Celiac disease (CD) is a complex autoimmune disorder in genetically predisposed individuals of all age groups triggered by the ingestion of food containing gluten. A reliable diagnosis is of high interest in view of embarking on a strict gluten-free diet, which is the CD treatment modality of first choice. The gold standard for diagnosis of CD is currently based on a histological confirmation of serology, using biopsies performed during upper endoscopy. Computer aided decision support is an emerging option in medicine and endoscopy in particular. Such systems could potentially save costs and manpower while simultaneously increasing the safety of the procedure. Research focused on computer-assisted systems in the context of automated diagnosis of CD has started in 2008. Since then, over 40 publications on the topic have appeared. In this context, data from classical flexible endoscopy as well as wireless capsule endoscopy (WCE) and confocal laser endomicrosopy (CLE) has been used. In this survey paper, we try to give a comprehensive overview of the research focused on computer-assisted diagnosis of CD. •The state-of-the-art research in automated diagnosis of celiac disease is presented.•A systematic review of methods and techniques used in this field is given.•Specific issues and challenges in the field are identified and discussed. There are also numerous extraintestinal CD manifestations like dermatitis herpetiformis In untreated or inappropriately treated CD the inflammation caused by the dysregulated immune response can disrupt the intestinal mucosa thus leading to a total atrophy of the villi, which are finger-like projections of the mucosa. After embarking on a strict gluten-free diet (GFD), which is the CD treatment modality of first choice, the inflammation gradually subsides allowing for mucosal healing. Strict adherence to a GFD for life is required if acute and chronic complications are to be avoided Besides for a small proportion of children fulfilling certain clinical, serological and genetic criteria The mucosal alterations caused by CD are classified into different stages of severity. Oberhuber Unfortunately, the histological staging of biopsies is subject to a significant degree of intra- and inter-observer variability An interesting field where computer-assisted video analysis could be useful is the application within follow-up endoscopies of celiac patients on a GFD, testing if a re-growth of villi has taken place. Another advantage of computer-assisted video analysis is quality improvement rendered possible by means of telemedicine, for example, by obtaining a second opinion after endoscopic video clips have been transmitted to institutions that have video analysis software at their disposal allowing for an observer independent objective diagnostic evaluation.A further limitation of the current gold standard for the diagnosis of CD is due to the possibly patchy distribution of intestinal mucosa areas affected by CD in the midst of normal mucosa In this work, we try to draw a comprehensive picture of the research focused on computer-assisted diagnosis of CD in endoscopic data. In 2Besides standard upper endoscopy, several new endoscopic approaches for diagnosing CD have been applied Narrow band imaging NBI  uses speConfocal laser endomicroscopy  is a novel technology allowing real-time in vivo microscopy. CLE allows the inspection of multiple mucosal layers, employing a laser at different focal points and has been shown to be a promising technique for diagnosis of CD in endoscopy A general drawback of endoscopy using flexible endoscopes is the limited range. As a way of inspecting a much larger area of the intestine, wireless capsule endoscopy WCE  is used.2.1The most prevalent endoscopic markers for CD include scalloped folds, mosaic patterns of the mucosa and a nodular mucosa It has been reported that the prevalence of endoscopic markers is significantly lower for partial villous atrophy (58%) than for subtotal or total villous atrophy (82%) Effort has been put into the identification of temporal features in CD such as the variations in brightness and texture 2.2The natural features of endoscopic techniques used in the diagnosis of CD call for different approaches towards automated diagnosis. Data from flexible endoscopy is characterized by high image resolution but rapid non-monotonic movement. As a consequence, spatio-temporal features are rather inappropriate for this type of data and most work in this context was done using the approach from a more classical texture classification perspective. CLE combines microscopy with standard endoscopy, providing the highest image resolution of all endoscopic methods. Although classic endoscopic degradations are not expected during endomicroscopy, targeting of suspect areas for inspection is a vital part of the diagnosis chain and comparable to flexible endoscopy. Consequently, a significant number of challenges are shared between flexible endoscopy and CLE. The most significant difference of those two techniques compared to WCE is the possibility of interaction with a clinician during the procedure.Data captured during WCE is characterized by slower, monotonic movement and lower resolutions. This is resulting from the passive propulsion of the camera through the intestine caused by peristalsis. Due to the nature of the data, spatio-temporal features are a much more promising concept as compared to flexible endoscopy and CLE. The missing possibility of interaction and the large amount of recorded data requires different concepts for computer-assisted systems as compared to flexible endoscopy and CLE. In WCE, automated systems focused on reducing the workload of a manual analysis and interpretation by clinicians and providing additional, discriminative statistics for diagnosis seem to be most valuable.The properties of flexible endoscopy, CLE and WCE are quite divergent. Consequently, it is unlikely that methods developed for one endoscopic technique can be used in the other in a straightforward manner. 3The nature of data provided by endoscopy requires systems for computer-assisted diagnosis to perform visual analysis. Consequently, the main focus of research found in the literature is focused on methods for the visual classification of duodenal tissue.3.1The unconstrained gastrointestinal environment provides a challenging scenario for visual analysis. Endoscopic image degradations such as blur, bubbles, specular reflections, non-opaque fluids as well as rapidly changing viewpoints and camera-distances complicate a systematic analysis of developed methodologies. To avoid unwanted side-effects caused by such degradations, current research focused on the visual classification of intestinal mucosa affected by CD is based on a defined set of  constraints. Due to the lack of publicly available data-sets experimental evaluation and development is performed using specific private data-sets.WCE: The data used during experimentation and consequently all reported results in WCE Flexible endoscopy: The data used during experimentation in flexible endoscopy varied between publications. Initial work The flexible endoscopy data-set is based on video data captured during standard endoscopy (the majority using the MIT) in children suffering from signs and symptoms making upper endoscopy necessary. The severity of the disease was classified based on histological findings (Marsh–Oberhuber) in children with positive CD serology. During the procedure, still images of areas with specific visual manifestations of CD or the absence of the disease were captured by the endoscopist. The full image frames were later manually segmented by a domain expert into possibly multiple, non-overlapping regions of size 128×128 pixels CLE: The CLE data-set used by Grisan et al. k-nearest neighbor classifiers (kNN), Bayes classifiers and random forests were used in this context. According to the published literature, it seems clear that the most significant impact on the accuracy of automated diagnosis lies within the proposed image representations however. Consequently, the focus of the presented methodologies in the following subsections lies on the feature extraction methods used for classification of CD. Due to different data-sets and evaluation methodologies used across the literature, it is difficult to compare the obtained results. Consequently, herein we will only report the results of methods that were evaluated in a comparable fashion. The presented experiments were based on the data described in this section. Note that the data-sets used in experimentation was approximately balanced between cases and controls (in terms of samples) in this experiments. For the sake of consistency we present the classification accuracy ) of each paper in the following section. A variety of different classification methodologies, including variations of support vector machines (SVM), 3.2In flexible endoscopy, special attention was payed to image representations in the spatial-domain. A method particularly developed for classification of CD is the Shape-Curvature-Histogram (SCH) Ciaccio Other, more general purpose image representations that were applied include the Edge Co-Occurrence Matrix A very promising class of spatial image representations was based on Local Binary Patterns LBP . LBP repVarious specialized LBP-variations have been developed for computer-assisted diagnosis of CD. Vécsei et al. Explicit frequency filtering using appropriate cut-off frequencies in combination with LBP-based image representations Spatial domain features seem to be very well suited for the visual classification of CD. In addition to providing a high classification accuracy, the majority of methods in this category are robust in terms of distortions and fast to compute. Both of these strengths are necessary requirements for real-time applications in endoscopy.3.3Various feature extraction methods used for classification of CD in flexible endoscopy are based on image domain transformations. A benefit of computing features in transform domains is the possibility of employing different categories of information, such as multi-scale and multi-orientation information in wavelets subbands or frequency and phase information in the Fourier domain.Wavelet-based methods have been used frequently for the classification of CD throughout literature. The most elementary features Other wavelet-based image representations that have been applied include classical Gabor statistics In addition to the standard wavelet transform, the dual-tree complex wavelet transform DT-CWT,  has beenIn a complementary fashion to the wavelet transform, Fourier based features have been proposed as well. Ring shaped filters with variable width, optimized in an evolutionary framework, were used to compute elementary statistics of the frequency domain coefficients Comparing the classification performance achieved by features computed in transform domains (OCR 70–82.5) with the rates of spatial features (OCR 81–90), a lower accuracy was obtained when using transform domain features. This could potentially be caused by endoscopic distortions, negatively influencing the transformation process or a generally lower discriminative power of the image representations.3.4Due to highly varying camera-perspectives and scales in endoscopic sequences, image representations invariant to scaling and rotation could be superior to features affected by such transformations. Consequently, scale-invariant image representations have been applied to data from flexible endoscopy 3T-CWT The majority of scale-invariant methods perform similarly to non-invariant image representations however. This is true for methods based on the DT-CWT and the DAmong the worst methods in terms of classification accuracy were features based on pulse coupled neural networks such as SCM The highly variable performance of scale-invariant features illustrates that such image representations are not always suited for difficult environments such as in endoscopy. Specular reflections, blur or bubbles are potentially misleading the identification of key-points or the estimation of affine shapes. Even more, the scale-invariance properties of a large number of methods are based on theoretical concepts and assumptions, which rarely hold true in practice. Consequently, the majority of features specifically designed for scale-invariance perform similarly to features affected by scaling. In general, scale-invariant image representations are computationally more demanding as compared to more elementary features. Therefore, the availability of such methods could potentially be restricted to offline scenarios in computer-assisted diagnosis.3.5Spatio-temporal features are a powerful tool for analyzing sequences of images or videos such as produced by WCE. The general benefits of this type of image representation are a higher robustness in terms of extraneous endoscopic degradations and the possibility of identifying CD even if the gastrointestinal manifestations of the disease are not visualized directly in the recorded data.Initial work In celiac patients, gastrointestinal motility abnormalities were reported Based on the assumption that the reduced gastrointestinal motility in celiac disease affects peristalsis, Ciaccio et al. Shape-from-shading is a technique for the reconstruction of the three dimensional structure of an object, based on illumination information. In Due to the relatively low accuracy but complementary characteristic of the presented features, a polling protocol for predicting CD in WCE analysis was presented, based on a majority voting scheme using a variety of features 4The gastrointestinal tract is a very challenging environment for computer-assisted diagnosis. As mentioned in The appearance of duodenal tissue is highly dependent on extrinsic camera parameters such as distance and angle towards the mucosa. As a combined effect of the geometric properties of the gastrointestinal tract with the large field of view of optical systems used in endoscopic hardware, certain areas of the visualized tissue are generally blurred or underexposed and noisy. The insufflation and suction of air during flexible endoscopy as well as the instillation of water into the lumen can lead to a significant amount of bubbles on the duodenal walls. Fluids on the mucosal surface can potentially cause specular reflections of the illuminating point light sources attached to the endoscope. These types of image degradations are likely to affect the feature extraction process and the performance of a computer-assisted system for diagnosis.Due to the challenging environment, methods for informative frame identification and segmentation are generally applied across the literature in related fields of endoscopic image processing. Most of the proposed methodologies, however, are tailored toward specific applications or endoscopic scenarios and cannot be used in a straightforward manner for CD diagnosis.An approach combining informative frame detection and segmentation in classification of CD was proposed by Gadermayr et al. An alternative concept by Hegenbart et al. In WCE, a way of handling extraneous features is based on robust spatio-temporal features computed from noise insensitive basis images 4.1It is safe to assume that endoscopic image degradations have a negative effect on the performance of computer-assisted diagnosis. The severity of these effects is unclear however. Consequently, Hegenbart et al. The authors report that certain types of image degradations, such as bubbles and reflections, only affect a subset of LBP-based methods and can actually be compensated using the proposed approach. Blur and noise had the most impact on the accuracy of the system. The unconstrained classification of CD based on LBP using a one-class SVM is feasible to some degree. Extreme cases of image distortions might require an additional step of informative frame identification however. By relaxing the needs for informative frame identification to extreme cases, the general reliability of a fully automated system could possibly be increased.Another, unorthodox approach is based on degradation adaptive texture classification 4.2Sequences in flexible endoscopy are commonly non-monotonic in terms of the passage through gastrointestinal regions. During the procedure, the endoscopic tip often traverses the stomach and the duodenum multiple times. Consequently, the visual appearance of esophageal and gastric tissue in endoscopic data is a common thing. A classification model based on duodenal tissue is potentially subject to error if visualized tissue of other (unknown) gastrointestinal regions is provided. Consequently, Hegenbart et al. The authors reported that the visualized appearance of esophageal and gastric tissue can be very close to duodenal tissue affected by villous atrophy see . The exp4.3Highly varying extrinsic camera parameters such as distance and angle to the mucosa can potentially lead to a blurred visualization of the tissue (close distance) or to a missing visualization of small spatial structures such as villi (far distance) and could therefore be inappropriate for visual classification see .The effects of varying camera-scales were explicitly studied by Hegenbart et al. Consequently, scale- and viewpoint-invariant methods have been employed Recently, a scale- and rotation-invariant image representation based on highly discriminative LBP (SOA-LBP) has been proposed, particularly for scenarios with significantly varying camera-scales 4.4Interlaced scanning is a technique that has been widely used in video systems to double the perceived frame rate without increasing the required bandwidth. This technique is still in use by certain endoscopic video hardware today. Various specialized de-interlacing techniques have been developed over the last decades to re-construct full frames from two interlaced half-frames. The impact of interlaced scanning and the benefits of applying suited de-interlacing techniques for computer-assisted systems was specifically studied The authors state that de-interlacing does not have a significant positive effect on the classification accuracy of endoscopic data with indication for CD. The benefits of applying de-interlacing were comparable to the effects of Gaussian filtering. Considering the accuracy of the system, the authors could not identify significant differences between simple and more complex de-interlacing techniques. Consequently, computer-assisted systems based on interlaced data could potentially be used without an explicit need for de-interlacing.4.5A special type of endoscopic image degradation, present in all endoscopic images, is a consequence of the wide-angle nature of the optical systems used in endoscopic hardware. Such barrel-type distortions introduce non-linear changes in the images, leading to a significantly smaller visualization of outer areas. The effects of endoscopic lens distortions as well as distortion correction on computer-assisted diagnosis have been extensively studied Interpolation artifacts and varying camera-scales were identified as the main restrictions of distortion correction performance A particular application for lens distortion correction is an improved visualization for clinicians during endoscopy 5The nature of medical data differs from the characteristics of data used in more classical texture classification scenarios. As a consequence of a potentially small number of available patients and an uneven distributions of healthy and unhealthy individuals undergoing treatment, multiple samples per patient are often used to build balanced data sets of sufficient size. This often results in an intrinsic bias of data sets used in medical image classification.To deal with restricted amounts of data available for experimentation, cross-validation techniques are used for predicting how well developed methodologies will generalize. Particularly in medical image classification, assumptions of such techniques are often violated by the inherent intrinsic bias of the created data-sets. The performance predicted by cross-validation is consequently subject to error.Methods for feature extraction or classification are usually parametrized by a set of values such as thresholds, number of neighbors or filter coefficients. The optimal range of values of such parameters is often unclear from a theoretical standpoint and usually determined empirically. Consequently, parameter optimization is often performed in the process of development or evaluation. In a combination with cross-validation, optimization can be dangerous and can potentially lead to over-fitting, reducing the accuracy of performance prediction significantly.A common flaw in the evaluation of methods is based on using the predicted classification accuracy of the cross-validation as the objective function for optimization. Hegenbart et al. Due to violated assumptions of cross-validation techniques, caused by the intrinsic bias of medical image sets, errors of up to 7 percentage points were reported . The violation of assumptions in cross-validation techniques can be avoided by using a data partition based on patients instead of images.The prediction error of nested-cross validations using patient-based partitions was reported to be only 1.4 percentage points as compared to the most realistic scenarios with two independent data-sets. Although nested-cross validations add a significant amount of computational complexity to the experimental setup, such schemes are mandatory for realistic predictions if optimization is performed.5.1In a revision of the Marsh-scheme for staging the severity of CD, Oberhuber et al. Only four publications As a side-effect of the potentially high intra- and inter-observer variability, the histological Marsh–Oberhuber based ground-truth used for developing computer-assisted systems is subject to a certain amount of noise. As a consequence of the patchy distribution of CD, discrepancies between areas with known histology and images used for developing computer-assisted systems could potentially exist.A noisy ground-truth as basis for development and training of a computer-based system could be problematic and effectively reduce the accuracy of and confidence in the automated diagnosis. Recently, Kwitt et al. 6Since the first publication on computer-assisted diagnosis of CD in 2008, a lot of progress towards a fully automated system has been made. A large variety of image representations has been studied and a solid knowledge of the behavior of methods in an endoscopic environments has been acquired. Based on constrained data-sets from flexible endoscopy, CD can currently be classified with an accuracy of up to 92%. Based on a majority voting using multiple complementary spatio-temporal features, classification accuracies in sequences of WCE currently reach 88%. The small number of sequences used for evaluation, however, still leaves open questions about the general performance of this methodology. Recently reported results by Grisan et al. using data from CLE indicate that this imaging modality could potentially be promising for automated diagnosis (OCR 93). Again, the small data-set size in CLE is problematic.Significant effort was put into the study and development of concepts for handling various challenges in endoscopic imagery such as image degradations, heavily varying extrinsic camera-parameters, interlacing and lens distortion. As an alternative approach to informative frame detection, a classification pipeline based on a one-class SVM has been proposed for the implicit handling of the most common endoscopic image degradations.Robust features computed from degradation insensitive basis images have been used to implicitly handle extraneous features in WCE and in an unorthodox approach, degradation adaptive classification has been successfully performed.Lens distortion has been shown to affect the accuracy of automated diagnosis. Consequently, distortion adaptive classification, distortion compensated features as well as intrinsic distortion correction have been used to improve the accuracy of classification.A solid understanding of issues and common flaws in the evaluation of methods in a medical context has been gained. It was shown that medical data in particular has to be treated with extreme care if cross-validation is used in combination with any type of parameter optimization. Empirical data indicates that a moderate amount of label noise in the ground-truth can be compensated if a large amount of training data is available.Although a big step towards the establishment of a fully automated system has been made, there are still a lot of challenges to be solved before a system for computer-assisted diagnosis can be used in clinical routine. One of the most stressing issues, especially in flexible endoscopy and CLE, is the development and establishment of robust and accurate methodologies for informative frame detection and segmentation. Although the implicit handling of various endoscopic image degradations is possible to some degree, images affected by blur and large camera distances are not very well handled in such an approach.Combining spatio-temporal features with highly discriminative texture features as used in still image classification is another challenging but promising concept. It may be possible that other highly significant celiac markers could be integrated into such an approach, potentially improving the general accuracy and robustness of the systems.Finally, it should be a general ambition to provide publicly available data-sets of CD. We are highly convinced that the research progress and interest on computer-assisted diagnosis of CD would thrive if public data-sets were available to fellow researchers.None declared.


The aim of the present study was to investigate the social cognitive functioning of participants with depression when compared with healthy controls, and to assess the impact of symptom severity. One hundred and eight patients with depression (66 remitted and 42 current) and 52 healthy controls were assessed using the Wechsler Advanced Clinical Solutions: Social Perception Subtest, measuring facial affect recognition in isolation and in combination with prosody and body language interpretation. When healthy controls, remitted depression and currently depressed groups were compared, no associations were found on any of the social cognition subscales. Severity of depressive and anxious symptoms predicted performance on all social cognition subscales in currently depressed participants, controlling for age, gender, education and psychotropic medication. Affective depressive symptoms were inversely related to ACS Pairs and Prosody subscales, while somatic symptoms were inversely related to the ACS Affect Recognition and Total scores. There was no association between severity and the WAIS ACS in remitted depression participants. People with MDD exhibiting more severe depressive and anxious symptoms and a cluster of affective symptoms have greater difficulty undertaking complex social cognitive tasks. Given the state like nature to these deficits, these impairments may cause problems with day to day functioning and have implications in targeted therapeutic interventions. Individuals with major depressive disorder (MDD) have reported pervasive impairments in cognitive functioning, including difficulties in attention  history of depression based on the MINI 6.0.0.Approval for the project was gained from the human research ethics committees of the University of Adelaide and Royal Adelaide Hospital. Inclusion criteria for the study were (1) aged 15 or over, and (2) adequate reading and writing skills and the ability to speak the English language. Exclusion criteria included diagnosis of schizophrenia, dementia, a learning disorder, eating disorder, or a Pervasive Developmental Disorder . In total, 160 subjects met the inclusion criteria and were included for analysis.MDD participants were recruited from the general community and clinical services within the Eastern Mental Health network, in Adelaide, South Australia. Advertisements were placed throughout the Royal Adelaide Hospital, The University of Adelaide campus, and local community noticeboards to allow further recruitment.Healthy controls were recruited via word of mouth from the general community, or again through posters advertisements placed throughout the Royal Adelaide Hospital, The University of Adelaide campus, and local community noticeboards. The sample was comprised of 52 healthy controls, 66 participants with remitted MDD, and 42 participants with current MDD.All participants were assessed with the MINI-6.0.0 Neuropsychiatric Diagnostic Interview  : This section involved showing the participant multiple pictures of male and female faces expressing one of seven different emotions—happiness, sadness, anger, fear, disgust, surprise, or neutral—and instructing them to select the correct emotion expressed from the above list. The maximum raw score for this subscale is 24.Prosody-face matching (ACS Prosody): This subset involved playing the participant a recorded voice and instructing them to match the emotional tone of the speaker with one of six faces displaying various expressions (the seven emotions from Affect Naming with sarcasm and confusion added). The maximum raw score for this subscale is 24.Prosody-pair matching (ACS Pairs): For this task, the participant again listened to a recorded statement and selected the most appropriate picture for the tone of the speaker from four different pictures of two actors interacting. After selecting a picture, the participant was asked to describe the emotion expressed by the speaker, and to determine whether the tone of voice used altered the meaning of the comment (such as with sarcasm). If so, they were required to state the real meaning behind the speaker's comment. The maximum raw score for this subscale is 42.Social Perception Total Score : The Social Perception Total score is derived by adding all of the correct matches of pictures of one to two people from the affect naming and prosody tasks, with a raw maximum score of 48.Statistical analyses were performed using Stata, version 12 . Categorical variables were analyzed using chi-squared tests and continuous variables were analyzed using One-Way ANOVA. Adjustments for multiple comparisons were not performed, as these corrections have been criticized for masking potentially important findings in clinical research  and symptom severity as assessed by the SIGH-AD. Age, gender, years of education and use of psychotropic medication were controlled for in the linear regression analyses. In the first step of the multiple regression analysis, the covariates were entered into the model. In the second step, the covariates plus the main effects of depression, anxiety or total symptom severity were entered into the model.Two depressive symptom clusters were also composed from the SIGH-AD , and significantly less likely have a family history of MDD  or have a current prescription for psychotropic medication . Significant differences in symptom severity were found between MDD and healthy control participants for the SIGH-AD Depression , SIGH-AD Anxiety  and SIGH-AD total score . One-Way ANOVAs revealed there was a significant difference between healthy controls, remitted depression and currently depressed groups on the SIGH-AD depression  and anxiety  subscales. As expected, post-hoc Scheffe's tests showed that patients with current depression had significantly higher SIGH-AD depression scores compared with the healthy controls (p < 0.001) and the remitted depression group (p < 0.001), significantly higher SIGH-AD anxiety scores , and significantly higher SIGH-AD total scores .Table There were no differences between the healthy controls, the remitted group or the currently depressed group on any of the ACS subscales or the total score Table . The meaBoth the ACS and SIGH-AD total scores were assessed for restriction of variance separately in the current and remitted groups. Figures Multivariate linear regression analyses were performed in the overall depressed sample to assess the impact of symptom severity on social cognition Table . In the Further diagnostic group stratified analyses showed that higher scores on the SIGH-AD scale  in the currently depressed group were all significantly associated with poorer social cognitive scores on all ACS subscales and the ACS total score. In contrast, no significant effects of the SIGH-AD scores on social cognition were found in the remitted depression subgroup.SE = 0.17, p = 0.014) and Prosody , while the somatic subscale had a significant inverse relationship with ACS affect recognition  and Total score .Finally, analysis of the affective and somatic symptom clusters revealed significant relationships with the ACS subscales and total score in the currently depressed group. The affective symptom subscale had a significant inverse relationship with both the ACS Pairs  functions (Cusi et al., The key question arising from this investigation is whether impairments with social cognition causes problems with functioning or quality of life over and above that which is already associated with depression. Finally, further studies need to elucidate whether social cognition is impaired by both emotion-processing deficits as well as by cognitive deficits within the same study. These questions are beyond the scope of the present study, but are important in order to establish the clinical significance of the findings.The results suggest that in a currently depressed state, as symptom severity increases, people with MDD have more difficulties in processing complex social visual and auditory cues. It also appears that specific symptom clusters are likely to be associated with aspects of impaired social cognition. Further study is needed to determine the relationship between social cognition, overall cognition, depression and functioning.TA collected data, analyzed data and wrote a first draft. MW collected data, managed data and performed first analyses. BB conceived the study, the study design and revised and edited manuscript drafts. All authors approved the final manuscript.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.


A biofilm is found on the inner side of endotracheal tubes (ETT) in mechanically ventilated patients. Saline instillation inside the ETT during the suctioning procedure is very common. This procedure could displace bacteria to the lower airways, increasing the risk of ventilator-associated pneumonia (VAP).Evaluation of the bacteriological cultures of the ETT lavage with saline after extubation of mechanically ventilated patients to verify dislocation of bacteria through this procedure.The ETT was removed using an aseptic technique during extubation. Saline (10 ml) was instilled into the tube, and the drainage fluid was collected on the other side. This material was sent to microbiological cultures in two different culture mediums (chocolate blood agar and MacConkey). We considered the quantitative culture of more than 100,000 UFC/ml as positive. The characteristics of the patients with and without positive cultures were compared.n = 40). Positive culture was observed in eight tubes (20 %). The bacteria observed were: five Gram-positive  and three Gram-negative . We did not observe differences between the group with positive and negative cultures in relation to demographic and clinical characteristics, intubation time and tube diameter (p >0.05).Forty endotracheal tubes were analyzed (The use of saline during an endotracheal suctioning procedure can dislocate pathogenic bacteria from the endotracheal tube biofilm to the lower airways, and could increase the risk of VAP. The use of saline should be minimized during patient care.


The development of immuno-oncologic agents poses unique challenges, namely that both efficacy and safety profiles differ from previously characterized cytotoxic and pathway-specific agents. In addition, exponential distribution is usually assumed in study designs with time-to-event endpoints such as overall survival or progression-free survival. This assumption might lead to wrong estimates of study duration and statistical power if the phenomena of long term survival and delayed clinical effects are present. The aim here was to evaluate the magnitude of the impact caused by the violation of this assumption, and to describe new ways of analyzing efficacy and safety of immuno-oncologic agents.Monte Carlo simulation was implemented to explore the impact of long term survivors and delayed treatment effect on study power and trial duration. Scenarios with various combinations of long term and delayed treatment effects were considered. Study power and duration were evaluated based on 10000 randomly generated trial data sets. The utility of group sequential study designs was discussed. A new set of immune-related response criteria (irRC) was considered for efficacy analysis. Two new methods for identifying adverse events, termed immune-related adverse events (irAE) and immune-mediated adverse reactions (imAR) were described. The key features of the safety profiles derived using these two methods were similar. Both methods were aimed at identifying inflammatory adverse events caused by immunotherapies.The presence of long term survivors usually lengthened the study duration. Depending on the treatment effect post survival curve separation, delayed clinical effect in general led to a loss of power. The irRC offered a new way of identifying clinical responses. Both safety analyses demonstrated higher sensitivity of identifying adverse events of immune system origin.This simulation study showed the importance of accounting for the delayed treatment effect and long term survivors when these phenomena were expected. Interim analyses for the purpose of stopping the study for either positive or futile outcome should be implemented with caution in immuno-oncology trials. The new efficacy analysis offered a potential new way of assessing signs of activity in immunotherapies. While the irAE method facilitated prompt and effective management of adverse events, the imAR method captured truly immune-related events. Innovative research in recent years has led to the discovery of many promising targeted anti-cancer agents, including selective or multi-targeted inhibitors of tyrosine kinases, signal transduction, angiogenesis, or matrix metalloproteinase as well as targeted immunotherapies such as monoclonal antibodies, T cell infusion, and cancer vaccines. The varying mechanisms of action introduced by these novel agents challenge the researchers to reconsider whether the conventional efficacy and safety analyses as well as trial designs adequately address these new mechanisms under study.Cytotoxic and cytostatic agents are classified based on their mechanism. Classical cytotoxic agents derive their anti-tumor activity from dose-dependent rapid cell kill. This mechanism of action, nevertheless, usually results in undesired toxicities due to the lack of selectivity between normal and cancerous cells. In contract, cytostatic compounds are agents that suppress cellular growth and division. These compounds are usually characterized by minimal or less severe toxicity, prolonged duration of the treatment, anti-tumor activities at dose levels potentially lower than the maximum tolerated dose (MTD), and inhibition of tumor growth with absence of or minimum tumor shrinkage.Immunotherapies, on the other hand, stimulate the patient’s own immune system to fight against cancers by targeting antigens expressed on cancer cells. More than any other discovery, monoclonal antibodies (mAbs) have enabled us to identify and manipulate molecules regulating the immune system. They reThe development process of cytotoxic and cytostatic agents has been well established. The design of clinical trials progresses from the early phase studies with the goal of assessing safety to later phase studies evaluating efficacy. Phase IIn this article, the focus will be on the late stage oncology drug development and the issues introduced by immuno-oncologic agents. First, several immunotherapies have been demonstrated to show delayed clinical effect,5-7, in α-2b in the treatment of adjuvant melanoma. In this setting, this long-term phenomenon can also be observed in other time to event endpoints such as recurrence-free survival (RFS) and distant metastases free survival (DMFS). Since a subset of the patients in the study is no longer at risk of progression or death, this implies that the study duration could be substantially prolonged. In some occasions, delayed clinical effect and long term survival were present in the same study. For instance, a randomized double blind phase III study comparing ipilimumab with and without gp100 vaccine vs. gp100 vaccine alone in patients with pre-treated advanced melanoma has shown that the Kaplan-Meier survival curves did not separate until approximately 4 months with a survival probability leveling off at 20%[In addition, therapies for certain cancer types are believed to induce a subset of long term survivors, such as melanoma,3,9-12, Another important aspect of randomized studies is the use of interim analyses. The implementation of the group sequential designs has become standard practice in phase III pivotal studies to allow early study termination in the face of either positive or negative outcome. Data have suggested that this standard approach warrants further reconsideration with immuno-oncologic products. For example, a phase III study comparing tremelimumab to standard-of-care in advanced melanoma was terminated early due to futility as the interim analysis failed to demonstrate an overall survival benefit during the follow-up.The irRC guidelines for evaluating immune response were developed based on the conventional WHO or RECIST criteria to capture the unique characteristics exhibited by immuno-oncology agents. Finally, the conventional safety analysis in the ipilimumab studies revealed that the adverse event rates were similar between treatment arms. It was clear that to accurately characterize the safety profile of immuno-oncology agents such as ipilimumab, it was necessary to develop new methods to increase the sensitivity and specificity of capturing the events that were truly of immune system origin.Here the main goal was to raise the awareness in both the statistical and clinical communities the importance of fully understanding the characteristics of the compounds under investigation, especially immuno-oncologic agents, in order to determine the optimal trial design and selection of the best endpoints, as well as the most appropriate efficacy and safety analysis approaches.In a study with time-to-event endpoints, we are interested in the time interval between the entry of the study and an event, e.g., the interval between time of randomization and death or disease progression in a comparative study. The study is usually designed based on exponential distribution assumption in which we assume that anything which affects the hazards does so by the same ratio at all times, i.e., proportional hazards. This implies the clinical effect of the experimental arm over the control is observed from the beginning and the survival curves will eventually drop down to zero survival probability FigureA. In genDue to recent advancement in oncology therapy, a proportion of patients are expected to be cured (or non-susceptible) in certain diseases, that is to remain alive or disease-free even after long follow-ups. This phenomenon is usually observed in Kaplan-Meier curves with non-zero tail probabilities FigureB, D. SinWhen the population under study consists of susceptible and non-susceptible  patients, the number of patients who are at risk of the event of interest is smaller. This implies that the time it takes to reach the required number of events with desired level of statistical power is lengthened as the events can only be observed in the subset of susceptible patients.Another observation that has been made in most randomized immunotherapy trials is the delayed separation of Kaplan-Meier survival curves FigureC, D. OccLarge randomized clinical trials usually take considerable time to enroll patients. In clinical trials involving human subjects, it is imperative to ensure that individuals are not exposed to unsafe or ineffective treatments. Due to the life-threatening nature of cancer and the unmet medical need, it has become common practice to build in group sequential procedures to assess the possibility of terminating the studies early for unexpected large treatment effects or lack of efficacy that suggests a positive result at the end of the study would be extremely unlikely. The former is usually referred to as the interim analysis for superiority, the latter is that for futility.The most popular approaches were group sequential methods proposed by O’Brien and Fleming, PocockIn an immuno-oncologic randomized clinical trial with long term survival and delayed clinical effect, one needs to reconsider the implementation of conventional interim analyses when the intention is to stop the study early for either positive or futile outcome. If the treatments exhibit delayed clinical benefit, implementation of superiority interim analysis may have smaller stopping probability for a positive outcome whereas futility interim analysis could increase the chance of terminating the study early and erroneously discarding an active agent.On the other hand, when the treatments under study yield long term survivors, the outcome of interim analyses can not reflect this unique characteristic of the treatments since most of the patients are unlikely to have sufficient follow-ups. Furthermore, the conventional interim analysis at the information fraction of 50% may not be the optimal analysis time since the study duration post interim analysis could take substantially longer due to the decreasing event rate. Therefore, the timing of the interim analysis requires careful plannings such that an interim analysis at a later time may be desired.A simulation study was performed in order to evaluate the impact of long term survival and delayed clinical effect introduced by immunotherapy as well as the utility of the interim analysis. A randomized study was first designed using the conventional exponential distribution assumption, i.e., Proportional Hazards Model (PHM), as a benchmark: 512 events were required to detect an overall hazard ratio of 0.75 between two treatment arms using a log-rank test with an experiment-wise two-sided type I error rate of 5% and power of 90%. Furthermore, the accrual duration for 680 randomized patients was assumed to be 34 months. The study was expected to attain 512 events approximately 48 months after the first patient was randomized.To describe the impact of long term survival and delayed clinical effect, three survival models were introduced. First, a Proportional Hazards Cure Rate Model (PHCRM) added a cured fraction of patients into the proportional hazards model. Under the same assumptions, the proportional cure rates of 10% vs. 18% were incorporated between two treatment arms. The proportional cure rates maintained the risk ratio of the entire population at 0.75 and the power of 90% so the impact on the study duration could be assessed without inducing the loss of power simultaneously. If the magnitudes of the proportional cure rates among non-susceptible patients and the proportional hazards among susceptible patients were different, the power would be impacted either upwards or downwards.To assess the impact of statistical power under delayed clinical effect, a Non-Proportional Hazards Model (NPHM) was used where the first 3 months were assumed to have hazard ratio of 1 and 0.75 thereafter. This implied the treatment effect of immunotherapy did not take effect until month 3.The last model, a Non-Proportional Hazards Cure Rate Model (NPHCRM) incorporated both the long term survival and delayed clinical effect by assuming the hazard ratio of 1 during the first 3 months and 0.75 post separation with proportional cure rates of 10% vs. 17%.Superiority and futility interim analyses with O’Brien-Fleming procedure at the 50% information fraction were also built in for the four models with various combinations of long term survival and delayed clinical effects to evaluate the efficiency of the interim analysis implementation.Each scenario was evaluated based on 10000 simulations. The simulated power of each design was the proportion of iterations that met the criterion of log-rank test p-value of less than 0.05. The interim stopping probabilities were based on the proportion of iterations among which the estimated efficacy effect crossed the O’Brien-Fleming boundaries. The study duration was calculated based on the median of the simulated durations from 10000 iterations. The median instead of the mean of simulated study durations was chosen in order to prevent potential outliers from skewing the result, i.e., pre-specified number of events not reachable.The simulated statistical powers and study durations from PHCRM, NPHM and NPHCRM were compared to those of PHM Table. When a TableIn addition to the challenges that immuno-modulating agents created with regards to the study design and interim monitoring, two additional issues were being considered. The first was the choice of response assessment criteria that accounted for long term benefits of these agents, and the second was the safety analysis algorithm that efficiently identified inflammatory adverse events.Anticancer activity derived from chemotherapeutic agents traditionally has been assessed using modified World Health Organization (WHO) or RespoWhile these guidelines have served us well in evaluating chemotherapeutic agents, recent research experience in immuno-oncology has indicated that the clinical benefit from immunotherapy might extend beyond that of cytotoxic agents. For example, stable disease or responses to immunotherapy may occur after conventional PD due to clinically insignificant new lesions in the presence of other responsive lesions and reduction of the total tumor burden. Therefore, discontinuation of immunotherapy at the first sight of PD may not be appropriate in some cases. In addition, measurable antitumor activity may take longer for immunotherapies than for cytotoxic agents, and durable stable disease (SD) may represent meaningful antitumor activity. A novel set of anti-tumor assessment criteria, irRC, was therefore proposed based on WHO and RECIST criteria and has been applied to a series of phase II and phase III ipilimumab clinical trials,5,26-28.One of the biggest challenges of using irRC in assessing immunotherapeutic responses is the uniformity of implementation among treating physicians. For example, when treatments are available for patients with PD due to the appearance of new lesions per conventional modified WHO or RECIST criteria, treating physicians may incline to switch the patients to other available therapies prior to observing delayed benefit rather than prolonging the time on the current experimental therapies. A large number of physicians and sites are usually involved in randomized clinical trials. This will render the interpretation of response assessment results difficult since different criteria were implemented in determining the clinical benefit within the same study.Despite the implementation challenge outlined above, the potential need of a new set of guidelines for immuno-oncologic agents can not be overlooked. The utility of irRC will be studied in depth in the near future with richer data collection when the criteria are more widely adopted.Consistent with the idea that immunotherapies fight cancer by augmenting the immune response, most adverse events are expected to be inflammatory in nature. As such, immunotherapy associated adverse events differed in character from those observed in melanoma patients treated with other therapies.To better identify adverse events likely due to immuno-oncologic agents such as ipilimumab, a method was developed to quantify immune-related adverse events (irAEs). IrAEs wIn contrast to regular safety analyses, the irAEs were able to better discriminate between adverse events caused by ipilimumab versus those due to other factors. Nevertheless, adverse events being classified as irAEs continued to be observed among patients treated with other therapies. The incidence of irAE among these patients should be closed to zero if the irAE methodology truly captured only events with immune system origin. A greater specificity was needed to accurately identify immunotherapy-specific events and accurately characterize the safety profile of immuno-oncologic agents such as ipilimumab.A new method was developed for the identification of immune-mediated adverse reactions in order to determine which adverse events were truly immune-related. This meSimilar to irAE, the description of the adverse event had to first include at least one of a set of pre-specified preferred terms in order for an adverse event to be considered an imAR. The adverse event records were then reviewed against a predefined list of criteria for attribution as an imAR specific to each of the same system organ classes defined in the previous section . The determination of imAR was based on the rule of elimination. If any of the exclusion criteria was met, e.g., administration of intervening treatment with chemotherapy proximal to the event known to cause irAE, or rapid resolution of the adverse event (< 1 week) without initiating concomitant immunosuppressive agents, the event was adjudicated as not attributed to ipilimumab. Hence, these adverse events would not be characterized as an imAR.For the identification of imARs in ipilimumab,3, each Statistical models for time to event analysis typically assume that everybody in the study population is susceptible to the event of interest and will eventually become an event. In recent years, due to the innovative medical advancement, new treatments such as immunotherapies have yielded long term survivors. Some people in the population may be considered cured or non-susceptible. Failing to account for these subjects in the study design could potentially impact the process of drug development and resource planning. Furthermore, the newly introduced immuno-oncologic agents may not show early benefit due to their mechanism of action. This leads to a delayed separation in Kaplan-Meier curves in time to event analysis.In this article, the consequence on statistical power and study duration in the presence of long term survival and delayed clinical effects when the study was designed based on the conventional assumption of exponential distribution was thoroughly discussed. For illustration purpose, the clinical trial example provided in this article assumed a 3-month delayed separation in overall survival curves. If the separation occurred at a later time, the loss of power would become more severe. Note that the statistical power was also dependent on the magnitude of the treatment effect post the survival curve separation. If the true treatment effect post separation exceeds expectations, the statistical power will improve based on the magnitude of the treatment effect.In the simulation study, the proportional cure rates were assumed in order to evaluate the study duration without introducing power change. If a PHCM study was designed and in reality the cure only existed in the experimental arm, this design would yield an over-powered study. On the other hand, if the cure existed in the control arm only, or the magnitude of the proportional cures was weaker than that of proportional hazards, the study will be under-powered. Another element that dictates the study duration is the magnitude of the cure rate. The bigger the subset of non-susceptible population in a study, the longer it would take to reach the pre-specified number of events.Furthermore, the objective of group sequential procedure is to terminate the study in the face of either positive or futile result prior to the completion of the study. When the treatment under study possessed the unique immuno-oncologic characteristics, the necessity of the interim analyses, for superiority or futility, need to be considered with caution. If the interim analyses are to be built in, it is imperative to implement them at the optimal time points, accounting for clinical, statistical and operational considerations.One area that was not touched upon in this article was the time to event analysis with long term survival and delayed clinical effect. The most commonly used statistical methods for time to event analyses have been the log-rank test and Cox regression analysis. These standard analyses have maximal statistical power under the proportional hazards assumption. However, they do not emphasize the treatment effect on the long-term survivors, which may be of primary interest. In some occasions, researchers may be interested in estimating the cured fraction. One way of demonstrating long term survival is to present the survival rates at given time points, such as one-year or two-year OS rates. If such analysis is to be conducted, one should ensure the minimum follow-up duration is at least as long as the time point of interest to reduce the number of censored observations. For example, a minimum follow-up of two years will yield robust estimates of OS rates up to two years.Cure rate models have been a popular topic within statistical literature, these models can be a useful tool to analyze and describe time to event data-35. NeveStatistical methodology such as weighted log-rank test (WLR),36,37 alThe newly proposed efficacy (irRC) and safety (irAE and imAR) analyses were also discussed when the treatments under study were immunotherapies. The irRC modified the widely used WHO or RECIST criteria by considering the total measurable tumor burden in the evaluation of anti-tumor activities. The new criteria allow continuation of immunotherapy treatment in the face of clinically insignificant new lesions in the presence of responsive lesions, leading to potential late responses. Ultimately, a proportion of patients who would have fulfilled conventional criteria for progressive disease was shown to have long term survival rate similar to that from the conventionally defined responding patients. The challenge of implementing irRC, similar to any assessment guidelines, is to ensure the data interpretability by applying uniform evaluation across sites and investigators in clinical trials. The utility of irRC will be studied in depth in the near future with richer data collection when the criteria are more widely adopted.Two new safety analysis methods were also proposed to account for the characteristics of immuno-oncologic therapies. While the prospective irAE method facilitated prompt and effective management of adverse events, the retrospective imAR method captured truly immune-related events. If these new safety analysis methods are to be implemented, the criteria of irAE/imAR identification require careful considerations based on biological and clinical evidence for the immunotherapies under study.When designing randomized clinical studies with immunotherapies, the simulation study indicated that the conventional study design with exponential assumption could lead to an underestimation of either statistical power or study duration in the presence of delayed clinical effect or long term survival. The necessity and timing of superiority or futility interim analysis also required careful consideration due to decreasing true positive rate or increasing false negative rate. New efficacy and safety analyses were proposed to account for the mechanism of action in immunotherapies. These findings have important implications for clinical trial researchers aiming to optimize the drug development process and bring the novel treatments to cancer patients in need.The author is an employee of Bristol-Myers Squibb.The author is director in oncology biostatistics and the lead biostatistician of Yervoy (Ipilimumab) at Bristol-Myers Squibb. He is also an Adjunct Assistant Professor of Biostatistics at Columbia University, New York, NY, USA.


Bladder schwannomas are exceedingly rare, benign or malignant, nerve sheath tumors that are most often discovered in patients with a known diagnosis of Neurofibromatosis type 1 (NF1). A few sporadic case reports of bladder schwannoma have been published in urologic, obstetric/gynecologic, and pathologic journals. We report a case of an isolated schwannoma of the urinary bladder. To our knowledge, this represents only the sixth case of benign schwannoma of the urinary bladder in a patient without von Recklinghausen disease. Schwannoma of the urinary bladder is an extremely rare tumor. It arises from Schwann cells in nerve sheaths and may be malignant  or benigWe report the case of a female patient aged 50, with no particular history admitted to our department for management of hematuria.Her history of the disease was within 3 months of the onset of intermittent total hematuria associated with irritative lower urinary tract signs namely urgency and voiding burns. Clinical examination was normal, apart from hypogastric tenderness.Before the clinical abdominopelvic ultrasound was asked a table, she showed a Right and left kidney of normal size, and bladder smooth contour seat was a mass of tissue echo structure (58 * 52 * 15mm) of the postero -lateral right . LaboratThe cystoscopic exploration objectified non- papillary solid tumor of the left bladder trigone and lateral side, both ureteral meatus were free. Biopsies of the lesion were sent to pathology for further evaluation .On macroscopic examination, the submucosal mass appeared tan, smooth and rubbery. The mass was sectioned and stained with Hematoxylin and Eosin (H&E) for further evaluation. Light microscopy revealed a spindle cell neoplasm with areas of hypocellularity (Antoni B) and areas of dense cellularity (Antoni A). Within the densely cellular areas, palisading nuclei alternated with pink, nuclear free zones (Verocay bodies). These findings are highly characteristic of a schwannoma.. Immunohistochemical study showed that tumor cells express the anti PS100 Ac, which confirms the final diagnosis of schwannoma of bladder  .CT of the abdomen and pelvis was performed documenting no evidence of tumor extension outside the confines of the bladder; the mass was well circumscribed with a density of 32 Hounsfield units (HU) on the left side of the bladder wall. The mass was isodense relatively to the wall of the bladder and measuring 5.4 X 6.1 cm of axial dimensions .The final treatment consisted of the production of a transurethral resection of bladder with good control of the tumor. The patient had no immediate post-operative complications. She was followed for 5 months without tumor recurrence before moving out of state.It was in 1910 that VEROCAY described the first case of nerve sheath tumor and gives it the name of neuroma. In 1932, Masson .Schwannoma is a ubiquitous lesion may sit in any part of the body where a nerve sheath is present, including the bladder. ROBERT  giving tClinical symptoms are nonspecific, most often provide hematuria and irritative lower urinary tract seats. Nevertheless, additional examinations of imaging are needed to advance in the diagnosis .Ultrasound has give a notion of mass is now widely supplanted by scanner (CT) and Magnetic resonance imaging (MRI). Both tests give a clear idea of the location of the tumor . The CT The diagnosis can only be made by histology. Two highly characteristic patterns for schwannoma can be seen on H&E staining. Antoni A areas consist of compact intersecting spindle cells with elongated nuclei arranged in parallel bundles, incomplete whorls and complete whorls (Verocay bodies) . Antoni Treatment of these tumors has included cystectomy, transurethral resection, observation, radiotherapy, chemotherapy, and urinary diversion. The current belief regarding treatment is that in the absence of other sequelae, these neural sheath tumors can be treated conservatively .The prognosis is related to the risk of recurrence, which is extremely rare, if the exeresis is complete. The Benin schwannoma rarely escalates. One case has been described  or maligBladder schwannoma is a very rare tumor whose diagnosis is histological. Treatment of this tumor remains uncodified, but a full excision of the tumor is mandatory to avoid recurrence. Although the degeneration of the tumor is exceptional surveillance by an annual scanner is legitimate.


Q value, was maximized and compared in three groups. Topological roles with the progression of MHE were illustrated by intra- and intermodular connectivity changes. Results showed that the Q value of MHE patients was significantly lower than that of controls (P < 0.01) rather than that of non-HE patients (P > 0.05), which was correlated with neuropsychological test scores rather than the ammonia level and Child-Pugh score. Less intrasubcortical connections and more isolated subcortical modules were found with the progression of MHE. The non-HE patients had the same numbers of connect nodes as controls and had more hubs compared with MHE patients and healthy controls. Our findings supported that both intra- and intermodular connectivity, especially those related to subcortical regions, were continuously impaired in cirrhotic patients. The adjustments of hubs and connector nodes in non-HE patients could be a compensation for the decreased modularity in their functional connectivity networks.Minimal hepatic encephalopathy (MHE) is associated with changes in functional connectivity. To investigate the patterns of modular changes of the functional connectivity in the progression of MHE, resting-state functional magnetic resonance imaging was acquired in 24 MHE patients, 31 cirrhotic patients without minimal hepatic encephalopathy (non-HE), and 38 healthy controls. Newman's metric, the modularity  The human brain can be regarded as a complex network, which is organized intrinsically as highly modular architectures with inter- and intramodular links between brain regions –5. The mHepatic encephalopathy (HE) is a serious neuropsychiatric complication of both acute and chronic hepatic dysfunctions , which iBased on the previous findings of widespread decreased cortical and subcortical network connectivity in MHE patients, we hypothesize that the community structure itself, including inter- and intramodular links between brain regions, is impaired in MHE patients, and functional connectivity change in the modular organized brain is associated with the development of MHE. The aim of this study was to quantitatively evaluate the modularity changes of functional connectivity network in healthy subjects, cirrhotic patients without minimal HE (non-HE), and MHE patients and to illustrate the patterns of spatial change of modular community structure in the development of MHE. Additionally, we aimed to evaluate the relationship between quantitative measures of modular community structure and the venous ammonia level, Child-Pugh score, and neuropsychological test scores in cirrhosis patients.This study was approved by local institutional review board and was conducted in compliance with Health Insurance Portability and Accountability Act. All subjects gave written informed consent before fMRI or neuropsychologic evaluation. 61 adult patients with cirrhosis  were recruited from our inpatient or outpatient departments during June of 2009 and June of 2013. The patients MHE was defined and classified according to the final report of the working party at the 11th World Congresses of Gastroenterology in Vienna in 1998 . Changes in Q values based on high-resolution parcellation network  were consistent with those on AAL 90 template . In our study, we mainly displayed our results at 8% network sparsity . We also showed the modules of three groups at the 7% and 9% sparsities . Our module results at three differe sparsities were quite similar, indicating that they were not sensitive to the selection of thresholds.


Theories on visual perception agree that scenes are processed in terms of spatial frequencies. Low spatial frequencies (LSF) carry coarse information whereas high spatial frequencies (HSF) carry fine details of the scene. However, how and where spatial frequencies are processed within the brain remain unresolved questions. The present review addresses these issues and aims to identify the cerebral regions differentially involved in low and high spatial frequency processing, and to clarify their attributes during scene perception. Results from a number of behavioral and neuroimaging studies suggest that spatial frequency processing is lateralized in both hemispheres, with the right and left hemispheres predominantly involved in the categorization of LSF and HSF scenes, respectively. There is also evidence that spatial frequency processing is retinotopically mapped in the visual cortex. HSF scenes (as opposed to LSF) activate occipital areas in relation to foveal representations, while categorization of LSF scenes (as opposed to HSF) activates occipital areas in relation to more peripheral representations. Concomitantly, a number of studies have demonstrated that LSF information may reach high-order areas rapidly, allowing an initial coarse parsing of the visual scene, which could then be sent back through feedback into the occipito-temporal cortex to guide finer HSF-based analysis. Finally, the review addresses spatial frequency processing within scene-selective regions areas of the occipito-temporal cortex. Scenes containing more realistic and more natural stimuli have increasingly become the object of scientific interest over the last 20 years, as they involve the perception of stimuli which are more complex and more realistic than simple objects or drawings. It is now widely agreed that visual recognition of scenes is a fast, automatic and reliable process. Experimental studies have shown that complex natural scenes can be categorized very rapidly  However, the cerebral circuit of the coarse-to-fine perception of scenes has never been investigated in humans. On the basis of neurophysiological recordings in nonhuman primates, In addition, there is considerable evidence suggesting that spatial frequency processing takes place in a predominantly and default coarse-to-fine sequence . Using hierarchical visual stimuli displayed in either the left visual field (projecting directly to the right hemisphere) or the right visual field (projecting directly to the left hemisphere), The first experimental evidence in support of hemispheric specialization for global and local processing comes from psychophysical studies using hierarchical forms as visual stimuli  or scene images . It should be noted that this type of manipulation is not feasible with hierarchical forms because low-pass filtering cancels out the local form and renders the task impossible. We evaluated hemispheric asymmetry in healthy participants in a series of psychophysical studies . This method revealed greater activation in the right than the left middle occipital gyrus for LSF scene recognition, and greater activation in the left than the right middle occipital gyrus for HSF scene recognition . This study provided new evidence for hemispheric specialization at the first cortical level of visual analysis. Analyzing fMRI data with a more traditional approach which contrasts spatial frequencies to one another, we observed a higher degree of activation for LSF scenes (as opposed to HSF), while the reverse contrast did not reveal any significant activation. This study suggests that the results considerably differ according to the method applied to analysis fMRI data. Inter-hemispheric comparison seems more appropriate for the investigations of cerebral asymmetries, since it allows any main effect deriving from spatial frequency bias to be canceled out.Based on behavioral studies in which performances between the two visual hemifields are directly compared . Importantly, the distribution of retinal photoreceptors and retinal ganglion cells is nonhomogeneous throughout the retina . The retinotopic organization of spatial frequencies was also assessed at individual level by projecting LSF and HSF related activations onto retinotopic maps established for a number of participants. Functional activations projected onto individual retinotopic maps revealed that LSF processing is mapped in the anterior part of V1, whereas HSF processing is mapped in the posterior and ventral part of V2, V3, and V4. Furthermore, at the group level, the direct inter-hemispheric comparisons performed on the same fMRI data revealed a right-sided occipito-temporal predominance for LSF scene categorization and a left-sided temporal cortex predominance for HSF scene categorization, according to the hemispheric specialization theories. By using suitable method of fMRI analysis on the same data, as well as visual stimuli filtered in spatial frequencies covering a large part of the visual field, After demonstrating retinotopic organization of spatial frequency processing, However, results from certain neurophysiological, computational, and behavioral studies indicate that the totality of spatial frequency information is not immediately conveyed through the brain, but that analysis follows a predominantly coarse-to-fine processing sequence. If LSF extraction and analysis occurs first, followed by that of HSF, why should there be any hemispheric lateralization for the processing of LSF or HSF? Identification of the neural basis of the coarse-to-fine analysis in scene perception is the first step toward responding to this question.Data from the functional neuroanatomy of magnocellular and parvocellular visual pathways indicate that the totality of visual information is not conveyed immediately, but that LSF reach the visual cortex before HSF , althougAlthough LSF information may be perceptually available before HSF, it is important to note that it does not necessarily follow that it is always used first to support visual recognition in all tasks. In Importantly, results from We do not as yet know exactly how and where in the brain LSF and HSF information is differentially analyzed and eventually merged during visual processing. Traditional models generally maintain that incoming visual cues are combined at successive stages along the cortical hierarchy , and sugHowever, to date, the neural architecture and temporal dynamics of such top-down mechanisms have never been systematically investigated via direct testing of the preferential coarse-to-fine processing sequence during visual scene perception in humans. The influential models of visual perception assume a predominantly coarse-to-fine sequence of spatial frequency processing in the whole brain, based on the functional properties of the visual pathways. However, as mentioned previously, many studies have also shown that it is possible that the two hemispheres of the human brain may complement one another in the processing of LSF and HSF. The critical issue here is how to reconcile hemispheric specialization of spatial frequency processing with coarse-to-fine analysis of scenes.The hemispheric specialization observed for spatial frequency processing raise the crucial question of the legitimacy of suggesting that coarse-to-fine sequencing is applied throughout brain. As far as the higher-level stages of visual scene processing are concerned, several studies have highlighted the sensitivity of scene-selective areas to low-level features, such as spatial frequencies and amplitude spectrum properties, in scenes . HoweverThere is considerable evidence suggesting that the occipito-temporal cortex contains a mosaic of different areas that respond selectively to different category of stimuli . More spCoarse-to-fine processing of faces in high level visual cortex was the central focus of a recent study by Figure 5). Equivalent activations were observed for both types of sequence in the RSC and OPA. This study therefore suggests that coarse-to-fine sequence processing constitutes the predominant strategy for scene categorization in the PPA. It should be noted that evidence of spatial frequency sensitivity within other scene-selective areas, such as the RSC and the OPA, is still lacking.A recent fMRI study  tested wThe present review aimed to identify cerebral regions differentially involved in low and high spatial frequency processing and to clarify their attributes during scene perception. Several neuroimaging studies suggest that spatial frequency processing could be retinotopically mapped and lateralized in both hemispheres. Right occipital areas are more activated than the left ones during the processing of LSF scenes, while left occipital areas are more activated than the right ones during the processing of HSF scenes. Concomitantly, the processing of HSF scenes (as opposed to LSF) activates the foveal representation in retinotopic areas of the occipital cortex, and LSF scenes (as opposed to HSF) activate more peripheral representations in retinotopic areas.The present review also studied the neural bases of coarse-to-fine analysis as a default and predominant processing strategy. According to influential models , LSF infFigure 6). These two regions might play a predominant role during the coarse-to-fine categorization of scenes. Involvement of the orbitofrontal cortex was previously evidenced in rapid LSF-based categorical inferences (Overall, these results obviously raised the question of the connectivity between the PPA and the cortical network specifically involved in coarse-to-fine processing. ferences  and the ferences . In a prferences . In humaferences . Bar et To conclude, the results reported in the present review provide critical support for influential models of visual perception mainly based on a spatial frequency analysis which follows a coarse-to-fine strategy .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.


Radiotherapy is an important treatment modality in the multidisciplinary management of rectal cancer. It is delivered both in the neoadjuvant setting and postoperatively, but, although it reduces local recurrence, it does not influence overall survival and increases the risk of long-term complications. This has led to a variety of international practice patterns. These variations can have a significant effect on commissioning, but also future clinical research. This study explores its use within the large English National Health Service (NHS).Information on all individuals diagnosed with a surgically treated rectal cancer between April 2009 and December 2010 were extracted from the Radiotherapy Dataset linked to the National Cancer Data Repository. Individuals were grouped into those receiving no radiotherapy, short-course radiotherapy with immediate surgery (SCRT-I), short-course radiotherapy with delayed surgery (SCRT-D), long-course chemoradiotherapy (LCCRT), other radiotherapy (ORT) and postoperative radiotherapy (PORT). Patterns of use were then investigated.The study consisted of 9201 individuals; 4585 (49.3%) received some form of radiotherapy. SCRT-I was used in 12.1%, SCRT-D in 1.2%, LCCRT in 29.5%, ORT in 4.7% and PORT in 2.3%. Radiotherapy was used more commonly in men and in those receiving an abdominoperineal excision and less commonly in the elderly and those with comorbidity. Significant and substantial variations were also seen in its use across all the multidisciplinary teams managing this disease.Despite the same evidence base, wide variation exists in both the use of and type of radiotherapy delivered in the management of rectal cancer across the English NHS. Prospective population-based collection of local recurrence and patient-reported early and late toxicity information is required to further improve patient selection for preoperative radiotherapy. •Wide variation exists in both the use of and type of radiotherapy delivered in the management of rectal cancer.•Population-based capture of local recurrence and toxicity information are required to further improve patient selection. Radiotherapy is an established treatment modality in the multidisciplinary management of rectal cancer. In the 1990s, phase III trials reported reduced local recurrence and improved overall survival using a combination of postoperative chemotherapy and concurrent chemoradiation (CRT). Subsequently, randomised trials, mainly in Europe, showed a reduction in local recurrence with the preoperative addition of either a 1 week short course of radiotherapy or the addition of concurrent chemotherapy to a 5 week course of preoperative radiotherapy Two recently reported phase III trials have confirmed a halving of the rate of local recurrence when a 1 week short course of radiotherapy was added to surgical resection Although preoperative radiotherapy can reduce the risk of local recurrence, it can also increase the risk of long-term side-effects when added to surgical resection In the National Health Service (NHS) of England, weekly multidisciplinary team (MDT) meetings take place to review the clinical and radiological staging of all rectal cancer patients. Pelvic magnetic resonance imaging (MRI) is routinely used to determine the use of preoperative and postoperative radiotherapy in management, further increasing the complexity of decision making. International evidence suggests there is significant variation in the use of radiotherapy in the management of rectal cancer This study explored the use of radiotherapy in surgically treated rectal cancer at a population level using the first available data from the national Radiotherapy Dataset (RTDS) All individuals diagnosed with a first primary rectal cancer between 1 April 2009 and 31 December 2010 and who underwent a major resection for the disease within the English NHS were identified  To investigate patterns of use of radiotherapy, any records for this cohort of individuals within the RTDS  were identified. The RTDS contains information on every episode of radiotherapy delivered, but the dataset does not consistently capture whether the intent of the dose delivered was adjuvant, radical or palliative. In addition, the disease coding within the resources varies between centres and total attendances are captured rather than intended fractionation patterns. An individual may also have multiple summary RTDS records that overlap the same time period and seem to relate to the same episode of radiotherapy being delivered. An algorithm was therefore developed to identify neoadjuvant or adjuvant treatment records from the resource among all other episodes of radiotherapy administered to this rectal cancer population. First, only episodes of radiotherapy that the RTDS stated had been used to treat colorectal ICD10  C18-20, Patterns of use of radiotherapy in rectal cancer were then investigated in relation to both the characteristics of the patients, their tumours, the interval to surgery and their management. The statistical significance of any differences in the type of radiotherapy used was assessed using the chi-squared test.The work was given ethical approval by the East of Scotland Research Ethics Service (LR/08/S0501/66).In total, 9201 individuals were identified within the NCDR as having undergone major resection for a first primary rectal cancer diagnosed in the study period. Overall, 4616 (50.2%) of this population did not receive any radiotherapy in the management of their primary disease. By contrast, 1113 (12.1%) received SCRT-I, 110 (1.2%) SCRT-D, 2713 (29.5%) LCCRT, 435 (4.7%) ORT and 214 (2.3%) PORT.The characteristics of the population in relation to their treatment group are shown in Significant variation in the use of the different modalities of radiotherapy for the management of rectal cancer was seen across English NHS Trusts . The proA significant, although slightly less marked variation was observed across the larger aggregation of MDTs within the English NHS's Local Area Teams . The proThere was also significant variation in practice in relation to the interval between the start of radiotherapy and surgery. This retrospective population-based study is the first to provide a comprehensive national perspective on the use of radiotherapy in the management of surgically treated rectal cancer patients across England. Overall, 49.8% of the population received some form of radiotherapy, but there was variation across the population, with radiotherapy used more commonly in men and in those receiving abdominoperineal resection and less commonly in the elderly and those with comorbid disease. Significant variation in practice was also observed across the English NHS, irrespective of patient case mix, with regards to both the type of radiotherapy used and the interval between its initiation and surgery.These data can be compared with those in the National Bowel Cancer Audit Project This study not only showed variation in whether radiotherapy was used but also in what type was delivered and how long the interval was between the start of the radiation and surgery. To our knowledge no data have previously been published quantifying the extent of this variation across the English NHS. All these observed variations in radiotherapy usage were seen despite the routine weekly colorectal MDT meetings, which occur across the NHS, in which clinical and radiological staging investigations, including pelvic MRI, are reviewed to determine the selection of patients for preoperative treatment. MDTs are, therefore, adopting very different treatment strategies. How can this wide variation in radiotherapy usage be explained? A number of factors may have influenced MDT decisions. First, the Colorectal Improving Outcomes Guidance from 2004 Second, there has been a growing body of evidence that preoperative radiotherapy lowers the risk of rectal cancer recurrence without any measurable impact on overall survival in moderate risk disease accompanied by lower rates of local recurrence with total mesorectal excision (TME) alone Further evidence has been published relevant to the optimal use of radiotherapy in rectal cancer management subsequent to the study period. For example, several relevant phase III trials reported their outcomes after 2004 and new National Institute for Health and Care Excellence (NICE) colorectal cancer guidelines incorporating their findings were published in 2011 et al.Several international studies have investigated the variation in use of radiotherapy for rectal cancer The significant variation in the range of intervals between the start of radiation and surgery is also of interest. The evidence based around what constitutes the optimal interval in either SCRT or LCCRT is relatively weak Indeed, a significant limitation of this study was the quality and extent of the data available in the RTDS. Numerous weaknesses were identified, including poor recording of the site of treatment, limited and unreliable information on treatment intent and, in certain centres, multiple episodes of care for a single course of treatment. However, linkage of the RTDS to other data sources available in the NCDR (notably cancer registry and HES data) alongside detailed clinical review and analysis did enable courses of radiotherapy to be related to both definitive diagnoses and surgical information. Patterns of care could then be quantified. A future development of the RTDS should, however, seek to both extend the data scope and its quality so that such robust analyses assessing the effect of variation in the time between radiotherapy and surgery initiation can be quantified and guidance produced to define optimal practice.Recent changes in clinical practice may also alter future radiotherapy uptake Although the present study has shown significant variation in the use of radiotherapy, it is unable to determine what influence this is having on locoregional failure or patient-reported outcomes. What is the correct balance between the benefits and risks of preoperative radiotherapy? Randomised trial evidence suggests that radiotherapy may reduce the risk of local recurrence, but it does not influence long-term survival. However, the addition of radiotherapy increases long-term side-effects Although MDTs now routinely collect considerable information on the process of treatment, including histopathological assessment of the resected specimen, there is no systematic and prospective approach to record the timing and pattern of failure after rectal cancer resection and patient-reported outcomes. Extending the capture of such robust data to enable population-based assessment of the true effect of treatment variation on patient outcomes is vital if the NHS is to offer the best possible service. Our approach will be used to monitor the influence of the 2011 NICE guidelines. However, optimising the recommendations for the use of preoperative radiotherapy in future guidelines will depend on robust data linkage of radiotherapy data to both validated patient-reported outcomes and local recurrence rates. Additional linkage to fully completed Royal College of Radiologists and Pathologists minimum reporting datasets for each tumour would also give further insights to the choices made at MDT meetings.This population-based study has shown a wide variation in both the use of radiotherapy and radiotherapy schedules across the English NHS. Prospective population-based collection of locoregional recurrence, patient-reported toxicity and radiology and pathology datasets is required to understand and improve patient selection for preoperative radiotherapy, reduce variation in treatment and improve outcomes.


Clostridium pasteurianum is becoming increasingly attractive for the production of chemicals and fuels such as n-butanol and 1,3-propanediol. Previously we have shown that dual substrate fermentation using glucose and glycerol enhanced the cell growth and butanol production significantly. Although C. pasteurianum can grow efficiently with either glucose or glycerol alone, under certain conditions, glucose limitation in the mixed substrate fermentation leads to growth cessation. To understand this phenomenon and for process optimization, fermentation experiments were performed in the presence of excess glycerol but with varied initial concentrations of glucose which were followed by physiological, metabolic and proteomic analyses.C. pasteurianum in the different growth phases (e.g. before and after glucose limitation) correlated well with the expression level of the ATP dependent pyruvate carboxylase and with the expression level of biotin synthase which provides the cofactor biotin for the formation of oxaloacetate from pyruvate. Bioenergetic analysis based on the formation rates of metabolites further show that ATP supply is not a limiting factor for the pyruvate carboxylation to oxaloacetate.Physiological characterization showed that the observed cease of growth is not due to the toxicity of n-butanol. Furthermore, the growth can be resumed by addition of glucose or the intermediate oxaloacetate. Proteomic analysis shed more light on the system-level regulation of many proteins directly or indirectly associated with this phenomenon. Surprisingly, it is found that the specific growth rate of C. pasteurianum in fermentations with mixed substrates of glucose and glycerol. This study provides interesting targets for metabolic engineering of this emerging industrial microorganism.The results of physiological and proteomic analyses clearly show that the anaplerotic synthesis of oxaloacetate plays a key role in determining the growth behaviour of The online version of this article (doi:10.1186/s12934-016-0497-4) contains supplementary material, which is available to authorized users.