture induces VEGF mRNA expression (This determines an abnormal development both in proliferative and secretory phase. A close relationship exists between VEGF and estrogens: an estrogen response element is located upstream of the pression , 46. Likpression .Clinical impact of adenomyosis on fertilityAdenomyosis may have a negative impact on fertility acting on various mechanisms. The pathogenetic insight underlying this condition is progressively leading to the comprehension of how fertility is impaired by adenomyosis , 4.Local hyperestrogenismThe TIAR system causes an over-production of PGE2 with an increase in local estrogen concentrations. This may explain the high comorbidity between adenomyosis and endometrial polyps, myomas, endometrial hyperplasia and endometriosis, that in their turn is a cause of female infertility. The hyper-expression of ER induces a down-regulation of progesterone receptors and loss of their action with a consequent progesterone resistance. This state contributes to determine an adverse effect on fertilization, implantation and time to pregnancy -14.Hyper-peristalsisThe increase in PGE-2 and estrogens may lead also to uterine hyper-peristalsis, which has two consequences: an alteration in tubal sperm transportation and an alteration of embryonic implantation . AdenomyThe high concentration of PGE2 production could also explain the increase risk of preterm delivery and of PPROM in patients with adenomyosis. PG stimulates uterine contractions in vitro and in vivo and control inflammatory responses that result in dilatation and thinning of the cervix -50.Autoimmune alterationsThe abnormal immune responses associated with adenomyosis might be involved in determining the poor reproductive performance, eventually causing an implantation failure. Activated macrophages producing persistently large amounts of nitric oxide, may impede fertilization and/or implantation. Even after successful implantation, the embryo may be attacked by activated macrophages or T cells, resulting in early miscarriage -31.Free radicalsAn excessive free radical environment similar to that present in the atmosphere directly may have a negative impact on intracellular DNA and cell membranes, damage fertilized eggs and inhibit embryo development and, thus, pregnancy -31. A loet al reported that the frequency of neural suture deformities increased in a dose-dependent manner when rats were exposed to excessive active oxygen or the injection of nitric oxide donor and nitric oxide synthase inhibitor into the amniotic cavity of rats resulted in malformed embryos (Jenkinson  embryos , 52. MorManagement strategieset al have published interesting results following insertion of an intrauterine system releasing danazol in term of relief from the symptoms and fertility after removal (Therapeutic strategy is directed to interrupt some of those pathological events and it is actually based on anti-oestrogen agents, in order to reduce PGE2 levels and to stabilize immunological environment. In the last 20 years, a variety of drugs have been used to treat adenomyosis and infertility associated with adenomyosis. GnRHa is the first drug used for this purpose, because it decreases expression of aromatase cytochrome p450 and of nitric oxide synthases. As far as the use of progestin concerns, Igarashi  removal .et al verified that concomitant use of GnRHa and AI was an effective treatment of choice for adenomyosis cases resistant to conventional treatment methods or for women rejecting surgery (Also the levonorgest-releasing intrauterine system has been used for the relief of symptoms associated with adenomyosis, but it is not known yet whether the system may be useful in infertile patients . Aromata surgery .et al have confirmed that aromatase inhibitors are as effective as gonadotropin-releasing hormone agonists in reducing adenomyoma volume and improving symptoms (et al has expressed an age-related impairment of ovarian function following uterine artery embolization leading to amenorrhoea, they concluded that pregnancies after uterine-artery embolization are possible, but with a risk of obstetric complications, possibly due to abnormal placentation (Badawy symptoms . Severalsymptoms . Althougentation . FinallyA better comprehension of the adenomyosis aetiology and pathology has allowed realizing that adenomyosis may affect young women and can have a great impact on their fertility through different mechanisms. The understanding of the pathogenetic mechanisms underlying this condition helps to clarify the potential usefulness of current therapies such as local progesterone given as anti-oestrogen agent, and at the same time can suggest new therapeutic approaches. Since the major adenomyosis alterations are intrauterine, a local therapy, released for example by an intra-uterine device, may represent the best choice.The drug administered may be chosen among the anti-oestrogens, such as aromatase inhibitors or among the anti-inflammatory category, in order to reduce PGE2 levels and to stabilize the immunological environment. In order to reduce the hyper-peristalsis, patients could take advantage from a local muscle-relaxant. Finally, in order to reduce the free radicals patients could receive an anti-oxidant therapy such as vitamin E.The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.


The PDO-hydroclimate relationships appear to be bridged by the atmospheric circulation between central North Pacific Ocean and Tibetan Plateau, a key area of PDO. While, in some periods the atmospheric circulation between central North Pacific Ocean and monsoonal Asia may lead to significant interdecadal hydroclimate variations in monsoonal Asia.Hydroclimate variations since 1300 in central and monsoonal Asia and their interplay on interannual and interdecadal timescales are investigated using the tree-ring based Palmer Drought Severity Index (PDSI) reconstructions. Both the interannual and interdecadal variations in both regions are closely to the Pacific Decadal Oscillation (PDO). On interannual timescale, the most robust correlations are observed between PDO and hydroclimate in central Asia. Interannual hydroclimate variations in central Asia are more significant during the warm periods with high solar irradiance, which is likely due to the enhanced variability of the eastern tropical Pacific Ocean, the high-frequency component of PDO, during the warm periods. We observe that the periods with significant interdecadal hydroclimate changes in central Asia often correspond to periods without significant interdecadal variability in monsoonal Asia, particularly before the 19 Hydroclimate changes in central and monsoonal Asia have generated much concern due to their close linkages with water resources, critical for increasing population and economical development Tree-ring records are very useful for investigating the spatiotemporal climate changes extending before the industrial era on interannual and interdecadal timescales due to their annual resolution and wide spatial distribution, although the long-term variations on timescales longer than a century may not be well preserved due to the “segment length curse” problem in the developments of tree-ring chronology The study region  covers regions of topographic complexity from the Tibetan Plateau to the low-lying regions such as the basins and river valleys . PrecipiWe investigate the percentage of areas affected by drought over the past 700 years, i.e. the Drought Area Index (DAI). The DAI is calculated as a ratio between the number of PDSI grids exceeding a threshold value and the sum of the PDSI grids of a given year. That is, high DAI indicates enlarged dry areas, and vice versa. This index has been applied in tree-ring based reconstructions in western North America http://jisao.washington.edu/pdo/) To explore the linkages between hydroclimate and sea surface temperature (SST), we applied the singular value decomposition (SVD) method The prominent feature of the DAI series is the increasing trend of the dry area since the 1950s . This trth century. Most of the long-term tree-ring chronologies are located in the central Asia and the marginal areas of monsoonal Asia According to the wavelet analyses, shifts in frequency bands between the presence and absence of the interdecadal changes for central Asia were identified in the 1460s, 1590s, 1770s, 1820s, and 1850s . SimilarSince the DAI displayed frequency-dependent variations, we further calculated the 51-year running correlations between the DAI in central and monsoonal Asia at interannual and interdecadal timescales . The relAs for the first leading SVD mode between MADA and SST, significant (0.01 level) positive heterogeneous correlation with MADA are found in central Asia , and are surrounded by horseshoe-like negative correlations in monsoonal Asia of eastern Mongolia, eastern China and Indochina . Signifith century and since the 1850s on interdecadal timescale, which account for the significant interdecadal variations from the 1460s to 1590s and since 1850s in central Asia. There are significant correlations on interannual timescale before the 14th century and from middle 17th century to 18th century, and since the 1850s, which correspond to the significantly interannual variations of the hydroclimate changes in central Asia. The good matches of the significant common powers and correlations between PDO and hydroclimate changes add in proofs to the close linkages between PDO and hydroclimate changes in central Asia. We also found correspondence between PDO and DAI in monsoonal Asia  of ENSO with its interannual variability focusing on the tropical ocean and the interdecadal variability focusing on the north central Pacific Ocean On the interdecadal timescale, the PDO-hydroclimate relationships may be linked via the atmospheric circulation between Tibetan Plateau and central North Pacific Ocean. An upward atmospheric circulation over Tibetan Plateau and a downward limb in the central North Pacific Ocean can lead to an increase in SST over the central North Pacific Ocean th century, and vice versa, indicating different hydroclimate regimes between the two regions. This may be due to their linkages with PDO. The relationship between PDO and hydroclimate in central Asia is more robust than in monsoonal Asia. The positive correlations between the PDO and hydroclimate in central Asia are more robust in warm periods. This is because the interannual PDO variability, similar to the interannual ENSO variability, tends to be enhanced (weakened) in warm (cold) periods, resulting in high (low) interannual variability in central Asia during the warm (cold) periods prior to the industrial era. The significant interdecadal hydroclimate changes in central Asia are likely linked to the PDO via the atmospheric circulation between Tibetan Plateau and the central North Pacific Ocean. The significant interdecadal hydroclimate changes in monsoonal Asia may be linked to the atmospheric circulation between monsoonal Asia and the central North Pacific Ocean.We calculated DAI for central and monsoonal Asia and investigated their relationships and linkages with coupled ocean-atmosphere patterns. The presence (absence) of interdecadal variability in central Asia often correspond to periods without significant interdecadal variability in monsoonal Asia, particularly before the 19Figure S1The time-varying number of tree-ring chronologies used in MADA.(TIF)Click here for additional data file.Figure S2The 51-year running correlations between DAI in central and monsoonal Asia for the high-passed and low-passed data derived from a reciprocal pair of low-pass and high-pass Gaussian filters.(TIF)Click here for additional data file.Figure S3Squared wavelet coherence (WTC) of the drought area index (DAI) between central and monsoonal Asia. The arrows pointing left (right) indicate anti-phase (in-phase) relationship. The areas with significance (p<0.05) relationships are indicated by thick contours.(TIF)Click here for additional data file.


The availability of clinically established DBPCFC minimal eliciting doses determined in food-allergic individuals is increasing and previous work has shown these data can be used to determine population based reference doses for allergen risk management. Despite the large amount of data for peanut, milk, egg and hazelnut, EU and US public health authorities have not established population thresholds for any of the allergenic foods. In the absence of regulatory guidance regarding thresholds, food producers have attempted to manage risk through the widespread application of precautionary "may contain" labelling. In turn, food-allergic consumer quality-of-life has decreased and some food-allergic individuals are ignoring these advisory statements.This study aimed to assess the effects of the number of individual threshold doses and the dosing scheme intervals on the accuracy of estimates of population thresholds for allergenic foods. A simulation study was performed to evaluate the effects of sample size (N=20-750) and dosing scheme  on the accuracy of the resulting threshold distribution curve. The simulations were based on clinical data on individual subject thresholds from peanut, egg and soy flour allergic individuals.The relationships between sample size, dosing scheme and the employed statistical distribution on the one hand and the accuracy of estimation of population based eliciting doses on the other hand were obtained. The largest relative gains in accuracy were seen when sample size increases from N=20 to N=60. Additionally, proper allocation of the dosing steps is important. So, while the EuroPrevall dosing scheme is a good start, the scheme may need revision for a specific allergen as more data become available.These results may guide risk assessors in determining minimum sample sizes for new studies and in the allocation of proper dosing schemes for allergens in provocation studies. In turn, these results will help determine dataset requirements when establishing population thresholds and reference doses leading to improved allergen risk management of food products.


Despite advances in the pharmacologic and interventional treatment of coronary artery disease (CAD), atherosclerosis remains the leading cause of death in Western societies. X-ray coronary angiography has been the modality of choice for diagnosing the presence and extent of CAD. However, this technique is invasive and provides limited information on the composition of atherosclerotic plaque. Coronary computed tomography angiography (CCTA) and cardiac magnetic resonance (CMR) have emerged as promising non-invasive techniques for the clinical imaging of CAD. Hereby, CCTA allows for visualization of coronary calcification, lumen narrowing and atherosclerotic plaque composition. In this regard, data from the CONFIRM Registry recently demonstrated that both atherosclerotic plaque burden and lumen narrowing exhibit incremental value for the prediction of future cardiac events. However, due to technical limitations with CCTA, resulting in false positive or negative results in the presence of severe calcification or motion artifacts, this technique cannot entirely replace invasive angiography at the present time. CMR on the other hand, provides accurate assessment of the myocardial function due to its high spatial and temporal resolution and intrinsic blood-to-tissue contrast. Hereby, regional wall motion and perfusion abnormalities, during dobutamine or vasodilator stress, precede the development of ST-segment depression and anginal symptoms enabling the detection of functionally significant CAD. While CT generally offers better spatial resolution, the versatility of CMR can provide information on myocardial function, perfusion, and viability, all without ionizing radiation for the patients. Technical developments with these 2 non-invasive imaging tools and their current implementation in the clinical imaging of CAD will be presented and discussed herein. Despite major advances in the treatment of coronary artery disease (CAD), it still remains one of the leading causes of death in Western societies   can provide non-invasive imaging with sub-millimeter spatial resolution and high blood-to-tissue contrast  resolution for the assessment of cardiac function. The latter is almost 10-fold higher compared to competing nuclear scintigraphy techniques. Although earlier CMR studies had limitations, such as poor slice coverage and low temporal resolution, limiting the detection of CAD, subsequent data demonstrated that CMR compares favorably to SPECT for the detection of myocardial ischemia  and spatial , 86%  and of 91%  and 81% , respectively were reported Tables . In thisAn example of a patient with inducible wall motion abnormality of the anterior-septal apical wall during peak dobutamine stress CMR is illustrated in Figures p < 0.05) for the detection of obstructive CAD  in at least one myocardial segment, which persists for ≥5 consecutive image frames, is considered as indicative of inducible ischemia  is an established method for the assessment of infarct size and for the risk stratification of patients after acute myocardial infarction and with chronic ischemic heart disease . More than 10,000 have already been enrolled in this study and first results are expected in 2015.Ongoing clinical trials such as the PROMISE study now aim at comparing functional stress tests such as CMR and echocardiography with anatomical modalities such as CCTA in order to determine which might be better at finding out who has heart disease and will require more testing and treatment (Cardiac Computed Tomography Angiography (CCTA) can provide non-invasive imaging of moving coronary arteries with sub-millimeter spatial resolution and high signal-to-noise ratio. This technique has seen rapid progress in its utility for the assessment of CAD in the last years and can provide delineation of both vessel lumen and coronary vessel wall. The latter enables the assessment of atherosclerotic plaque composition, which seems to be of great importance not only for the diagnostic classification but also for the estimation of future cardiac events in patients with suspected CAD. In contrast to CMR, the administration of iodine contrast agents is necessary with CCTA for the visualization of cardiac structures and coronary arteries.In addition CCTA is associated with radiation exposure for the patients, which limits its serial applicability, particularly in younger patients  compared to those without proximal coronary stenosis. In this regard, the number of proximal segments with stenosis >50% and the number of proximal segments with mixed or calcified plaque were identified as the best predictors of outcome surpassing the value provided by standard clinical variables, including the Framingham and the Morise score. In addition, the value of risk assessment in patients with CAD using a CCTA-based semi-automated plaque assessment has been recently shown . In this regard, cardiac troponins were shown to aid the diagnostic classification and risk stratification of such patients  on the other hand, was previously proposed as a central mediator in atherosclerotic plaque development and vascular inflammation  to non-invasively visualize moving coronary vessels with high spatial resolution, excluding significant CAD with high precision and (2) to assess the composition of atherosclerotic plaque components. Its main limitation is the resultant radiation exposure for the patients, which limits its serial applicability particularly in younger patients. However, scientist, clinicians, and manufacturers managed significant reductions of radiation exposure in this field within the last 5 years. The strength of CMR on the other hand, is its ability to assess inducible wall motion abnormalities and perfusion defects during stress testing aiding the detection of functionally significant CAD. Thus, it represents the optimal technique for the risk stratification of patients with suspected CAD and for guiding revascularization procedures in patients with diagnosed CAD by CCTA or invasive angiography. Current guidelines encourage the liberal use of both CCTA and CMR as first choice modalities for the diagnostic work-up of patients with low and intermediate likelihood for CAD in experienced centers.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The flux phenotype describes the entirety of biochemical conversions in a cell, which renders it a key characteristic of metabolic function. To quantify the functional relevance of individual biochemical reactions, functional centrality has been introduced based on cooperative game theory and structural modeling. It was shown to be capable to determine metabolic control properties utilizing only structural information. Here, we demonstrate the capability of functional centrality to predict changes in the flux phenotype.We use functional centrality to successfully predict changes of metabolic flux triggered by switches in the environment. The predictions via functional centrality improve upon predictions using control-effective fluxes, another measure aiming at capturing metabolic control using structural information.The predictions of flux changes via functional centrality corroborate the capability of the measure to gain a mechanistic understanding of metabolic control from the structure of metabolic networks. The metabolic state of a cellular system is characterized by the fluxes of the underlying biochemical reactions and the concentrations of the involved metabolites . In the functional centrality to predict changes in experimentally determined metabolic fluxes based solely on the structure of the metabolic network captured by its stoichiometric matrix.Alterations in the flux phenotype are triggered by internal or external shifts and imply rerouting of metabolic flux, for example from respiration towards fermentation in facultative aerobic bacteria , which iFunctional centrality combines cooperative game theory, in particular a modified version of the Shapley value for arbitrary restricted games , with flEscherichia coli.In our previous study we examined the relationship of functional relevance and transcriptional readout , wherebyE. coli resulting from a shift between aerobic and fermentative conditions and the corresponding changes of the two investigated measures. The flux data were obtained via stationary 13C labeling experiments and metabolic flux analysis by Fischer et al. [We examine the capability to predict flux changes using functional centralities as well as control-effective fluxes, which were found to be the two best-performing contending predictors of transcriptional change in a recent study of structural control of metabolism . To thisr et al. .E. coli’s central carbon metabolism provided by Schuetz et al. [In accordance with the definition of control-effective fluxes , we utilz et al. . For botz et al. .Table 1Aith (log-transformed) data point and the (log-transformed) predicted value, respectively; ith residual and The ability of control-effective fluxes and functional centrality to predict the observed flux changes (23 data points) is assessed by employing two statistical procedures. In the first, we fit a regression model. Inspection of the dataset indicates a non-linear relationship in the case of both measures. We utilize logarithmic transformation of the predictor’s and of the regressor’s values, respectively, to discount non-linearity and to render the distribution of the predicted quantity closer to normal. A linear regression model is fitted to the double-log-transformed data . The slope of the linear regression line then indicates the relative  change of flux resulting from a relative  change of the predictor. The goodness of fit is determined by the coefficient of determinationFunctional centrality, like control-effective fluxes, does not require any further information besides reaction stoichiometry, characterization of exchange fluxes and the choice of a metabolic function. Here we demonstrated that functional centrality enables prediction of changes in metabolic flux with improved accuracy, exceeding the results of control-effective fluxes. The functional centrality measure is based on the rich axiomatic framework of power indices in cooperative games, and is suitable for the analysis of structural control of metabolic networks, as supported by the analyzed data. Our results provide further indication that concepts from cooperative game theory can help in obtaining a better understanding of control in metabolic networks.z representing the objective to be optimized, Flux balance analysis is a structural modeling framework enabling prediction of steady-state metabolic flux . It reliFunctional centrality quantifies the contribution of individual reactions to a metabolic function, e.g., biomass production, by utilizing a formulation of the Shapley value for restricted cooperative games . The metv in a subnetwork formed by the reaction set S is determined by FBA. Let maximal chains. The calculation of functional centrality is as follows:The optimal value of the objective function i in maximal chain W is given byl(W) being the length of the maximal chain W and i with respect to the objective function v isLet efficienciesl in the EFM Control-effective fluxes are defined by advance) :6\documeE. coli originally published by Schuetz et al. [mglABC and ptsGHI is constrained from above arbitrarily by one. Isozymes in the model were deleted. We examine two environmental conditions: (i) aerobic respiration and (ii), fermentation (no oxygen and no nitrate import). The utilized objective functions are the fluxes through the reactions: (i) maint (ATP production) and (ii), biomass (biomass production).We utilize a model of central carbon metabolism of z et al. . Import


Human land use tends to decrease the diversity of native plant species and facilitate the invasion and establishment of exotic ones. Such changes in land use and plant community composition usually have negative impacts on the assemblages of native herbivorous insects. Highly specialized herbivores are expected to be especially sensitive to land use intensification and the presence of exotic plant species because they are neither capable of consuming alternative plant species of the native flora nor exotic plant species. Therefore, higher levels of land use intensity might reduce the proportion of highly specialized herbivores, which ultimately would lead to changes in the specialization of interactions in plant-herbivore networks. This study investigates the community-wide effects of land use intensity on the degree of specialization of 72 plant-herbivore networks, including effects mediated by the increase in the proportion of exotic plant species. Contrary to our expectation, the net effect of land use intensity on network specialization was positive. However, this positive effect of land use intensity was partially canceled by an opposite effect of the proportion of exotic plant species on network specialization. When we analyzed networks composed exclusively of endophagous herbivores separately from those composed exclusively of exophagous herbivores, we found that only endophages showed a consistent change in network specialization at higher land use levels. Altogether, these results indicate that land use intensity is an important ecological driver of network specialization, by way of reducing the local host range of herbivore guilds with highly specialized feeding habits. However, because the effect of land use intensity is offset by an opposite effect owing to the proportion of exotic host species, the net effect of land use in a given herbivore assemblage will likely depend on the extent of the replacement of native host species with exotic ones. Consumer-resource interactions between herbivorous insects and their host plants represent a large fraction of terrestrial food webs. In pristine habitats, plant-herbivore networks are mostly characterized by highly specialized interactions, since most insect species consume only a small subset of the total set of host plant species –2. GivenBecause many herbivorous insects have a high degree of feeding specialization –15, the Exotic plant species, in general, have little shared evolutionary history with native insects, thus making them less likely to be consumed by specialized native herbivores when compared with native plants . Hence, An important feature of herbivorous insects is the way in which they feed on their host plants. Perhaps the most distinctive dichotomy is between endophages and exophages. Endophagous herbivores feed and often develop concealed within plant tissues . In contrast, exophages are free-living herbivores that feed externally on plant tissues . Exophages have been shown to be more generalist, in terms of host range, than endophages –21. The In this study, we retrieved plant-herbivore networks surveyed under different levels of land use intensification and with distinct proportions of exotic host species, to investigate the extent to which human alteration of habitats leads to predictable changes in the specialization of plant-herbivore interactions. Because most plant-herbivore studies provided only binary  interaction records, we used network connectance and proportion of monophagous herbivores as proxy variables for network specialization. Connectance is the proportion of possible interactions that are realized  in a network. In plant-herbivore networks, connectance can be interpreted as the mean proportion of host plant species used by the herbivores as well as the mean number of herbivorous species recorded on each plant species. Monophagous herbivores are the insect species recorded on a single host plant species and thus represent the highest level of feeding specialization. Specifically, we addressed the following questions: 1) Do higher levels of human land use and higher proportions of exotic host species lead to consistent changes in the connectance of plant-herbivore networks? 2) Are monophagous herbivores more sensitive to the effects of land use intensity and proportion of exotic host species? 3) Do plant-herbivore networks composed of internal- versus external-plant feeders respond differently to the increase in land use intensity and in the proportion of exotic host species? We outline the expected effects of land use intensification and proportion of exotic host plant species in a conceptual model . Connectwww.nceas.ucsb.edu/interactionweb) and the cited literature in some key review studies on plant-insect interactions [We produced a comprehensive compilation of sets of local interaction records between host plants and herbivorous insects  Tables. ractions –24. We aThe following criteria were applied to include a plant-herbivore network in our analyses: (1) The original study should provide at least a basic description of the study area to allow categorization of land use intensity; (2) herbivores were recorded on their host plants; (3) all plants should be potential hosts for any herbivorous insect; (4) the network should contain at least five plant and five insect species, totaling at least 10 species; and (5) at least 70% of the herbivores should be identified at the species or genus level.In order to assess the degree of habitat alteration to which each plant-herbivore network was subjected, we developed an index of land use intensity. Because most of the compiled studies did not include a detailed description of land use or human-induced modifications that might allow a fine classification of land use intensity, we used a simple classification scheme based on the descriptions of the sampling sites in the original studies. We defined the following four categories of land use intensity: (1) pristine natural habitats ; (2) natural habitats moderately impacted by human activities ; (3) agricultural or ruderal habitats with high diversity of plant species ; and (4) agricultural or urban habitats with low diversity of plant species . This categorization of land use was used as an ordinal variable ranging from 1 to 4.For each network, we classified the plant species as native or exotic according to plant databases available for the country where the network was studied . This biWhen describing plant-herbivore networks, authors often choose to limit the sampling procedure within a taxon. For example, some networks include only plants from a given family , or onlyThe taxonomic spans of plants and insects are necessarily related to the phylogenetic diversity of the plant and insect assemblages, respectively. Because of the difficulty to obtain well-resolved phylogenies for insects and plants, we used taxonomic diversity as surrogate of phylogenetic diversity of the plant-insect networks. For this, we used the index Average Taxonomic Distinctness (AvTD), which is based on topological distances between species in the taxonomic tree . This inWe used network connectance and the proportion of monophagous herbivores as proxies for network specialization. Connectance is, in fact, an inverse measure of overall interaction specialization because, in networks with higher connectance, species tend to have more connections ; thus, the higher the connectance, the lower the specialization of plant-herbivore networks. The connectance was calculated as the residuals from a linear regression between the number of realized interactions and the number of potential interactions (both log-transformed) across plant-herbivore networks . By using the residual connectance, we controlled for the negative relationship between network size  and connectance, a well-known issue when comparing distinct networks . ResiduaThe proportion of monophages  in each network was used as a further measure of network specialization. Note that we measured specialization at the local scale, so that a monophagous species in a given plant-herbivore network may be a generalist herbivore if all its populations are considered . In addiWe used a path analysis approach  to quantThe model fits were assessed through chi-squared tests and by examination of the Tucker-Lewis Fit Index (TLI), the Comparative Fit Index (CFI), and the Root Mean Square Error of Approximation (RMSEA). Statistical power was calculated using the approach introduced by MacCallum et al.  and the We selected the 72 plant-herbivore networks that meet the five inclusion criteria used in this study see . These nThe path models explained 27%, 70% and 18% of the variation in residual connectance considering all networks, only plant-endophage networks and only plant- exophage networks, respectively . The thrWe found that the total effect of land use intensity on the residual connectance is partly offset by the proportion of exotic host plant species ; Fig. 3.We found similar results when the proportion of monophagous herbivores was used as a measure of interaction specialization in plant-herbivore networks . Land usOur results show that land use intensification and an increasing proportion of exotic host plant species have opposite effects on the overall interaction specialization of plant-herbivore networks. Contrary to our expectations, land use intensity has a direct negative effect on network connectance and a positive effect on the proportion of monophagous herbivores. The term “direct effect” here means an effect that is not mediated by other variables in the path models, but that can be mediated by non-measured variables. Conversely, connectance increases and the proportion of monophagous herbivores decreases as the proportion of exotic host species increases. Since the proportion of exotic host species tends to increase at higher levels of land use intensity –8, the pIt is possible that network specialization increases with habitat changes, because more specialized herbivorous insects tend to be associated with more resilient plant species . Thus, aAnother explanation for the increase in network specialization in highly impacted habitats could be that, at the local scale, generalist insects tend to become specialized in a few plant species after habitat conversion by human activities. In fact, spatial and temporal variation in the use of host plants might cause herbivores to have few local host species , 30. AltFrom the standpoint of herbivorous insects, an increase in network specialization can be interpreted as a decline in the number of alternative host-plants, which increases the probability of secondary extinctions of herbivores following the loss of host species , 25. ThiLand use intensity also has a negative indirect effect on specialization mediated by an increase in the proportion of exotic plants. An explanation for our results is that the herbivore fauna associated with exotic plants is restricted, composed of few species  that areOur findings provide evidence that external and internal plant feeders have different responses to land use intensity. In the present study, we found that land use intensity has direct and indirect effects on the community-wide specialization of endophagous insects, but little or no effect on the community-wide specialization of exophagous insects.Endophages tend to be more specialized than exophages , 41, andWe recently showed that an increase in the proportion of exotic plants has a greater impact on the diversity of endophagous than on the diversity of exophagous herbivore insects . We alsoSeveral studies on plant-herbivore interaction networks have shown that interactions between species are phylogenetically compartmentalized , 43. PhyOur results show that estimates of network specialization are negatively affected by herbivore taxonomic range. Thus, networks studied over a broader taxonomic range  are likely to have a smaller proportion of realized interactions than networks that span a more restricted taxonomic unit . This can be explained by the fact that interaction connectivity within a given network compartment is greater than interaction connectivity between the different compartments . The samPhylogenetic diversity (as measured by AvTD) of herbivores also influenced network residual connectance; however, the effect was positive. This might occur because phylogenetically diverse assemblages are more likely to contain super-generalist herbivores. Additionally, when sampling a wider taxonomic span of herbivores  in phylogenetically diverse assemblages, researchers are likely to sample a smaller fraction of the diversity of these taxa, with the overrepresentation of generalist species leading to higher perceived network specialization.Human-induced modifications of natural habitats have promoted the rapid loss of biological diversity, mainly through changes in the diversity of species and their interactions. Our study indicates that land use intensity is an important driver of network specialization, reducing the local host range of herbivore guilds already characterized by highly specialized feeding habits. However, because the effect of land use intensity is also offset by an opposite effect of the proportion of exotic host species, the net overall effect will depend on the extent of the replacement of native with exotic host plant species. Our findings also point to different effects on assemblages of endophagous or exophagous herbivores, so that only plant-herbivore networks of endophagous insects show a change in interaction specialization due to increases both in land use intensity and in the proportion of exotic host speciesS1 TableIn the case of repeated references the same study contained more than one network.(DOCX)Click here for additional data file.S2 TableList of assemblage characteristics related to insect diversity and geographical aspects. The codes of the networks correspond to references listed in (DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


The Hospital-based Influenza Morbidity and Mortality (HIMM) surveillance system is an emergency room (ER)-based influenza surveillance system in Korea that was established in 2011. The system was established under the assumption that integrated clinical and virologic surveillance could be performed rapidly and easily at seven tertiary hospitals' ER. Here, we assessed the correlation between data generated from the HIMM surveillance system and the Korean national influenza surveillance systems during the 2011–2012 influenza season using cross-correlation analysis and found strong correlations. Rapid antigen-test-based HIMM surveillance would predict the start of influenza epidemic earlier than pre-existing influenza-like-illness-based surveillance. Public influenza surveillance systems are important for early detection and rapid response to an epidemic. In Korea, the two separate national surveillance networks that report on the circulation of influenza are the outpatient influenza-like illness (ILI) surveillance network  and the laboratory virus surveillance system . In 2011, the Trans-government Enterprise of Pandemic Influenza in Korea (TEPIK) developed another hospital-based influenza surveillance system, named “Hospital-based Influenza Morbidity and Mortality” (HIMM). The HIMM consists of an integrated clinical and laboratory surveillance system, in which seven nationwide tertiary teaching hospitals collect data of patients who visit the emergency room with ILI. This system aims to monitor not only influenza activity but also influenza severity, such as hospitalization, complication and mortality, which cannot be reflected by national surveillance systems. The objective of this study was to compare the surveillance data of HIMM with KISS and KINRESS in its first year of operation during the 2011–2012 influenza season.Analyses were performed according to the week of the year with week 1 defined as starting with the week (from Monday through Sunday) in which the January 1 is allocated. The study period was from October 2, 2011, through June 30, 2012. We restricted our analysis to the period during which HIMM surveillance was initiated, from week 41 of 2011 through week 26 of 2012.In the HIMM surveillance network, participating sites prospectively entered the data of patients who visited the emergency room with an ILI  into the Internet database. The weekly incidence of ILI per 1000 patients who visited the ER was calculated from the database. A rapid antigen test  for influenza virus was performed using the respiratory samples that were collected by nasopharyngeal swab or aspirate, and throat swab if the patient consented to the test. During the study period, samples were taken from 41·3% of 10 872 patients presenting with ILI. The influenza test positivity was defined as the ratio of the number of positive cases divided by the total number of tests. RAT positivity was reported weekly.To compare the HIMM data, the data from the two national influenza surveillance systems were obtained from the Korean National Institute of Health (KNIH). Both HIMM and KINH use same definition of ILI. KISS surveillance consists of a network of about 800 public health centers and private clinics that record the weekly proportion of patients who have ILI symptoms.R) were calculated, and a relationship is reported as significant at P < 0·05. Correlation coefficients were subsequently calculated for regional HIMM and KISS surveillance data to monitor regional influenza trends. We undertook an additional correlation analysis to determine whether HIMM RAT surveillance was correlated with KINRESS RT-PCR surveillance. Data analysis was performed using spss, version 10·0 . The study was approved by the ethics committee of each institution involved and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.The influenza epidemic period was defined as the week in which the ILI rate crossed a certain value based on a seasonal threshold set by the KNIH. Baseline ILI rate was calculated as the average of the values of the ILI rate during the pre-epidemic period. Scatter plots were constructed to compare HIMM ILI surveillance data with KISS surveillance data. From these comparisons, Pearson's correlation coefficients . The initial rise occurred earlier in KINRESS surveillance from week 51 and in HIMM from week 52. In addition, HIMM RAT surveillance and KINRESS RT-PCR surveillance, respectively, showed strong correlation with HIMM ILI surveillance and KISS ILI surveillance .The weekly influenza cases detected by HIMM RAT and KINRESS RT-PCR surveillance during the study period are shown in Figure HIMM ILI and HIMM RAT surveillance systems were established under the assumption that effective influenza surveillance could be performed easily and rapidly at the tertiary hospital emergency room level. This study provided a report of the first year of HIMM surveillance and assessed the correlation with the two Korean national influenza surveillance systems.The comparison between HIMM ILI and national ILI surveillance demonstrated the reliability of tertiary hospitals' ER-based surveillance to monitor influenza activity. KNIH collects data from sentinel practitioners and disseminates the results weekly by an online report, and this process takes about one week. In the first operating year, HIMM collected data and released the reports at the same time as KNIH. However, HIMM could achieve daily analysis of ILI rates by asking sentinel sites, and this suggests that HIMM could identify the daily influenza activity. This may provide an advantage of HIMM ILI surveillance compared with other established small-scale influenza networks.3It is interesting that HIMM surveillance showed a higher baseline ILI rate than national ILI surveillance. Because the cost of ER care in Korea is not as expensive as in other countries and over-the-counter drugs are not available in supermarkets, many patients tend to visit the ER when local clinics are closed, regardless of the severity of the disease. Therefore, patients with ILI are always found visiting the ER.The ILI rates need to be interpreted with caution because they may not represent true cases of influenza. Additional laboratory surveillance is important to initiate proper preventive measures with confidence. For this reason, the results produced by virologic surveillance should be available with as little delay as possible. Although virologic surveillance can be carried out by various techniques, RT-PCR is commonly used in most influenza surveillance systems. However, it is labor-intensive and time-consuming. The strong correlation between RAT-confirmed positivity by HIMM and RT-PCRs by KINRSS supports the use of RATs for evaluating real-time confirmed influenza activity. Previous studies revealed the simplicity and reliability of RAT for surveillance of influenza epidemics, and our study supports these results.5Early detection of an epidemic is important to prepare for the potentially serious threat to public health. Although few studies have evaluated the timeliness of ILI surveillance compared with laboratory surveillance, ILI surveillance has been reported to detect the onset of seasonal influenza before an increase in laboratory notification.We note that our study had several limitations. Compared with KISS surveillance, the baseline ILI rates of HIMM surveillance showed fluctuation during the initial operating period, and this may have affected the results. This fluctuation may be due to the immaturity of data collection at that time. Another limitation was the limited information of epidemiological features in national surveillance systems, so comparison along with age, sex, influenza vaccination, and comorbidities was not available.In conclusion, the HIMM surveillance system has some strengths compared with national influenza surveillance. HIMM surveillance can monitor influenza circulation based on a small number of nationwide tertiary institutions, so more rapid data processing and reporting are possible. Moreover, it demonstrated the possibility of detecting early signals of influenza epidemics by using simple and quick RATs. HIMM surveillance can also monitor severity of influenza infection by collecting the data of the hospitalization, intensive care unit admission, complications, and mortality, which cannot be reflected by national surveillance system. We hope that HIMM surveillance will prove to be an excellent complementary tool to national influenza surveillance systems in the future.