In this paper, the behavior of a clinically-oriented, multiscale model of solid tumor response to chemotherapy is investigated, using the paradigm of nephroblastoma response to preoperative chemotherapy in the context of the SIOP/GPOH clinical trial. A sorting of the model's parameters according to the magnitude of their effect on the output has unveiled the relative importance of the corresponding biological mechanisms; major impact on the result of therapy is credited to the oxygenation and nutrient availability status of the tumor and the balance between the symmetric and asymmetric modes of stem cell division. The effect of a number of parameter combinations on the extent of chemotherapy-induced tumor shrinkage and on the tumor's growth rate are discussed. A real clinical case of nephroblastoma has served as a proof of principle study case, demonstrating the basics of an ongoing clinical adaptation and validation process. By using clinical data in conjunction with plausible values of model parameters, an excellent fit of the model to the available medical data of the selected nephroblastoma case has been achieved, in terms of both volume reduction and histological constitution of the tumor. In this context, the exploitation of multiscale clinical data drastically narrows the window of possible solutions to the clinical adaptation problem.The development of computational models for simulating tumor growth and response to treatment has gained significant momentum during the last few decades. At the dawn of the era of personalized medicine, providing insight into complex mechanisms involved in cancer and contributing to patient-specific therapy optimization constitute particularly inspiring pursuits. The  The last few decades have witnessed an increased interest of the scientific community into the development of computational models for simulating tumor growth and response to treatment The major modeling approaches can be distinguished into predominantly continuous and predominantly discrete models. Predominantly continuous models rely primarily on differential equations to describe processes such as diffusion of molecules, changes in tumor cell density and invasion of tumor cells into the surrounding tissue This paper investigates the behavior of an actual clinical trial-driven model simulating the response of nephroblastoma tumors to preoperative chemotherapy. Nephroblastoma  is the most common renal malignancy in children This research is approved by the Ethical Committee of the Aerztekammer des Saarlandes (104/10 from 20 July 2010). Written informed consent was given by the parents of the child whose clinical data were used in this work.In Silico Oncology Group (ISOG), National Technical University of Athens (NTUA). A “top-down” simulation approach is formulated The model is a predominantly discrete, clinically-oriented multiscale cancer model of solid tumor response to chemotherapy The following five categories  of cancer cells are considered in the model: stem cells , LIMP cells , terminally differentiated cells, apoptotic and necrotic cells. The various cell cycle phases  and the dormant (G0) phase constitute subclasses in which stem or LIMP cells may reside. Cycling of proliferating cells through the successive cell cycle phases.Symmetric and asymmetric modes of stem cell division.Terminal differentiation of committed progenitor cells after a number of mitotic divisions.Transition of proliferating cells to the dormant phase due to inadequate supply of oxygen and nutrients.Reentering of dormant cells into the active cell cycle due to local restoration of oxygen and nutrient supplies.Cell death through spontaneous apoptosis.Cell death through necrosis (due to prolonged oxygen and nutrients' shortage).Cell death due to chemotherapy-induced apoptosis.In order to simulate chemotherapy-induced cell death, lethally hit cells are assumed to enter a rudimentary cell cycle leading to apoptotic death. Cell cycle-specific, cell cycle-non specific, cell cycle phase-specific and cell cycle phase-non specific drugs can be simulated, as detailed in For a relatively short time interval compared to the tumor's lifetime (such as the duration of a simulated chemotherapeutic schedule) the various cell category/phase transition rates are considered approximately constant and reflect the means of the actual cell category/phase transition rates over the interval.9 cells/cm3) A three-dimensional cubic mesh discretizing the region of interest is considered. The elementary volume of the mesh is called geometrical cell (GC). Each GC of the tumor accommodates initially a number of biological cells (NBC), which is defined based on typical solid tumor cell densities (e.g. 10The model supports the division of tumor area into different metabolic regions (e.g. necrotic and proliferative) based on pertinent imaging data and the handling of each region separately. In this case different values of specific model parameters can be assigned to each region.At each time step the discretizing mesh is scanned and the basic cytokinetic, metabolic, pharmacokinetic/pharmacodynamic and mechanical rules that govern the spatiotemporal evolution of the tumor are applied. Practically, each complete scan can be viewed as consisting of two mesh scans, as described in A simplified flowchart of the entire simulation procedure is provided as supporting material . A detaiA thorough study of nephroblastoma literature preceded the simulations, so as to define -in conjunction with accumulated basic science and clinical experience-plausible reference values and value ranges of the various model parameters .A protocol of preoperative chemotherapy with a combination of actinomycin-D and vincristine for unilateral stage I-III nephroblastoma tumors, treated according to the SIOP 2001/GPOH clinical trial , in the Vincristine's antineoplastic effect is basically attributed to its ability to bind to the protein tubulin, thereby destroying the functionality of the cell's microtubules, which form the mitotic spindle, and ultimately resulting in apoptotic cell death at mitosis (an M-phase specific drug) Actinomycin-D is a cell cycle-nonspecific antitumor antibiotic that binds to double-stranded DNA through intercalation between adjacent guanine-cytosine base pairs The method used for the initial estimation of typical values of the cell kill ratios of vincristine and actinomysin-D is based on relevant pharmacokinetics and pharmacodynamics literature According to the SIOP 2001/GPOH clinical trial protocol, vincristine i.v. bolus injection is directly followed by an i.v. bolus injection of actinomycin-D, with no delay in-between. As a first approximation, an additive drug effect of vincristine and actinomycin-D has been assumed for all active cell cycle phases. For dormant cells only actinomycin-D exerts a cytotoxic effect.The results of the sensitivity analyses performed permitted the sorting of the model's parameters –and hence of the corresponding biological mechanisms- according to the magnitude of their effect on selected outputs. These are cellular-level biological mechanisms, but are governed by—and thus summarize—various genetic determinants which may diversify the tumor phenotype, prognosis and response to therapy for each particular clinical case. More specifically, all model parameters pertaining to tumor dynamics have been studied , andThe oxygen and nutrients availability status of the tumor (as expressed mainly by the fraction of cells entering the dormant phase following mitosis - Psym)The balance between the symmetric and asymmetric modes of stem cell division, reflecting intrinsic properties of stem cells and/or extrinsic controls from their microenvironment The cytotoxicity of the chemotherapeutic agents  tumor cells - RG0toG1 (which constitutes a further way through which the oxygenation and nutrients' availability status of the tumor plays a role in the model).The fraction of the dormant cells having just left the G0 compartment that re-enter the cell cycle -Psleep, Psym, CKRtotal, Tc, RA, PG0toG1). The combined effects of a number of parameter dyads on the reduction percentage of a chemotherapeutically treated tumor and on the growth rate constant characterizing its free growth or re-growth after completion of therapy have been studied. The considered parameter dyads are: i) Psym and Psleep, ii) TC and RA, and iii) CKRtotal and PG0toG1.An additional parametric analysis is presented in For tumor regrowth after therapy studies, an exponential free growth pattern has been considered, which in fact approximates a segment of the Gompertzian curve, as explained in sym and Psleep on the growth rate of the tumor. An intuitive observation is that a tumor is more aggressive (with a higher growth rate constant) for higher values of Psym and lower values of Psleep, which points out the counteracting effect of the two mechanisms. The growth rate “isosurfaces”  form parallel stripes, implying that the effect of the combination of the two parameters retains the same character over the entire value space considered.C and RA. Virtual tumors with prolonged cell cycle duration are less aggressive (with a lower growth rate constant) than tumors with short cell cycle durations. This difference becomes greater for higher values of the spontaneous apoptosis rate. The tumor growth rate “isosurfaces” appear almost parallel to the axis of RA for low values of TC: the influence of spontaneous apoptosis on the growth rate of the tumor is much less pronounced than the effect of the cell cycle duration  and the second one 3 days after the last drug administration. At this first clinical adaptation step, the spatial distribution of macroscopically distinct tumor subregions was not available for the particular clinical case and therefore an equivalent tumor of the same constitution in terms of cell categories population numbers has been considered. Based on the imaging data, chemotherapy has achieved tumor shrinkage equal to 73%. Post-surgery histological data indicated a highly malignant, blastemal type of tumor, with a regression/necrosis component after chemotherapy approximately equal to 60% and a 100% blastemal component for the remaining viable tumor. The available histological information for the particular tumor has been used in the model so as to provide a means of appropriately adjusting the corresponding populations percentages in the equivalent homogeneous virtual tumor considered.Results of sensitivity analyses such as those presented in the previous section, have provided guidance for the selection of the model parameter values so as to succeed in implementing a virtual tumor consistent with the actual clinical data, both in terms of tumor volume measurements and histological constitution of the tumor. Four virtual tumor scenarios in agreement with the tumor volume imaging data measurements have been specified. The values assigned to the model parameters for the implementation of the four virtual tumor scenarios are presented in sym and Psleep, and tumor T2 by adjusting TC and RA. The third scenario (T3) has been specified, by considering an initial tumor with all parameters kept at their reference values, apart form the total cell kill ratio, which has been adequately perturbed in order to fit the tumor volume measurements. As will be subsequently described, the final virtual scenario (T4) incorporates all necessary parameter perturbations to achieve full compliance with all medical and literature data.The volume reduction for these simulated tumors is equal to 72% for T1, T2, and T3, and 73% for T4. These results are in very good agreement with the imaging data-specified volume shrinkage of 73%. After having initially assigned reference values to all model parameters, exploratory perturbations have been performed in order to achieve agreement with clinical data. Tumor T1 has been derived by appropriately perturbing PSince all four virtual tumors are in good agreement with the data in terms of tumor volume reduction, they would be thought of as fairly good solutions of the simulation problem if no further information was available. Nevertheless, as revealed by the detailed tumor characteristics of these solutions, the corresponding tumors' subpopulation constitution and growth rate characteristics could be highly variable. To the best of our knowledge, all attempted adaptations of simulation models to clinical data reported up to now in the literature involve agreement in terms of tumor volume or total cell population, with the exception of modeling efforts that include a distinction between proliferating and quiescent cells sym, Psleep). Our sensitivity analyses indicate that, under all the concurrent constraints considered, large deviations from the specified values of these critical parameters, and hence radically different solution characteristics, would not be expected, if an “exhaustive” solution search to the particular adaptation problem was attempted. Rather, different solutions would result mainly from alternative values in parameters that remain largely unspecified based on the available data. Such an example is the NLIMP parameter, which currently remains unspecified based on the available data; an indication regarding the relative percentages of stem and committed progenitor cells would restrict the range of permitted perturbations in its value.Tumor T4 is a scenario fully satisfying the available histological constraints of the clinical case considered, with a post-chemotherapy population of dead cells close to 60% (≈57%) and a quite negligible population of differentiated cells (≈1%) since a blastemal type of tumor is being studied. At the same time, this scenario is in a rather good agreement with nephroblastoma literature regarding those tumor characteristics for which no clinical input was available: volume doubling time of 21 days .Since PT1 and, particularly, T4 are characterized by the highest stem cell content, as they have the highest symmetric division fraction values. It is interesting that the currently derived high stem cell content of T4 correlates with the high malignancy and poor prognosis of nephroblastomas of blastemal type, particularly so in the context of recent reports in literature suggesting that individual tumors that are, at the histopathological level, relatively undifferentiated may contain higher proportions of stem cells than their more differentiated counterparts sleep value and high TG0 value lead to a significantly higher initial percentage of dormant cells compared to the rest of the virtual tumors.T1's high Psym, have higher fractions of differentiated cells compared to T1.T2 and T3 due their lower PThe large duration of necrosis in the case of T4 is directly related to the large dead cell component of this tumor.The central focus of this work has been a thorough sensitivity analysis of the simulation model, revealing the relative importance of its parameters. A sorting of the parameters, and hence of the corresponding cellular-level biological mechanisms, with major impact on the simulation outcome has been performed. Indicative parametric investigations that shed light on complex parameter interrelations, which often cannot be grasped intuitively, have been presented. The two biological mechanisms mostly implicated in the result of therapy are the oxygenation and nutrients availability status of the tumor and the balance between the symmetric and asymmetric modes of stem cell division. These results constitute part of an extensive series of such parametric studies, aiming at deepening and advancing quantification of our understanding of tumor response to chemotherapeutic treatment in the nephroblastoma and, more specifically, the SIOP/GPOH clinical trial context.A clinical case of nephroblastoma from the SIOP 2001/GPOH trial has been selected and by using plausible values of the model parameters derived from clinical experience and relevant literature, an excellent fit of the model to the available clinical data has been achieved in terms of both volume reduction and histological constitution of the tumor. Furthermore, derived critical tumor characteristics for which no direct clinical information was available are in good agreement with relevant nephroblastoma literature. Whereas various attempts of model adaptations to volumetric data have already been reported in the literature, agreement with clinical data in tumor volumetric terms alone may mask tumors with radically different characteristics. The potential to readily exploit additional data available in the context of clinical trials, thereby narrowing the window of possible solutions, is a particularly distinctive feature of the ISOG model.The fitting of the selected nephroblastoma case to the clinical data serves as a proof of principle example, demonstrating the basic philosophy of a possible procedure towards the selection of prevailing virtual scenarios, based on the combined use of the available multiscale clinical and literature data. As the available information regarding a particular tumor's characteristics increases, further narrowing of the window of possible solutions is to be expected. Availability of multiscale medical data imposes constraints on model parameter values. Conversely, after adequate “tuning” the simulation results could give valuable hints concerning tumor characteristics for which actual estimations might be missing in each case considered.Major scientific challenge for the ISOG modeling efforts is the eventual translation of its detailed multiscale cancer models to clinical practice. The use of anonymized data before and after treatment constitutes the basis for the clinical adaptation and validation process. As more and more sets of medical data are exploited the reliability of the model results is expected to increase and patient-individualized modeling to be strengthened. In future versions of the model, the individual patient's serum response to specific tumor antigens will be considered as well: in the context of the ACGT project, possible correlations of the autoantigen pattern with tumor histology  are under investigation It is envisaged that, at a later stage, after the completion of the necessary adaptation and validation procedure, such simulation platforms could support the design of new experiments or clinical trials, by identifying important scientific questions and open issues, brought forward through an in-depth understanding of the system; they could even offer the potential for studying various biological mechanisms and interactions without performing time-consuming and costly laboratory experiments or clinical trials. Designing some of these clinical trials or experiments is extremely difficult, if at all feasible, as they would have to refer to the basic science level.In silico oncology holds much promise in the field of cancer research. It certainly has not yet reached its full potential, multiple challenges of diverse nature exist and many unresolved issues remain to be addressed. Nevertheless, the presented successful initial adaptation step lends support that the ISOG modelling efforts are indeed on a viable track towards clinical adaptation.Figure S1Simplified flowchart of the simulation procedure. Simplified flowchart of the simulation procedure. GC: Geometrical Cell. Y:Yes, N:No.(TIF)Click here for additional data file.Figure S2Time evolution of various tumor subpopulations. Alternative presentation of various tumor subpopulations for the four virtual tumor scenarios implemented Click here for additional data file.Table S1Miscellaneous model parameters (unrelated to tumor dynamics) and typical values where applicable.(DOC)Click here for additional data file.Text S1Calculation of reference values for the cell kill ratios of vincristine and actinomycin-D.(DOC)Click here for additional data file.Text S2Details regarding sensitivity analyses.(DOC)Click here for additional data file.


Colocutaneous fistula caused by diverticulitis is relatively uncommon with colo-umbilical fistulas being even rarer. We herein report a rare case of a spontaneous colo-umbilical fistula due to diverticulitis of the sigmoid colon. The fistula developed from a diverticulum of the sigmoid colon that discharged through the umbilicus after two episodes of acute diverticulitis. The condition was successfully treated by resectional surgery. Diverticular disease is an increasingly common condition in Western countries especially among elderly people. The disease affects mostly the left colon. It is usually asymptomatic and becomes manifest only when complicated with bleeding or inflammation. Acute diverticulitis may complicate with free perforation resulting in fecal or purulent peritonitis or with pericolic abscess formation, involvement of adjacent organs, and fistulation. Fistulas occur in approximately 5% of cases either spontaneously or after surgical or drainage procedures , 2. The A 54-year-old man presented with a 15-day history of low-grade fever and continuous mild pain around the umbilicus. Three days before admission he noticed foul smelling discharge emanating from the umbilical pit. His medical history included irritable bowel syndrome, diverticulosis of the sigmoid colon, and two episodes of acute diverticulitis over the last two years that were treated conservatively.3) and C-reactive protein (2.8 mg/dL). A plain abdominal radiography was unremarkable.On physical examination the abdomen was slightly distended with mild tenderness in the left lower quadrant without palpable masses or any evidence of acute abdomen. Guarding, rigidity, and rebound tenderness were absent and bowel peristalsis was normal. The umbilicus and the periumbilical skin were inflamed and macerated, with spontaneous fecal discharge from the umbilical pit . The labAbdominal computed tomography (CT) revealed diffuse diverticulosis in the sigmoid colon with inflammatory changes and mesenteric stranding and a cavity beneath the abdominal wall at the level of the umbilicus communicating with the sigmoid colon . There wLaparotomy demonstrated a fibrotic fistulous tract between the umbilicus and the sigmoid colon lined with granulation tissue attributable to the previous attacks of diverticulitis. The affected part of the sigmoid colon along with the fistulous tract and the umbilicus were resected en bloc , and a HColonic fistulas to internal viscera such as urinary bladder, vagina, uterus, fallopian tube, ureter, jejunum, and colon or to the skin of the abdominal wall and the perineum (colocutaneous fistulas) arise either spontaneously due to perforation of a diverticular abscess into an adjacent organ or to the skin or as a complication after resection surgery for diverticulitis. Colovesical fistula is the most common internal fistula 48%) while colocutaneous fistula is relatively rare (5%) with the colo-umbilical type being even rarer. A colocutaneous fistula occurs usually after surgical intervention or percutaneous drainage of a diverticular abscess whilst spontaneous fistulation is uncommon –8. In ou% while cThe diagnosis of colocutaneous fistula is usually apparent from the history and the presence of a fistulous opening in the skin. Drainage of feces from the cutaneous opening is a constant and characteristic feature. Barium enema examination will often confirm the diagnosis. However, computed tomography is the preferred study for colocutaneous fistulas providing information on both the intra- and extraluminal features of the fistulous tract, the part of bowel involved, and the presence of abscesses, obstruction, or perforation . Water sConservative management of colocutaneous fistulas consisting of withdrawal of oral intake, fluid and electrolyte replacement and nutritional support with total parental nutrition, control of both local and systemic sepses, and local skin care results in low closure rates and has the possibility of fistula recurrence. However, it can be used as an initial step to control local or systemic sepsis, to reduce the inflammation, and to lessen the operation. In our patient, the short and wide fistulous tact made spontaneous closure of the fistula very unlikely and thus surgical management was undertaken. Currently, resection of the fistulous tract and the affected colon with primary colonic anastomosis in a single stage is the treatment of choice for diverticulitis-associated fistulas. The success rate of the single-stage procedure is approximately 90% without increased postoperative morbidity and mortality rates , 2, 5. TIn conclusion, we here presented a rare case of spontaneous colo-umbilical fistula complicating diverticulitis of the sigmoid colon which was successfully treated by resectional surgery.


During September–October 2010, an unprecedented outbreak of Rift Valley fever was reported in the northern Sahelian region of Mauritania after exceptionally heavy rainfall. Camels probably played a central role in the local amplification of the virus. We describe the main clinical signs  observed during the outbreak. Culex and Anopheles ; some of these species were known to be competent vector species for major arboviruses.From late September through the beginning of October 2010, unprecedented rainfall created large ponds in the oases of the Saharan region of Adrar, northern Mauritania . Such ragraret) of the Adrar region. Notably, the first probable reportable case in livestock was in a sick dromedary camel and occurred during the last week of October 2010 in the Aoujeft area; the camel’s signs were similar to those of pasteurellosis. The herdsman slaughtered the animal before it died but delayed the cutting up of the meat because of the remote location. Subsequently, the uncooked meat was shared within the extended family, and within a few days, several people died with intestinal and hemorrhagic symptoms. Health authorities requested testing for several pathogens, including Crimean-Congo hemorrhagic fever and RVF; results were positive for RVF. Although these persons likely did not become infected through the consumption of meat   were reported in several oases  were reported on a massive scale. At the end of December 2010, a total of 63 cases among humans, including 13 deaths, had been officially reported, but the true number is probably much higher due to the remoteness of the affected area. Of 14 initial blood samples from camels, 7 had positive test results by real-time reverse transcription PCR; the virus was isolated from 4 of those positive samples in the Laboratoire National d’Elevage et de Recherches Vétérinaires, Dakar, Senegal. The first serologic results obtained by the central veterinary laboratory using a competitive ELISA  indicated an immunoglobulin (Ig) M/IgG prevalence of 33% in camels and 44% in small ruminants, respectively. IgM titers .,,Serologic evidence of RVF in camels is frequently reported . The high mortality rates and severe clinical signs observed among dromedary camels indicate that these animals played a major role in the epidemiology of this outbreak. The capacity of RVF-infected During the course of the outbreak in Adrar, the price of livestock decreased by 40%, which created an attractive opportunity for traders who potentially could further disseminate the virus. Also, the possible role of oases as relay points has for some time been seen as a major risk for the introduction of RVF in the Maghreb, where eco-climatic and entomologic conditions are favorable for its emergence. These possible risk factors and the unusual appearance of RVF in an arid region call for further strengthening of surveillance and sanitary capacities and policies.


The mismatch negativity (MMN) is a differential brain response to violations of learned regularities. It has been used to demonstrate that the brain learns the statistical structure of its environment and predicts future sensory inputs. However, the algorithmic nature of these computations and the underlying neurobiological implementation remain controversial. This article introduces a mathematical framework with which competing ideas about the computational quantities indexed by MMN responses can be formalized and tested against single-trial EEG data. This framework was applied to five major theories of the MMN, comparing their ability to explain trial-by-trial changes in MMN amplitude. Three of these theories  were formalized by linking the MMN to different manifestations of the same computational mechanism: approximate Bayesian inference according to the free-energy principle. We thereby propose a unifying view on three distinct theories of the MMN. The relative plausibility of each theory was assessed against empirical single-trial MMN amplitudes acquired from eight healthy volunteers in a roving oddball experiment. Models based on the free-energy principle provided more plausible explanations of trial-by-trial changes in MMN amplitude than models representing the two more traditional theories (change detection and adaptation). Our results suggest that the MMN reflects approximate Bayesian learning of sensory regularities, and that the MMN-generating process adjusts a probabilistic model of the environment according to prediction errors. The ability to predict one's environment is crucial for adaptive and proactive behaviour. It requires learning a mental model that captures the environment's statistical regularities. A process of this sort is thought to be reflected by the mismatch negativity (MMN) potential, a non-invasive electrophysiological measure of the neural response to regularity violation by sensory stimuli. However, the exact computational processes reflected by the MMN remain a matter of debate. We developed a modelling framework in which competing hypotheses about these processes can be objectively compared by their ability to predict single-trial MMN amplitudes. We applied this framework to formalize five major MMN theories and propose a unifying view on three distinct theories which explain the MMN as a reflection of prediction errors, model adjustment, and novelty detection, respectively. We assessed our models of the five theories with EEG data from eight healthy volunteers. Our results are consistent with the idea that the MMN arises from prediction error driven adjustments of a probabilistic mental model of the environment. A key theme of contemporary neuroscience is the notion that the brain embodies a generative model of the environment, enabling inference on the causes of sensory inputs and predicting future events. This is also known as the “Bayesian brain hypothesis”  paradigm A major research theme has been the search for models of the neurophysiological and computational processes that underlie the MMN Change Detection Hypothesis: The MMN reflects the detection of a local physical change in the sensory input Adaptation Hypothesis: The MMN reflects the difference in stimulus-evoked activity between adapted and non-adapted sensory neurons Model Adjustment Hypothesis: The auditory cortex maintains a model of the acoustic environment, and stimulus-induced updates of this model are indexed by the MMN Novelty Detection Hypothesis: The MMN reflects the degree to which the current event is surprising (novel) Prediction Error Hypothesis: The cortex implements approximate Bayesian inference using predictive coding. The MMN reflects the neural activity encoding the prediction errors that drive this process; i.e., differences between actual and predicted inputs per se, but also how its single-trial amplitude changes as the subject learns statistical regularities during the successive presentation of stimuli. The mismatch response to the same stimulus differs depending on the history of all preceding stimuli, and our models should be able to predict these changes. The ensuing modelling of single-trial MMN amplitudes and their progressive changes represents a novel approach, which emphasizes the sensory learning on which the MMN rests. Two related studies using a similar approach recently suggested that single-trial MMN and P300 amplitudes reflect the trial-wise degree of Bayesian and Shannon surprise, respectively processes postulated by the five MMN theories introduced above in terms of specific process models; these are then subjected to Bayesian model comparison in order to assess how well each of them explains the variability of trial-wise MMN amplitudes. This formulation of detailed and quantitative models representing the 5 major contemporary MMN theories constituted the second goal of this paper. In constructing these models, the third goal was to show that the prediction error, model adjustment, and novelty detection theories of the MMN can be unified. Concretely, we propose that prediction errors, model adjustments and novelty are different manifestations of a common underlying process, namely variational free-energy minimization during perceptual inference and learning So far there has been no objective procedure to conclude which MMN theory is best supported by a given dataset, because most theories of the MMN are of a qualitative nature and do not make quantitative predictions. Furthermore, the inferences that could be drawn were limited by the averaging inherent to standard ERP analysis: this destroys any information about the temporal dynamics of learning. The first goal of this study was to overcome both limitations by providing a modelling framework with which competing MMN theories can be formalized and objectively compared against one another by their capacity to explain single-trial MMN amplitudes. Here, the explanandum was not just the mismatch negativity This paper is structured as follows. The The empirical data used in this study comprised trial-wise mismatch responses, acquired during a roving oddball experiment with electroencephalography (EEG) from eight healthy subjects in a previously published study standard) from the waveform elicited by its first presentation (the deviant). In other words, we compared responses to physically identical stimuli presented in different contexts (i.e. after different stimulus trains). This avoids confounding factors that would have arisen had we used a classical oddball or mismatch negativity paradigm In this study, we quantified the MMN by subtracting the average of waveforms elicited by the sixth presentation of a tone  and the length of the preceding train of tone repetitions.For each subject and each deviant trial the MMN amplitude was estimated by applying the procedure of Mars et al. For each deviant trial, subtract the “standard ERP” of the presented tone  from the EEG signal recorded in that trial. This isolates the deviance-specific potential.For each deviance-specific potential, subtract the average potential in the 100 ms preceding the deviant presentation from the ensuing response (baseline correction).Estimate each subject's MMN peak latency by the minimum point of his/her average difference wave  between 100 and 200 ms after stimulus onset Estimate each subject's trial-wise MMN amplitudes by averaging his/her deviance-specific potentials over a th element of vector th element of the kth row of matrix This section introduces our modelling framework for single-trial responses. In terms of notation, we denote vectors by lower case bold letters, matrices by upper case bold letters, and scalars and functions by lower case italics .The MMN indexes the difference in a physical property between the deviant and its predecessor .Here, the relevant physical stimulus property is the log-frequency of a pure sine tone. In our framework, the general notion of change detection can be formalized by assuming a one-dimensional internal representation cf.  see .adaptation hypothesis, the MMN elicited by a change in sound frequency reflects the difference in the responsiveness of adapted and non-adapted frequency-specific neurons in auditory cortex Neural adaptation is the process due to which the neural response to a stimulus or feature decreases with its repeated or prolonged presentation. According to the Here, we adopted a phenomenological description of adaptation that is agnostic to the exact underlying mechanism. We modelled seven populations of frequency-selective neurons, each of which is responsive to exactly one of the seven log-frequencies This model predicts that the MMN amplitude is proportional to the responsiveness of the stimulus-driven neuronal population. Therefore, the response function simply reads out the appropriate state value and combines it with a constant:pace see .Predictive coding, model adjustment, and novelty detection are formalized by models based on the free-energy principle . As a result, the mental model contains 10 tone categories  of complex sounds and their physical properties is complicated Furthermore, the temporal structure of the hidden sequence is represented by the transition matrix M5—M13 in This subsection derives the evolution function function  of the ofunction  of how sdel  see . The evoTo compute the temporal evolution of the internal states predicted by our free-energy models, the evolution function was iteratively applied to the known sequence of log-frequencies presented in the empirical study. This provides a succession of posterior beliefs that are encoded by neuronal activity and give rise to trial-wise MMN responses. To specify this mapping between posterior beliefs and MMN amplitudes, we now turn to the response models  with respect to the conditional probability distributions describing the observer's beliefs. Unlike prediction error, surprisal is an unsigned quantity, corresponding to the negative logarithm of the conditional probability of sensory inputs given expectations about hidden states (or of hidden states given expectations about model parameters). Because the mental model assumes additive Gaussian noise, the conditional surprise about a stimulus is determined by the precision weighted squared prediction error on the stimulus . This provides a tractable approximation to the Shannon surprise with respect to the prior predictive density over sensory inputs , the only model predicting the absence of trial-by-trial changes in MMN amplitudes, is not the best model. Contrary to the predictions of this model, the MMN amplitude appears to vary systematically over deviant trials. This suggests that the MMN is not simply a categorical response to regularity violation but context dependent, as predicted by trial-by-trial statistical learning. Notably, the best five models were all derived within the free-energy framework. Model 6M, which explains trial-wise changes in MMN amplitude as a manifestation of precision weighted prediction errors (on the hidden tone category), was best supported by our data , each with exceedance probability 6 was about five times as large as the exceedance probability of our “null” model M1, this was too small to yield an acceptably low probability of model selection error While the exceedance probability of the best model MFinally, we used BMS to examine whether the free-energy principle based models provide, in general, better explanations of the variability of single-trial MMN amplitudes than phenomenological models. This means we are now comparing only two families : the famls;  see .Finally, we asked which level of the processing hierarchy contributes most to the fluctuations in trial-wise MMN amplitudes. In other words, we examined whether response variations arise from lower auditory areas representing physical sound properties like frequency, or from higher areas that represent abstract temporal structure. For this purpose we re-partitioned the 13 models into two families according to whether they explain MMN generation in relation to a low-level auditory feature (sound frequency) or a high-level auditory feature . For the models based on the free-energy principle models the two levels of representation map onto the two levels of the mental model: sensory inputs and hidden sequence of tone categories . We assiaverage MMN amplitude as a function of the number of preceding standards and the change in frequency. Here we provide a conventional analysis of variance to demonstrate that our data did contain history-dependent effects that would have been removed by conventional averaging. By history-dependent effects we mean that the MMN amplitude evoked by a deviant following a given number of standards and a given frequency change will differ depending on the tones that preceded the current sequence of standards. The mere number of such tones is a minimal definition that ignores the effects of their statistical structure, some of which are captured by our models. However, it allows for a conservative test of history-dependence, i.e., whether a 3-way analysis of variance (ANOVA) of trial-wise MMN amplitudes reveals interactions among three factors: (i) number of preceding standards, (ii) frequency difference, and (ii) time, i.e., the number of preceding trial sequences. We found significant main effects for the number of preceding standards and for frequency difference  were found to have higher evidence than models which did not . One may ask, however, as did one of our reviewers, whether our single-trial approach was really necessary or whether it would have been sufficient to analyse the fference . More imIn this paper we presented a framework for modelling single-trial responses, applied it to formalize five major theories of the MMN see , and tesOur analyses suggested that stimulus history  affects the MMN in intricate ways. This was not only demonstrated by a simple ANOVA of single-trial MMN amplitudes, but, more importantly, by our systematic model comparisons which favoured free-energy based Bayesian information processing models that capture history-dependent effects. In particular, these models explain the dependence of the MMN on interactions between previous tone sequences and the current tone sequence in terms of trial-by-trial learning of statistical structure. Trial-by-trial statistical learning implies that the probabilistic expectation evoked by a given tone sequence is different for every presentation, and that each difference reflects what has been learned since the previous presentation. While traditional MMN studies have ignored trial-specific effects by averaging responses across deviant events, several studies have addressed sequential changes in the MMN across trials A number of previous studies reported that the MMN amplitude elicited by a change in sound frequency increases monotonically with the number of preceding standards model adjustment hypothesis how trial-wise changes in MMN reflect an approximation to Bayesian updating of a probabilistic mental model. The resulting models are consistent with the conclusion drawn by Our modelling results do not lend support to the adaptation hypothesis of the MMN 6; Predictive coding formulations of free-energy minimization assign prediction errors a critical role in the update of posterior beliefs. When comparing all models individually, the best model was indeed one that explained trial-wise fluctuations in MMN amplitude as a function of precision weighted prediction errors , rather than by its waveform, thereby ignoring its temporal dynamics and spatial topography. Fourth, each of our models relates trial-wise MMN amplitudes to a single computational variable, whereas it is known that the MMN scalp potential is a mixture of signals from several brain areas with (presumably) different functional characteristics Bayesian brain hypothesis. According to this hypothesis, the brain represents probabilistic beliefs, and updates them in an (approximately) Bayesian fashion. Previous work along these lines has assumed that the support of probability distributions is partitioned into small bins and that each bin's probability mass is represented by the firing rate of dedicated neurons Our models based on the free-energy principle link the MMN to the neuronal encoding of posterior beliefs that is postulated by the Our present results were based on a single “roving oddball” EEG experiment that was originally designed for comparing dynamic causal models of interactions among cortical areas during the MMN Furthermore, the link between single-trial mismatch potentials, on the one hand, and statistical learning and perceptual inference, on the other hand, could be exploited to measure the temporal dynamics of how the brain learns the probabilistic structure of complex environments. This is an attractive prospect, given that the MMN is elicited not only in simple oddball experiments, but also in more complex experiments involving speech, language, music, and abstract features, as well as various other sensory modalities Text S1Mathematical details of our . Sections 1—4 provide additional information about the models based on the free-energy principle. Concretely, these sections specify how we modelled the brain's internal model of tone sequences, learning and perception, individual differences, and the manifestation of neurocomputational variables in scalp potentials. Section 5 explains how we approximated each model's log-evidence. Section 6 sketches how the computations postulated by the free-energy models could be implemented in the brain.(PDF)Click here for additional data file.


Oral health education (OHE) in schools has largely been imparted by dental professionals. Considering the substantial cost of this expert-led approach, the strategies relying on teachers, peer-leaders and learners themselves have also been utilized. However the evidence for comparative effectiveness of these strategies is lacking in the dental literature. The present study was conducted to compare the effectiveness of dentist-led, teacher-led, peer-led and self-learning strategies of oral health education.A two-year cluster randomized controlled trial following a parallel design was conducted. It involved five groups of adolescents aged 10-11 years at the start of the study. The trial involved process as well as four outcome evaluations. The present paper discusses the findings of the study pertaining to the baseline and final outcome evaluation, both comprising of a self-administered questionnaire, a structured interview and clinical oral examination. The data were analyzed using Generalized Estimating Equations.All the three educator-led strategies of OHE had statistically higher mean oral health knowledge (OHK), oral health behavior (OHB), oral hygiene status (OHS) and combined knowledge, behavior and oral hygiene status (KBS) scores than the self-learning and control groups (p<0.001). The mean OHK, OHS and KBS scores of the three educator-led strategies did not differ significantly. The peer-led strategy was, however, found to have a significantly better OHB score than the respective score of the teacher-led strategy (p<0.05). The self-learning group had significantly higher OHB score than the control group (p<0.05) but the OHK, OHS and KBS scores of the two groups were not significantly different.The dentist-led, teacher-led and peer-led strategies of oral health education are equally effective in improving the oral health knowledge and oral hygiene status of adolescents. The peer-led strategy, however, is almost as effective as the dentist-led strategy and comparatively more effective than the teacher-led and self-learning strategies in improving their oral health behavior.SRCTN39391017 In South East Asian countries a significant proportion of adolescents are having poor oral hygiene and betel-nut chewing habit both of which have serious public health consequences-5. The fTraditionally oral health education (OHE) in schools has largely been imparted by dentists or dental hygienists. However the cost-effectiveness and sustainability of such an approach is questionable. There aAnother school-based resource person whose potential has been exploited in OHE programs is a trained peer of school children. There is a growing body of research that shows that the school-based peer-led health education is more effective than the teacher-led,11 and aThe dentist-led, teacher-led, peer-led and self-learning strategies of oral health education are not significantly different from one another as well as from the control group in increasing knowledge about oral health; and in bringing about a positive change in oral health behavior and oral hygiene status of school children aged 10-11 years.The trial was a parallel cluster randomized controlled trial of two years duration. It made a part of a preventive oral health care project designed for adolescents, aged 10-11 years at the start of the project. The trial involved five groups of boys and girls studying in class six of forty public and private schools. Three of the study groups were imparted oral health education (OHE) by dentist, teachers or peer group leaders. The fourth group was a self-learning group whiles the fifth one that did not receive any form of OHE, served as a control group. The dentist-led (DL), teacher-led (TL) and peer-led (PL) groups were given a single educational input after the baseline data collection by the end of January 2004. Afterwards the groups did not receive any form of oral health education till August 2004. The oral health education messages were then repeated and reinforced on a monthly basis from Sep 2004 to Feb 2005. This was followed by a period of one year of no oral health education. The three educator-led groups were subjected to four evaluations during the course of the trial. Evaluation I was conducted immediately after the first education session to observe the effect of the single OHE input on the dependent variables. Evaluation II was performed approximately six months after evaluation I to measure the sustainability of the effect resulting from one-time OHE. Evaluation III and evaluation IV were undertaken six months and a year after the reinforcement phase of the project to determine the long term impact of repeated and reinforced OHE on the outcome variables of the study. The self learning and control groups were surveyed at baseline and at the end of two years. The schematic diagram of the oral health component of the preventive oral health care project is shown in FigureThe primary outcome measures included improvement in oral hygiene status measured through a decrease in the number of sextants of oral cavity having dental plaque without bleeding on probing, plaque with bleeding on probing and calculus. The secondary outcome measures were oral health related knowledge and preventive oral health behavior about gingivitis and OSMF/ oral cancer.http://www.controlled-trails.com) under the ISRCTTN number 39391017.The ethical approval for the trail was given by the Institutional Review Board of Shaikh Zayed Medical Complex, Lahore (Ref. No. SZH/IRB/017-03). The trail was registered with the Current Controlled Trails  in 12 years old urban school children in Pakistan.All public and private boys’ and girls’ schools having more than one section of class six and not less than thirty five students per section in the two adjacent towns of the cosmopolitan city of Karachi, Pakistan were eligible to participate. The said towns were chosen because of their socio-economic and ethnic homogeneity. A total of 377 schools were assessed for eligibility, 124 public and 253 private  strategy, the teachers-in-charge of the selected sections of class six were assigned the responsibility of OHE. In case of peer-led (PL) strategy one student in each selected section was nominated as peer leader by the teacher-in-charge depending on his/ her academic record, regularity in attendance and the ability to socialize. For dentist-led (DL) strategy, a community dentist was chosen.The selected dentist, teachers and peer leaders were trained for OHE by organizing five 2-hour sessions. The training was highly structured and based on a written set of learning objectives and activities for each session. Pre- and post-training assessment of the oral health knowledge and attitudes of the educators towards OHE of students was undertaken. The training included a live demonstration of an OHE session taken by the first author. After training all educators practiced taking an OHE session each in their respective schools in a section of class six not included in the main study. Every educator was then evaluated by the first author using a ten-point check list while taking another OHE session. The points included in the check list were: a brief description of the importance of oral health and the objectives of the OHE session, a full coverage of the OHE contents in a sequential manner, proper use of posters, the use of layman language, ensuring active participation and appreciation of a positive behavior, timely completion of the session allowing time for questioning.OHE comprising of a one-hour session in all strategies was based on the contents of a booklet supplemented by a set of seven pre-tested posters and an instruction manual for the educators . The session included twenty minutes of oral health education, five minutes of brushing demonstration, five minutes of question-answer and thirty minutes of group activities.OHE during each session covered six main topics. The first introductory topic reminded adolescents of the functional and psychosocial role of healthy teeth and the importance of taking care of them. The second topic about human dentition dealt with some practical aspects of the anatomy of a tooth (e.g. enamel is insensitive while dentine and cementum are sensitive), the number of deciduous and permanent teeth and the approximate age of eruption of permanent molars. The third and fourth topics discussed the natural history of dental caries, chronic gingivitis and periodontitis including their important signs and symptoms. The fifth topic informed students about various betel nut and tobacco containing products available in the society as well as the health consequences of using these products. The last topic covered the caries preventive measures including reduced amount and frequency of sugary foods, consuming protective foods e.g. cheese, peanuts as snacks and twice daily use of fluoride tooth paste. The purpose  and the systematic method of tooth cleaning was explained and demonstrated using a tooth brush and a model of teeth. The OHE session ended up with a brief discussion about how to have a betel nut/ tobacco free environment in schools and in the society.The theoretical framework of OHE in the three educator-led strategies was based on the constructs of social cognitive theory including vicarious learning, active participation, skill training, self efficacy, reinforcement and social support. These cIn DL and TL strategies the educators took an OHE session with all children sitting in their respective sections. After the lecture and tooth cleaning demonstration, they divided the students into five groups of seven to nine students each and asked them to carry out group activities. In the meanwhile they kept moving from one group to another to maintain discipline in the class.In PL strategy students in each section were divided into five groups and an OHE session was conducted with each group in a separate room. The peer leader initiated and facilitated discussion about oral diseases and their prevention, and supervised the students’ activities. Two such sessions per day were arranged in each section till all children were covered in that section.Considering the involvement of non-dental personnel, the OHE intervention was designed to be simple, objective and easy to deliver. The objectives of oral health education were clearly defined and its essential elements stated explicitly in the instruction manual for the educators. The latter also contained a standardized format to be followed by all educators as well as a written description of different illustrations in every poster in a sequential order. The educators were trained and encouraged to follow this sequence throughout the program to ensure full coverage of the contents of the OHE booklet in all sessions.The children in the self-learning (SL) group were given the OHE booklet to read while the control (CL) group did not receive any form of OHE.The first author observed three sessions each of the teachers, the peer leaders and the dentist during implementation of the OHE program and scored them for fidelity (range: 0-10) using the ten-point check list. The first observation was undertaken during the one-time OHE session while the second and third observations were made in the beginning and the middle of the reinforcement phase of the program. The fidelity scores of different educators ranged from eight to ten. Every observed session was followed by a feedback provided to the educators.In addition two focus group discussions, one following one-time OHE and the second at the end of the repetition and reinforcement phase of the project formed a part of the feedback and process evaluation mechanisms.The data related to the outcome measures, at baseline and the following evaluations, were collected through a self-administered questionnaire, a structured interview and a clinical oral examination of the study participants.The questionnaire included twelve close-ended questions about oral health knowledge and four about oral health behavior. The oral health knowledge questions included questions about the number of deciduous and permanent teeth; the age of eruption of first molar tooth, the most important signs; causes and prevention of dental caries and gingivitis; and the health hazards of betel nuts and tobacco. The questions related to oral health behavior inquired about the method and frequency of tooth cleaning as well as the use of betel nuts and tobacco products. Most of the questions were based on the established scientific facts in OHE such as caries preventive effect of fluoride, etiological role of dental plaque in gingivitis, role of twice daily frequency and thoroughness of tooth cleaning in preventing gingivitis, cariogenecity of sugar and refined starches, and carcinogenic potential of tobacco and betel nuts-17. SomeThe questionnaire was filled by the study participants in each section in the presence of teacher-in-charge who replicated the examination conditions to prevent interaction of students during filling out of the questionnaire.The structured interview, conducted by a trained dental assistant before questionnaire survey, comprised of eight oral health behavior questions, five of which were about the practices of adolescents with regard to buying and sharing of commonly used eatables (the respondents were asked to pick their favorites jumbled up on a table), thoroughness of cleaning teeth and their cervical areas (adolescents were required to demonstrate on the model of teeth); and making sure that one uses fluoride while cleaning teeth . Two questions explored the stated behavior of adolescents towards keeping the company of peers with bad breath and of those using betel-nut containing products. The last question was about the adolescents’ stated role in persuading their peers to avoid/ quit the use of betel-nuts. All questions for the interview were having ‘right-wrong’ and ‘yes-no’ type of responses.The face and content validity of the questions was examined by a panel of six researchers, two each from the fields of community medicine and dentistry and two educationists, based on defined and mutually agreed criteria. The reliability of questions was assessed by a test-retest study on a group of forty class six adolescents and calculating the Pearson’s reliability coefficient (r) which was found to be 0.79 for the questionnaire and 0.87 for the interview questions. The triangulation technique was used to validate questions about self reported behavior by cross checking the responses with the findings of oral examination and by observing the behavior during the interview phase of the test-retest study. The values of ‘r’ as a measure of criterion validity of reported frequency of tooth brushing against the clinical measure of gingival bleeding, demonstrated behaviors of thorough tooth cleaning and cleaning of cervical areas of teeth were 0.67, 0.81, and 0.84 respectively. The reported behaviour of consuming betel nut products was found to be highly correlated to the common practices of adolescents of buying (r=0.89) and sharing (r=0.91) these products with their peers disclosed during the structured interview.The clinical oral examination of all study subjects was performed at baseline and subsequent evaluations by a trained and calibrated dentist. Teeth were examined for plaque, gingival bleeding on probing and calculus. The examination was carried out by employing a plain mouth mirror and Community Periodontal Index (CPI) probe under natural light coming through a window. During examination subjects were seated in an ordinary plastic chair facing the window while the examiner seated on the right side of the subjects on an examination stool with adjustable height. The mouth mirror was used for indirect visualization of teeth in the upper dental arch, to enhance illumination of teeth by reflecting light on them and to retract cheeks and lips. The CPI probe was used to confirm the presence of plaque and calculus visible to the naked eye by running the probe along the gingival margin from mesial to distal surface on labial/ buccal as well as on the lingual/ palatal side of the index teeth . The bleeding on gentle probing was also detected by inserting the probe into the gingival sulcus with a force of not exceeding 20 grams (the amount of force that does not cause blanching when probe tip is inserted under the nail bed) and withdrawing it parallel to and keeping its tip in contact with the tooth surface. The procedure was repeated on three sites  on both the labial/ buccal and lingual/ palatal surfaces of the index teeth. The resistance felt while withdrawing the probe showed the presence of calculus lying in the gingival sulcus/ along the gingival margin; and bleeding indicated gingivitis. A sterilized set of mirror and probe was used for every child and all instruments were cleaned, disinfected and autoclaved before they were reused.A standard format for clinical examination was used. The oral cavity was divided into six sextants: right upper posterior (from first premolar to second molar tooth), upper anterior (from right canine to left canine tooth), left upper posterior, left lower posterior, lower anterior and right lower posterior. The sextants were examined in a clock-wise direction taking a start from right upper posterior sextant and ending at the right lower one. The buccal/ labial surfaces of teeth were examined first followed by examination of lingual/ palatal surfaces. A dichotomous scale with ‘present’ and ‘absent’ categories was used for plaque, gingival bleeding and calculus. Dental plaque and calculus were scored as present if visible to the naked eye as well as detected by CPI probe. A note of bleeding was taken provided it was associated with accumulation of visible plaque along the gingival margin. The findings were recorded by a recorder (seated on the left side of the examining subjects close enough to listen to the examiner clearly) on a specially designed form. The oral hygiene codes which were entered in the recording form included: 0 = no plaque, 1 = plaque without gingival bleeding, 2 = plaque with gingival bleeding and 3 = calculus. The worst oral hygiene code for any of the two index teeth in each sextant was recorded.5% of total children in randomly selected schools were re-examined at baseline and all evaluations on the same day to have a check on the examiner’s reliability assessed by applying Kappa test. The Kappa values for these re-examinations were always well above 0.8,19.The dentist and the dental assistant who conducted oral examination and the structured interview respectively were kept blind to the group allocation of the study subjects right from baseline till the end of the study. Similarly, the names of the schools and their allocation to different OHE strategies were concealed by assigning numbers (1-40) to schools and alphabets (A-E) to the strategies at random to ensure blinding of the data entry operator and data analyst. Although, the educating dentist, teachers and peers-leaders were trained together, the participants of the training program as well as the head-teachers and administrators of the participating schools were requested in an introductory session of the project not to disclose to their students that a similar program is going on in other schools of the area as well. Furthermore, the students were kept unaware of the schedule of different activities of the project.The responses to all questions were dichotomized as either correct or incorrect. The correct responses were given a score of one each and incorrect zero. The questions were categorized in two domains, OHK  and OHB . The mean score for each domain was then estimated. In addition the scores for five questions related to knowledge about gingivitis and oral cancer were combined to form KGO  index.The clinical data were organized to estimate the number of sextants of oral cavity having dental plaque without bleeding on probing (PLQ), plaque with bleeding on probing (BOP) and calculus (CAL). Subsequently the individual scores of these three indicators were first added and then subtracted from twelve  to produce an oral hygiene index (OHS). The OHS reflected the number of sextants of dentition free of dental plaque, bleeding on probing and calculus.Finally an additive index KBS was constructed by combining OHK, OHB and OHS scores. The OHK, OHB and OHS scores had a range of 0 to12 each while the scores of the KGO and KBS indices ranged from 0 to 5 and 0 to 36 respectively.The data were analyzed using the SPSS 16 program. The mean OHK, KGO, OHB, OHS, KBS, PLQ, BOP and CAL scores of the study groups were compared using Generalized Estimating Equations (GEE) with logThe study started with 1657 adolescents studying in 40 randomly chosen schools in the study area. The data of 140 children were excluded from the final analysis as 121 children left their respective schools before the completion of the study while 19 children missed one or more evaluations. Therefore data of 1517 children who completed all evaluations conducted in their respective groups were subjected to analyses. TableThe present paper presents the results of the study pertaining to the baseline (BL) and final outcome evaluation (IV) scores of the study groups.TableThe percent change in the mean scores of the study groups along with the significant group differences at baseline and final evaluation are depicted in TableThe study groups did not have statistically significant differences at baseline with regard to OHK, KGO, OHB, KBS and BOP scores. The SL group, however, had a marginally better baseline KBS score than the CL group (p=0.042) Table. This grThe educator-led groups had insignificantly different OHK, KGO, OHB, OHS, KBS, PLQ, BOP and CAL scores at evaluation IV with only one exception in which case the PL group had a statistically higher OHB score than the TL group (p<0.05). All these scores of the educator-led groups were significantly better than the respective scores of SL and CL groups at p<0.001 except the BOP score of the DL group which was significantly better than that of the SL group at p<0.05. The SL and CL groups exhibited a statistically significant difference in favor of the SL group only in case of the OHB index score at evaluation IV (p<0.05).The effect sizes of different education strategies with reference to the control group (effect size=1) are presented in TableThe present paper discusses the results of the trial obtained at baseline and final evaluation to compare the study groups with regard to the outcome variables of the trial. Although the educator-led groups were subjected to three more evaluations in between, the findings of these evaluations will be utilized to discuss the role of repetition and reinforcement in oral health education in a subsequent publication of the authors.The results of the present study showed that the three educator-led strategies were not significantly different in improving the oral health knowledge and oral hygiene status of the study participants. The adolescents in the peer-led group, however, exhibited statistically better oral health behavior than their counterparts in the teacher-led group. All three educator-led strategies of oral health education investigated in the study proved to be more effective in enhancing oral health knowledge, behavior, and oral hygiene status of the study subjects when compared with the strategies based on the options of ‘self-learning’ or ‘imparting no education at all’.http://www.pakmedinet.com’ was explored to search for the relevant articles published in the local journals. The reference lists of previous reviews of dental/ oral health education/ promotion programs were also screened for any pertinent papers[A MEDLINE search was conducted through PubMed to find out school-based studies that compared two or more OHE strategies tested in the present study. Different combinations of the keywords  used for the search included ‘oral’, ‘dental’, ‘health education’, ‘health promotion’, ‘dentist’, ‘teacher’, ‘peer’, ’dentist-led’, ‘teacher-led’, ‘peer-led’, self-learning’, ‘school’, ‘school-based’. The website ‘t papers,22-29. TThe search of the dental literature revealed one study that comOne significant finding of the present study had been that the peer-led strategy was almost as effective as the dentist-led strategy and comparatively more effective than the teacher-led and self- learning strategies of OHE strategies in improving preventive oral health behavior of adolescents about gingivitis and oral cancer. It was also relatively better in reducing the level of gingivitis in adolescents as compared to the other education strategies. Since the issues of ‘poor oral hygiene causing gingivitis’ and ‘consumption of betel-nut containing products’ have been shown to be strongly influenced by the peer group pressures in adolescence-33, thesThe finding of a review of thirteen comparative studies of peer-led and adult-led school health education by Mellanby et al that theThe improvement in oral health knowledge resulting from dental health education interventions has been a consistent finding in the dental literature-29. In tThe percent reduction in gingival bleeding (about 5-11%) found in the three educator-led groups in the present study was slightly lower than 12.5% decrease in the gingival bleeding score mentioned in the review by Brown. HoweverBefore drawing any conclusions, certain limitations of the study are worth mentioning. The sample size estimation in the present study was based on the prevalence of gingivitis in 12 years old children reported in the last national oral health survey in Pakistan,35. AlsoA note of caution must also be exercised in generalizing the results of the study as the limited resources did not allow a random selection of different towns of the ethnically and socioeconomically diverse city of Karachi. This might have introduced a selection bias in the study and jeopardized its external validity. Therefore a large scale community trial is recommended to confirm the findings of the study and to ascertain the fidelity of implementation of the oral health education strategies in question under daily life conditions.Although the three educator-led strategies had a modest effect on the outcome variables included in the study, the results provide some evidence to show that the peer-led strategy may provide a feasible and almost equally effective alternative to the traditional dentist-led strategy of oral health education.The authors did not declare any competing interests.The research question was conceptualized by AH. He prepared research protocol, imparted training to the persons involved, managed the research project, analyzed the data and wrote the manuscript. MIS provided guidance in data analysis and critically reviewed the methodology and manuscript. AAK supervised the research project, managed the approval and funding aspects of the project, and refined the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6831/12/54/prepub


IJIC on Pathways [The organization of the care process pursuing a Triple aim improvement of healthcare is a common interest of clinicians, healthcare managers and policy-makers in this period of financial shortage especially as part of Obamacare in the US . The TriPathways  from whiClinical pathways have been defined and discussed by the European Pathway Association (EPA) as a response to the growing complexity of care . AccordiAn explicit statement of the goals and key elements of care based on evidence, best practice and patient expectationsFacilitation of the communication and coordination of roles by sequencing the activities of the multidisciplinary care team, patients and their relativesDocumentation, monitoring and evaluation of variances and outcomesIdentification of relevant resourcesIJIC [Not all care pathways implicate integrated care. We claim that the term integrated care pathway (ICP) should refer especially to pathways integrated across various health care settings, e.g. hospitals and municipal health services. Hence, multidisciplinary collaboration within a single ward is not in itself an ICP. In the oncoming special issue of IJIC , a set oThe first example of IHC is the early home-supported discharge (EHSD) for stroke patients presented by Langhorne et al. . It is rAs a forerunner of  the refeOther ICP than IHC may benefit patients, too! A survey among 120 patients on changes in lifestyle habits since attending a new Hepatitis C clinic is reported by Horwitz et al. [It takes new knowledge and skills of staff inexperienced in such collaborative working to understand the factors at stake, e.g. self-management of horizontal coordination of multidisciplinary skills. Development of generic service delivery strategies seems difficult as local implementation projects will be greatly influenced by their local cultural, financial and political contexts. However, EPA has presented a strategy for the proper use of clinical pathways. The idea is that a complete pathway product should have four distinct and interrelated levels, see A follow-up to Homecare 222954 focuses the local operation of IHC which differs substantially from the model pathway:In high-income countries with tax-financed health care as in Northern and Western Europe the primary local challenge is to establish good collaborative relations between hospitals and the surrounding municipalitiesIn Southern Europe lacking municipal welfare-resources, the local challenge seems to be to establish good hospital-based homecare-units to advance from a relative low quality to the level of best international practice in one developmental step.In private insurance-based healthcare systems in Central Europe, e.g. Germany and the Netherlands, the local challenge seems to be to establish sufficiently competent providers of integrated care outside the hospital.Further development and consolidation of ICPs require studies at the patient level. The prospective assignment of pathways may be studied by qualitative interviews to improve patient experiences while retrospective studies of completed pathways may be useful for economic rationalization e.g. giving feedback to the model level on barriers to change. A study on “Informal work and formal plans: articulating the active role of patients in cancer trajectories” by Dalsted et al.  exemplifWe hope that the studies presented in the oncoming special issue  may help


How sensory information is transformed into effective motor action is one of the most fundamental questions in neuroscience. The intrinsic dynamics of sensory networks can play an important role in the sensory-motor transformation. However, it is difficult to experimentally assess the study of all the stages present in the processing of a sensory-motor transformation. Biophysical models of sensory, central and motor systems can largely contribute to understand the information processing mechanisms involved in this transformation. Nevertheless, because of the lack of experimental results, there are very few models including all these stages to address the transformation of sensory dynamics into a motor program.Clione limacina[Clione's wing CPG model during routine swimming [Complex intrinsic sensory dynamics can be related to multifunctionality in the sensory-motor transformation. Multifunctionality of neural systems has only been partially addressed in neuroscience research. One remarkable example of relationship between intrinsic sensory dynamics and multifunctionality is the gravimetric organ of the mollusk  limacina,2. In thswimming . On the swimming . These tClione [These results support the view that the dual dynamics of the statocyst network by itself can explain the two motor programs observed during routine swimming and during hunting behavior in Clione . In othe


In 2007, before founding the World Society of Emergency Surgery (WSES), we developed a questionnaire to investigate how emergency surgery was organized and implemented as a practice throughout the world. We discovered two fundamental models, which were sometimes present simultaneously in the same country .One model was characterized by hospitals with designated emergency surgery departments and the other featured hospitals without an emergency surgery department in which surgical emergencies were subdivided among various general and specialized surgeons. Similarly, some hospitals had designated trauma teams while others had no such designated units.However, despite the heterogeneous complexity of emergency surgery in a worldwide context, the work of surgeons around the globe appears remarkably similar regardless of the name attributed to the facility in which they practice, be it emergency surgery, acute care surgery, or another generic title.Although it is difficult to succinctly define emergency surgery, which includes a broad spectrum of procedures, a universal definition could be poly-specialized surgery performed for traumatic and non-traumatic acute diseases. We have considered non traumatic emergency surgery as non CNS life-threatening diseases requiring urgent operative intervention (within 24 hr) with the exception of those requiring total cardiac bypass.There is a significant difference between traumatic and non-traumatic acute diseases. The dispersion of trauma programs sponsored by the American College of Surgeons has resulted in the near-uniform management of trauma patients around the world. By contrast, the management of patients with non-traumatic acute diseases  remains poorly standardized and varies dramatically between treatment centers. Standards for the management of non-traumatic acute diseases are just as important as those of ATLS.World Journal of Emergency Surgery (WJES).Practitioners of emergency surgery worldwide must develop standardized guidelines to streamline protocol and designate organizational models used to address acute diseases requiring urgent surgical intervention; this ambitious effort is the primary objective of the World Society of Emergency Surgery (WSES) and its publication affiliate the In recent years, the WSES has focused on non-traumatic acute diseases, proposing standardized protocol guidelines and prospective studies shared worldwide.In 2011, WSES published the first set of universal guidelines for the management of intra-abdominal infections in the WJES .In 2011, the WSES also presented guidelines for the management of obstructive cancer of the left colon  as well In an effort to promote global sharing on the topic of management of intra-abdominal infections and to garner international support and input, the WSES also conducted two prospective observational studies.Complicated Intra-Abdominal infection Observational” Study) was a multicenter investigation performed in 68 medical institutions throughout Europe over the course of a 6-month observational period (January-June 2012) [The CIAO Study  is a multicenter observational study currently underway in 57 medical institutions around the world [The CIAOW study . Experts of emergency surgery from around the world will discuss current research and findings throughout the three-day convention. The objective of the convention is to update the international surgical community on state-of-the-art advancements in emergency surgery and discuss how these advancements can be implemented in routine practice. Upon conclusion of the convention, all participants will undergo the Emergency Surgery Education Test to receive the WSES Emergency Surgery Diploma (ESD).The second WSES convention will be held in Bergamo, Italy, July 7–9, 2013 (World Journal of Emergency Surgery.During the convention, we will also announce the official impact factor of the


Plum rains and typhoons are important weather systems in the Taiwan region. They can cause huge economic losses, but they are also considered as important water resources as they strike Taiwan annually and fill the reservoirs around the island. There are many meteorological sensors available for investigating the characteristics of weather and climate systems. Recently, the use of GPS as an alternative meteorological sensor has become popular due to the catastrophic impact of global climate change. GPS provides meteorological parameters mainly from the atmosphere. Precise Point Positioning (PPP) is a proven algorithm that has attracted attention in GPS related studies. This study uses GPS measurements collected at more than fifty reference stations of the e-GPS network in Taiwan. The first data set was collected from June 1st 2008 to June 7th 2008, which corresponds to the middle of the plum rain season in Taiwan. The second data set was collected from September 11th to September 17th 2008 during the landfall of typhoon Sinlaku. The data processing strategy is to process the measurements collected at the reference stations of the e-GPS network using the PPP technique to estimate the zenith tropospheric delay (ZTD) values of the sites; thus, the correlations between the ZTD values and the variation of rainfall during the plum rains and typhoon are analyzed. In addition, several characteristics of the meteorological events are identified using spatial and temporal analyses of the ZTD values estimated with the GPS network PPP technique. In addition to typhoons, plum rains can cause a lot of damage in Taiwan every year as they produce a large amount of rainfall over a very short period of time. From spring to summer, the northeastern monsoon and the southwestern monsoon bring cold and warm air currents, respectively. When the air currents merge, they become a frontal surface, as shown in Because the strengths of the air currents are similar, they often form a stationary front. This front moves slowly from south to north, bringing plentiful rainfall. The rainfall in the southwest of Taiwan is usually much higher than that in the northeast of Taiwan due to the southwestern air current. As the frontal surface gradually moves north, the rainfall in the northern part of this region stops and the rainfall in the southern part remains. Typhoons are the most severe weather system in Taiwan. Four or five typhoons affect Taiwan every year, bringing destructive winds and plentiful rainfall. They pose a danger to agriculture, industry, and human life. For example, the economic losses due to typhoons can be up to 20 billion NT dollars and that due to plum rains can be up to 1.7 billion NT dollars [Despite their devastating effect, typhoons and plum rains together account for more than 50% of the annual accumulated rainfall, as shown in 2.There are many meteorological sensors available for studying the patterns and characteristics of meteorological events. Recently, many studies have used GPS as an alternative meteorological sensor. Distributed GPS stations around the earth can serve as a near real-time meteorological sensor network that can be used to detect potential threats. Continuous and well-distributed measurements of water vapor are of great interest for numerical weather forecasts, climate research, and atmospheric studies.GPS signals going through the atmosphere get delayed by ionosphere and troposphere refractions. The refraction due to the ionosphere (the ionosphere is a dispersive medium) can be easily removed by linear combinations of dual frequency measurements because the ionospheric delay depends on the signal frequency .When processing single frequency observations, the observations have to be corrected for ionospheric effects. Available empirical models include the broadcast Klobuchar ionospheric model, the post fit Klobuchar ionospheric model estimated by the Center for Orbit Determination in Europe (CODE), and the Global Ionospheric Maps available from International GNSS Service (IGS), respectively. The positional accuracy is generally not better than sub-meter when processing observations from single frequency receivers because of ionospheric effects.The tropospheric delay cannot be removed using dual frequency measurements because in the GPS signal frequency band the troposphere is non-dispersive. The tropospheric delay is composed of two parts: a hydrostatic delay term that depends on atmospheric pressure and temperature, and a wet delay term that depends on the partial pressure of water vapor and temperature. While the hydrostatic delay can be accurately modeled using surface pressure measurements, the wet component is difficult to model because of its large spatial and temporal variability. Because meteorological values are insufficient to account for the wet path delay, wet tropospheric delays are usually estimated as an unknown parameter.i.e., the pressure at the surface, and the columnar atmospheric moisture content.Reference  presenteConsequently, the primary meteorological measurements produced by GPS are tropospheric path delays at the zenith. The ZTD is estimated from the line of sight tropospheric delays corresponding to the GPS satellites in view. Each of these tropospheric delays is mapped to the zenith using an elevation dependent mapping function. The zenith tropospheric path delay of GPS signals can provide essential information on the long-term climate change of a given area of study.Current carrier phase based GPS kinematic positioning systems are primarily based on a double differencing data processing approach which can provide centimeter to decimeter positional accuracy in real-time. Since the reduction of common errors depends on the inter-station baseline lengths, the base and rover station separation must be short, typically about 20 kilometers. The need for a base station increases the cost of equipment and labor and introduces inconsistency .The availability of precise GPS satellite orbit and clock products provided by IGS has enabled the development of a novel positioning methodology known as PPP . Based oUsers can directly use IGS products to obtain highly accurate frames of International Terrestrial Reference Frame (ITRF) using the PPP technique. This decreases costs because PPP needs only one receiver to perform high positioning accuracy, therefore, it is widely used in studies of the atmosphere, meteorology, and tides .The present study investigates the applicability of using GPS network processed in PPP mode as meteorological sensors to monitor the characteristics of plum rains and typhoons in the Taiwan region.3.As mentioned in the previous section, the zenith tropospheric delay is often composed of two parts: a hydrostatic delay term and a wet delay term. About 85-90% of the tropospheric delay comes from the dry component which can be accurately modeled with a precision approaching 1% when the pressure is known (to mm accuracy) using most available troposphere modeling methods. The wet component, however, is more difficult to model because of its large spatial and temporal variability; an error of 15-20% is common.hzD the zenith hydrostatic delaywzD the zenith wet delayN GEG the horizontal delay gradient in the north and east directionshm(e) the hydrostatic mapping functionwm(e) the wet mapping functiongm(e) the gradient mapping functiona e the azimuth and elevation anglesSince the wet zenith troposphere delay residual is still significant for cm level positioning after a tropospheric correction model is used, it should be estimated as an unknown parameter along with other parameters such as the coordinates, the receiver clock offset, and the ambiguity. The estimation of tropospheric gradients is included to take into account the horizontal atmospheric variations. Neill Mapping Functions (NMFs) are applied for the hydrostatic and wet delays in this study. The following function was applied for gradient mapping :(2)mg to be set up at one of those stations to provide proper calibration to obtain absolute zenith troposphere delay at the other site. In practice, the WVR is too expensive and fragile to operate during the visitation of typhoons as well as thunderstorms. Thus, the applicability of a conventional DGPS/WVR based approach to monitor the extreme weather events is rather limited. On the other hand, PPP can provide the direct estimate of absolute wet zenith troposphere delay by using a dual frequency GPS receiver with meteorological sensors that can provide pressure, temperature and humidity. It does not require a WVR to perform calibration and its data processing scheme is straight forward comparing to DGPS data processing. Therefore, when processing massive amount of measurements provided by a GPS network, PPP based approach is a cost effective option. In addition,  indicate4.The electronic-global satellite real-time kinematic positioning system (e-GPS) is managed by the National Land Survey and Mapping Center (NLSC), Ministry of the Interior, Executive Yuan of ROC (Taiwan). The e-GPS network uses continuous satellite observations and processes them continually. Users need to receive more than four GPS satellite signals to obtain high accuracy positioning coordinates in a short period of time. Most on-site GPS receivers of the e-GPS network operate 24 hours a day, even under severe weather conditions, such as typhoons and plum rains. Therefore, this well distributed e-GPS network processed in PPP mode can be considered as a supplemental meteorological sensor to study the patterns of typhoons and plum rains.5.As mentioned previously, plum rains often occur from the middle of May to the middle of June. Therefore, the data set used to investigate the characteristics of plum rains was collected from June 1st 2008 to June 7th 2008. This time frame is right in the middle of plum rain season in Taiwan. iNL denotes the normalized value of ZTD ; iX is the realistic ZTD value estimated by PPP ; minX and maxX represent the minimum and maximum value of the realistic ZTD value  during the collected period, namely, Jun-01-2008 to Jun-07-2008, respectively. More than fifty e-GPS sites were used in this study; the number of CWB posts was twenty five. The density of the e-GPS network based monitoring approach is twice that of conventional meteorological sensors.The velocity of Typhoon Sinlaku was about 50 meters per second; the radius of the typhoon was approximately 250 kilometers. The typhoon made landfall in the northeast coast near Yilan at 1:40 AM, on September 14th, 2008. It left the island near Taipei at 8:00 AM, on September 15th, 2008. The ZTD values estimated by PPP and accumulated rainfall collected by the observation posts of CWB were normalized. The normalized algorithm of ZTD  is interpreted as 5.1.Before the typhoon made landfall, the normalized values of ZTD and rainfall were quite low, except for the north of the island, as shown in The rainfall in the western region increased significantly; the normalized values of ZTD and rainfall gradually increased, as shown in Eventually, the entire western region was covered with heavy rain; the normalized values of ZTD and rainfall were remained high. The typhoon left Taiwan from the northwest. When typhoon left Taiwan completely, the exterior air current of typhoon with the strong southwestern monsoon made the central of Taiwan suffered serious terrestrial rainfall, as shown in 5.2.The plum rain season often starts in May and ends in June, lasting approximately a month. The northeastern monsoon and southwestern monsoon cause a stationary front to remain in the northeastern region of the island. Although the strength of the northeastern monsoon is much stronger than that of the southwestern monsoon, it is usually blocked by the Central Mountains. Therefore, the stationary front gradually moves north, increasing rainfall in the north region. Generally speaking, the spatial distributions of normalized ZTD values estimated using PPP have similar characteristics to those of normalized values of rainfall recorded at CWB meteorological posts. As is well known, ZTD is altitude-correlated. The influence of site's altitude on ZTD should be removed before comparing with rainfall data by tropospheric correction model using the site's height information and the meteorological data, e.g. temperatures, humidity and pressure…etc. However, there were less than five e-GPS sites that had meteorological sensors onsite during the collected period thus it is not able to remove the influence of altitude in the mountain region without meteorological measurements with proper models. In fact, the impact of altitude on ZTDs in the mountain region are shown Consequently, the aim of this paper is to limit the scope of interpretations and discussions of the relationship between ZTDs and accumulated rainfall in the plain area marked by red rectangular in The well-distributed e-GPS network can be considered as supplemental meteorological sensors to monitor the patterns of typhoons and plum rains. With improved ultra-rapid products provided by IGS in the near future, or with real-time precise satellite orbit and clock products provided by other institutions, a near real-time PPP based meteorological sensors can provide useful information for developing early warning systems for meteorological events like typhoons, plum rains, and seasonal thunderstorms in this region.6.This study proposed using ZTD values estimated from the well-distributed e-GPS network of NLSC and PPP technique to implement supplemental meteorological sensors to investigate the characteristics of typhoons and plum rains. The preliminary results show strong correlations between the variations of ZTD values estimated using PPP and rainfall recorded at meteorological posts around the island during plum rain season and the passage of typhoon Sinlaku.Several characteristics of typhoons, including the terrestrial rainfall in northwestern and central Taiwan during the passage of typhoon Sinlaku, are identified using the spatial and temporal analyses of ZTD values estimated from PPP. The well-distributed e-GPS network combined with PPP can be considered as alternative meteorological sensors for monitoring the patterns of typhoons and plum rains.