And such a similarity is also demonstrated at individuals only in MSAD showing no statistically significant difference  as compared with the classical 40 Hz ASSR. The present results indicate that both stimulation rate and sequencing factor (ISI variation) affect transient AEP reconstructions from steady-state stimulation protocols. Furthermore, both auditory brainstem response (ABR) and middle latency response (MLR) are observed in contributing to the composition of ASSR but with variable weights in three templates. The significantly improved prediction accuracy of ASSR achieved by MSAD strongly supports the linear superposition mechanism of ASSR if an accurate template of transient AEPs can be reconstructed. The capacity in obtaining both ASSR and its underlying transient components accurately and simultaneously has the potential to contribute significantly to diagnosis of patients with neuropsychiatric disorders.The auditory steady-state response (ASSR) is one of the main approaches in clinic for health screening and frequency-specific hearing assessment. However, its generation mechanism is still of much controversy. In the present study, the linear superposition hypothesis for the generation of ASSRs was investigated by comparing the relationships between the classical 40 Hz ASSR and three synthetic ASSRs obtained from three different templates for transient auditory evoked potential (AEP). These three AEPs are the traditional AEP at 5 Hz and two 40 Hz AEPs derived from two deconvolution algorithms using stimulus sequences, i.e., continuous loop averaging deconvolution (CLAD) and multi-rate steady-state average deconvolution (MSAD). CLAD requires irregular inter-stimulus intervals (ISIs) in the sequence while MSAD uses the same ISIs but evenly-spaced stimulus sequences which mimics the classical 40 Hz ASSR. It has been reported that these reconstructed templates show similar patterns but significant difference in morphology and distinct frequency characteristics in synthetic ASSRs. The prediction accuracies of ASSR using these templates show significant differences ( The auditory steady-state response (ASSR) elicited by periodical auditory stimulation is a major approach in clinic for hearing screening and frequency-specific hearing assessment  were recruited in the present study that was carried out in accordance with the recommendations of the human research ethics committee of the Southern Medical University. All participants provided their written informed consents. Two subjects were excluded from the following analysis either because of the lack of a clear ABR or the inconsistency between the odd- and even-trial averages for the purpose of data quality control. No medical history of auditory or nervous system diseases, or psychiatric disorders was reported in all participants. All participants presented audiometric thresholds lower than 25 dB HL obtained with air conduction pure tones at frequencies between 0.25 and 8 kHz. During recording, the subject was instructed to recline and relax in a comfortable chair in a sound-attenuated and electromagnetic-shielded booth.st row in Figure nd row in Figure rd–10th rows in Figure Rarefaction clicks of 0.1 ms duration were presented monaurally to the right ear via an insert earphone  at 80 dB peak SPL . The stimulus sequences and AEP extraction processes for three paradigms are illustrated in Figure 5 times , filtered at 10–1,000 Hz, and sampled at 20 kHz.Electroencephalogram (EEG) was recorded at Fz using Ag/AgCl electrodes with the reference electrode placed on the right mastoid and the ground electrode on Fpz. The electrode impedance was kept below 5 kΩ. EEG data were amplified 10For each paradigm, more than 1,500 sweeps of EEG were recorded. A sweep of EEG used in the following averaging processing was defined as an epoch of EEG containing response to one click in the traditional or MSAD paradigm. In the CLAD paradigm, a sweep of EEG consisted of responses to a CLAD sequence with eight clicks. A sweep of classical ASSR EEG included four cycles of ASSR. The order of these four paradigms was randomly assigned to each participant.Raw EEG data and the consequent data analysis  were processed on the MATLAB  platformnd row in Figure rd ~10th rows in Figure The AEP of the traditional paradigm (teamed as tAEP hereafter) was obtained via averaging all sweeps (each of 200 ms starting from the onset of stimulus) of EEGs recorded at 5 Hz of stimulation. All sweeps of EEGs from the CLAD paradigm (each of 204.8 ms starting from the onset of the first stimulus of the sequence) were averaged to yield a quasi-periodical sweep-response  as shown in the bottom of Figure T2 test was performed on these difference vectors across all subjects to test statistical significance, where the multivariate normality of data was tested by a SPSS macro (normtest) developed by L.T. DeCarlo  were analyzed. Their differences were characterized by difference waveforms obtained by subtracting one AEP from another. Statistical significance was tested by a one-sample DeCarlo, .In addition, contributions of five components  in transient AEPs to the ASSR were also analyzed. With reference to the baseline, every component was manually isolated by zeroing other components. This isolated component was subsequently used as a template to synthesize the component-ASSR in order to calculate contribution of every component to the entire synthetic ASSR, which was defined as a root-mean-square (RMS) ratio between component- and synthetic ASSRs.Both recorded and reconstructed transient AEPs and rASSRs of individual participants are shown in Figure st row, cAEP–mAEP in the 2nd row, and tAEP–mAEP in the 3rd row) are displayed (red dotted curves) together along with transient AEPs (blue solid curves). Furthermore, the areas displayed with thick red curves are those with statistical significant differences between two compared conditions . The values of latency and amplitude for three representative positive waves  are labeled in pairs . The latencies of all three wave-components from both 40 Hz AEPs are prolonged relatively to the latencies of these components in tAEP. Such a phenomenon is in agreement with the previous report that the latencies of AEP components at high stimulation rates  are generally longer than those at low stimulation rates .The left column of Figure st row in the left column of Figure rd row in the left column of Figure th row in the left column of Figure nd, 4th, and 6th rows in the left column of Figure Visually, all three synthetic ASSRs closely resemble the rASSR in general, while the mASSR obviously fits the best. Further inspections lead to observations that tASSR presents a noticeable overestimation in peak-to-peak amplitudes and a phase leading problem . It is observed that the three major contributors to the formation of the positive part in ASSRs are wave-V (from the black trace), Pa (from the red trace), and Pb (from the blue trace). Although three synthetic ASSRs (red thick traces) do not differ from each other significantly, there seems to be a relatively large difference in the contribution of each component on the composition of ASSRs. As expected, these three main components superimposed in phase at 40 Hz stimulus rate account for the amplitude enhancement in ASSRs. However, amplitude and phase alignments of transient AEP components in the three synthesis procedures are different. For the positive peak in cASSR, waves-V, Pa and Pb are more synchronized than those in mASSR and tASSR where wave-Pa (red traces) leads other two waves (V in black traces and Pb in blue traces). The fact that three components are slightly out of phase in mASSR and tASSR leads to reduced magnitude of the positive peak. However, the relatively large Pa component (in amplitude) in both mASSR and tASSR, compared with cASSR, compensates such a reduction, which leads to the similar positive peak amplitudes in all three ASSRs. It is also observed that the large Na peak amplitude in both tAEPs and cAEPs should account for overestimation of the negative peak amplitude in both tASSR and cASSR, respectively. It is important to note that the ABR component  also contributes to the formation of ASSRs and such a fact suggests that ASSRs contain valuable information from sources in the brain stem. Its delineation from ASSRs might be of significant clinical applications.The right column of Figure The contributions of individual AEP components were qualified by separately calculating the RMS percentage of each component  to the entire ASSR Figure . The sumrASSR and three synthetic ASSRs were decomposed by FFT to a number of integral harmonics. Taking rASSR as an example, a four-cycle rASSR , all data were normally distributed (p > 0.05). The difference vectors between rASSRs and synthetic ASSRs for each individual  are shown in Figure p < 0.05, Hotelling's T2 test), if the origin of the coordinate is not covered by the ellipse  indicates that significant mismatches to rASSR are only found in cASSR and tASSR .Significant differences to rASSRs were found in cASSRs at three harmonics and tASSRs at 40 Hz harmonics. On the contrast, mASSR matched rASSR at all three harmonics without significant differences. It is demonstrated that mASSR shows the most stable fundamental frequency (40 Hz) measured by the metric of the area of ellipse, indicating the smallest data variance in the complex plane. Quantitative statistical analysis on the overall difference between synthetic and recorded ASSRs  using the MSAD method, while no significant improvements are achieved in reconstructing ASSRs using cAEPs obtained at 40 Hz  stimulus rate by the CLAD method as compared with the use of tAEPs at 5 Hz by the traditional method.Specifically, all three synthetic ASSRs closely resemble rASSR in general, the synthetic tASSR shows the phenomena of peak amplitude overestimation and phase leading problems, the synthetic cASSR shows the phase leading problem only and the synthetic mASSR is almost identical to rASSR in terms of waveform Figure . Such obSignificant differences between cAEPs and mAEPs, as well as morphological differences in estimated cASSRs and mASSRs, should be attributed to different stimulus-sequencing schemes used in CLAD and MSAD as there is no real-time ISI jitter in single MSAD sequences. Therefore, these results indicate that transient AEPs are dependent on not only stimulus rate but also sequencing factor . It is consistent with the previously reported stimulus-sequencing effect on ASSR predictions using the CLAD method with different ISI-jitter sequences .In the present study, the use of transient responses from the 40 Hz mAEP succeeds in predicting the 40 Hz rASSR, which strongly supports the linear superposition generation mechanism of ASSR. The finding is important in the advancement of the potential use of ASSR in clinical and basic research. The MSAD method is the technique behind that is able to reconstruct the precise transient response underlying the 40 Hz ASSR since MSAD uses a similar stimulus-sequencing scheme as in the classical ASSR and addresses the ill-conditioned inverse problem at the same time. As a result, the unique merging of obtaining the ASSR and its underlying transient responses at the same time provides valuable insights about activations and sequence of activations in the auditory pathway structures.This study was carried out in accordance with the recommendations of the human research ethics committee of Southern Medical University with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the human research ethics committee of Southern Medical University.XT, QF, and TW conceived and designed the study, performed the experiments, analyzed and interpreted the data, and wrote the manuscript. HY and LD conceived and designed the study, interpreted the data, and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In vitro diagnostic multivariate index assays are highly complex molecular assays that can provide clinically actionable information regarding the underlying tumour biology and facilitate personalised treatment. These assays are only useful in clinical practice if all of the following are established: analytical validation , clinical validation , and clinical utility . In considering the use of these assays, clinicians often focus primarily on the clinical validity/utility; however, the analytical validity of an assay  should also be evaluated and carefully considered. This review focuses on the rigorous analytical validation and performance of the Oncotype DX® Breast Cancer Assay, which is performed at the Central Clinical Reference Laboratory of Genomic Health, Inc. The assay process includes tumour tissue enrichment (if needed), RNA extraction, gene expression quantitation , and an automated computer algorithm to produce a Recurrence Score® result . This review presents evidence showing that the Recurrence Score result reported for each patient falls within a tight clinically relevant confidence interval. Specifically, the review discusses how the development of the assay was designed to optimise assay performance, presents data supporting its analytical validity, and describes the quality control and assurance programmes that ensure optimal test performance over time. This actionable information originates from pre-specified correlations between tumour biology, characterised through rigorously validated pre-analytical and analytical laboratory processes, and well-annotated patient clinical outcomes. Appropriate correlation between individual tumour biology and clinical outcome has been shown to provide quantitative information regarding the likelihood of recurrence, i.e. prognosis, and the likelihood of treatment response, i.e., prediction. Having this prognostic and predictive information for each individual patient facilitates personalised treatment decision-making.In the current era, highly complex molecular assays known as However, these molecular tests are only useful in routine clinical practice if only all of the following are appropriately established: analytical validation , clinical validation , and clinical utility  .The challenges in establishing analytical validity, clinical validity, and clinical utility are reflected in the huge discrepancy between the number of biomarkers identified in oncology literature (1000s of biomarkers), and the number of biomarkers in clinical use (just over 100 biomarkers)  result generation). All aspects of these phases including reagents, liquid-handling robots, analytical instruments, and methods are standardised and rigorously controlled  (GenomicA key element to this control is the Laboratory Information Management System (LIMS) that integrates control over the process with tracking of all qualified laboratory reagents/supplies and patient samples through barcoding. LIMS barcoding enables traceability of the history of each patient’s sample as it moves through the entire laboratory testing process. The LIMS also tracks the reagent lots, liquid handling robots, analytical instruments, as well as dates, times, and operators at the various process steps thereby allowing monitoring of test results generated in each of the process steps. In-process checks are used to verify the identity, quantity, and expiration date of the reagents used in each processing step. Another key component of standardisation is reagent quality control. To this end, in the Genomic Health Clinical Reference Laboratory, all critical reagents used in the testing process are inspected and tested (with very stringent specifications) as appropriate to ensure their suitability for use in patient sample testing. Each shipment of incoming raw materials is checked for conformance with the stringent quality specifications of the laboratory using various analytical and functional test methods. The quality specifications set forth by the laboratory are often far more stringent than those of the manufacturers and are specifically designed to ensure accuracy and reproducibility of the Oncotype DX assay results.Standardisation is maintained throughout the testing process. The standardisation of the pre-analytical phase begins with the pathologist at the local site following the Oncotype DX pathology guidelines  . The standardisation in the pre-analytical phase continues with the arrival of the sample to the Genomic Health Clinical Reference Laboratory. Once in the lab a pathology review of the FFPE tumour sample is performed by a board-certified surgical pathologist with expertise in breast pathology. They determine whether the block contains tumour, if so, the histologic subtype of the tumour and whether manual microdissection is required for tumour enrichment (depends if less than 50% is invasive carcinoma or there is presence of biopsy cavities). In the analytical phase—which includes RNA extraction and quantitation, testing for contaminating genomic DNA, reverse transcription, quantitative PCR and data-quality control—standardisation of RNA extraction is noted to be key, as this step can introduce significant levels of analytical variability/bias into the test results, particularly when the specimens used are paraffin-embedded . Assays The LIMS also facilitates identifying any bias that may arise in any step of the testing process as all the data are centralised . With the huge number of Oncotype DX tests performed thus far , Genomic Health through acquired experience has refined its ability to identify and manage biases related to testing.To monitor and control the reproducibility of the assay with respect to each of the real-time qRT-PCR tests being performed as well as the test as a whole, each of the 21 genes in the assay is tested in triplicate. Expression values for each gene are assigned when at least two of the three real-time qRT-PCR reactions provide acceptable results (PCR controls are run in every assay plate and non-acceptable results are identified by their amplification curves). In order for the Recurrence Score result to be calculated, all 21 genes included in the Oncotype DX assay must have an expression value assigned . Also, tIn the postanalytical phase of the testing process, an individualised report is generated for each patient that includes the Recurrence Score result. The report also includes the prognostic and predictive implications of the Recurrence Score result based on the validation studies that are appropriate to that specific patient with respect to their nodal involvement  . ProvidiThe routine evaluation of ER and PR status is performed by IHC by using anti-ER and anti-PR antibodies that interact with the ER and PR proteins respectively. This approach became the standard method for determining hormonal receptor status in the 1990s. According to the updated ASCO/CAP guidelines (2010), the pathological report should include the percentage of tumour cells that exhibit nuclear immunostaining, the intensity of the staining, and its interpretation. The interpretation section should state whether the tumour is ER or PR positive (≥1% of tumour cell nuclei are immunostained), negative (<1% of tumour cell nuclei are immunostained and positive intrinsic controls are immunoreactive), or uninterpretable (no immunostained tumour nuclei and no nuclear immunoreactivity in the positive controls) .The Oncotype DX-based assessment of ER and PR is based on mRNA expression levels. This assessment was demonstrated to be concordant with IHC-based assessment in several studies , 20. Thuin-situ hybridisation . According to the updated ASCO/CAP guidelines (2013), HER-2 status could be determined by either method and if the results are equivocal, reflex testing should be performed using the alternate assay (IHC or ISH) [The routine evaluation of HER-2 status is performed by IHC (protein levels) or  or ISH) . Similar or ISH) , 24. ThuHigh performance of genomic tests with respect to accuracy, reproducibility, standardisation and scalability is crucial for ensuring that the test results represent the biological characteristics of the tumour and should be considered in the treatment decision process. The performance of the Oncotype DX assay performed in the Clinical Reference Laboratory of Genomic Health is continuously monitored against the performance of the approximately 500,000 tests performed thus far, thereby ensuring reliable results over time for breast cancer patients and their physicians.


The shift towards person-centered care is ongoing within healthcare today. The Early Signs Action Plan was developed to facilitate participation of patients and their next-of-kin in outpatient psychiatric services specialized in the treatment of persons with schizophrenia and similar disorders. The aim was to investigate relatives’ experiences regarding the activation of the action plan for their next-of-kin.The study is a qualitative interview study using a semi-structured interview guide. The interviews are conducted with relatives (anticipated N=10) to outpatients whose Early Signs Action Plan has been activated. Interviews are digitally recorded and transcribed verbatim. The material is analyzed with qualitative content analysisPreliminary analysis based on the first six interviews suggests that relatives experience increased involvement in services as well as improved relations with care staff. Relatives felt a greater sense of security as they were more knowledgeable, and activation of the plan resulted in a more immediate response from service providers. However, some respondents expressed communication problems with staff, pointing to a need for improved flow of information and increased understanding of the situation. Some expressed a feeling of uncertainty related to lack of feedback from staff, as well as lack of continuity and limited inclusion in the care process. Results from the entire study will be presentedEarly Signs Action Plan may constitute a useful tool for the involvement of relatives in psychiatric services. However, relatives pointed out several areas for improvement


Paleoparasitology reveals the status of parasitic infections in humans and animals in ancient times based on parasitic particles found in biological remains from archaeological excavations. This line of research emerged in Iran in 2013. The identification of parasites from Neolithic times is an attractive subject that shows the oldest origins of parasitic infections in a given geographical region. From an archaeological point of view, this archaeological site is well-known for animal domestication and agriculture in ancient Iran. In this study, soil deposited on the surface and in the pores of a dog pelvic bone was carefully collected and rehydrated using trisodium phosphate solution. The results showed ascarid and taeniid eggs retrieved from the biological remains of a dog excavated at the East Chia Sabz archaeological site, which dates back to the Neolithic period (8100 BC). The current findings clearly illustrate the natural circulation of nematode and cestode parasites among dogs at that time. These ancient helminth eggs can also be used to track the oldest parasitic infections in the Iranian plateau and contribute to the paleoparasitological documentation of the Fertile Crescent. Fasciola hepatica and Dicrocoelium sp. in herbivores in ancient Europe  was when humans began animal domestication and agriculture, providing a driving force for the emergence of zoonotic parasites . Animal The East Chia Sabz archaeological site, located in Seymareh valley , dates bEthics - The samples were provided in accordance with national legislation with no conflict of interest among the authors.Taenia sp. egg  and Toxascaris leonina (75-85 × 60-75 µm)  , possibl


Several neurodevelopmental disorders and brain injuries in children have been associated with proprioceptive dysfunction that will negatively affect their movement. Unfortunately, there is lack of reliable and objective clinical examination protocols and our current knowledge of how proprioception evolves in typically developing children is still sparse.Using a robotic exoskeleton, we investigated proprioceptive acuity of the wrist in a group of 49 typically developing healthy children (8–15 years), and a group of 40 young adults. Without vision participants performed an ipsilateral wrist joint position matching task that required them to reproduce (match) a previously experienced target position. All three joint degrees-of-freedom of the wrist/hand complex were assessed. Accuracy and precision were evaluated as a measure of proprioceptive acuity. The cross-sectional data indicating the time course of development of acuity were then fitted by four models in order to determine which function best describes developmental changes in proprioception across age.First, the robot-aided assessment proved to be an easy to administer method for objectively measuring proprioceptive acuity in both children and adult populations. Second, proprioceptive acuity continued to develop throughout middle childhood and early adolescence, improving by more than 50% with respect to the youngest group. Adult levels of performance were reached approximately by the age of 12 years. An inverse-root function best described the development of proprioceptive acuity across the age groups. Third, wrist/forearm proprioception is anisotropic across the three DoFs with the Abduction/Adduction exhibiting a higher level of acuity than those of Flexion/extension and Pronation/Supination. This anisotropy did not change across development.Proprioceptive development for the wrist continues well into early adolescence. Our normative data obtained trough this novel robot-aided assessment method provide a basis against which proprioceptive function of pediatric population can be compared. This may aid the design of more effective sensorimotor intervention programs. Proprioceptive signals from peripheral mechanoreceptors give rise to our awareness of limb position and movement in space . Moreovematching error. For a true response the matching error is equal to zero. In contrast, precision is represented with the variability which indicates the agreement between the repeated responses and the lower is the variability, the higher is the precision.We here present a robot-aided method to assess joint position sense acuity for the three degrees of freedom of the wrist/hand complex in a cohort of typically developing children. The ability of such robotic device to provide valid and reliable proprioceptive measurements in adult subjects have been previously demonstrated . The stuThe aim of this study was threefold: (a) investigate if there are age related changes of proprioceptive acuity during development, (b) determine when children begin to reach adult levels of proprioceptive acuity, and lastly (c) characterize the isotropy/anisotropy of acuity across the three joint degrees of freedom of the wrist/hand complex .Proprioceptive acuity was assessed in 49 healthy children , from 8 years 1 month to 15 years 4 months and 40 healthy adults . The participants presented no neuromuscular disorders and were naive to the task. The Edinburgh Handedness Inventory was completed to determine right hand dominance . ExperimThe experiments involved a behavioral task where subjects used a wrist haptic device , holdingDuring the experiment subjects sat beside the robotic device with the frontal plane of their body aligned perpendicularly to the PS axis of the robotic device Fig. a. PositProprioceptive acuity was assessed with an ipsilateral Joint Position Matching (JPM) test , in thisWith the Joint Position Matching Task we tested the proprioception for all the three degrees of freedom: Flexion/Extension, Abduction/Adduction and Pronation/Supination Fig. b. TargeMatching Error [the Variability [Wrist joint rotations were recorded by the robot’s incremental encoders providing a resolution of micro radians. Acquired signals were post processed with a third-order Savitzky-Golay low-pass filter (cut-off frequency of 10 Hz) and converted to wrist angular displacement from the kinematics of the robot. To estimate wrist proprioceptive acuity and characterize the overall performance, two indicators were evaluated: the ng Error  and the iability .Matching Error, ME is the angular deviation from the proprioceptive target and it quantifies the performance accuracy during the active movement. It is defined as the absolute difference between the reference (proprioceptive target position) and the wrist matched angle: The θi is wrist’s final position of the i-trial, θT is the target position, averaged across the (N=12) repetitions of the same target (same DoF and condition).where Variability, V measures the consistency, or precision, in terms of subject performance repeatability trial-by-trial during the active phase, and it is evaluated as the standard deviation of the wrist matched position (θi) across all the (N=12) repetitions of the same target: The To evaluate if subject’s position sense was influenced by learning, we performed linear regression analyses on ME with trial number as predictor variable. a is the slope of the curve and b the intersect. If less than 25% of the variance in ME was explained by trial number and a slope close to zero was observed, then we concluded that no learning had occurred. We then performed three different analyses on ME and to answer the following questions.where What is the best approximating function describing the developmental progression of proprioceptive acuity? The first issue we sought to investigate was to characterize and mathematically express the way in which children proprioceptive acuity evolves with age. Therefore, in order to determine a function that accurately describes the developmental change, we performed multiple regression analyses of the matching error for each group of subjects, with the group age as the independent variable and identified the one that best fits the given set of data. In particular we compared four models:Linear: Exponential: Logarithmic: Inverse-root: R2), and the root mean square error (rmse) of the variance of the residuals.Goodness of fit was evaluated by computing the coefficient of variation , nor in terms of adjusted R2 . Overall results showed an increasing trend of performance from childhood into adolescence when proprioception matures, plateauing the adult level. The mean values of Matching Error and Variability are presented for each group and for the three wrist DoFs in Tables Matching Error and Variability for each subject and for the two opposite directions of the three wrist DoFs. No effect of motion direction within each DoF was found. Raw data show a highest variance of performance in the youngest groups. A one-way Analysis of Variance revealed a statistically significant main effect of age  among the nine groups (8 children groups and adults’ one).To determine if sensory learning had occurred during testing we investigated how ME changed over time. Regression analyses revealed that the respective slope  see Eq.  for all  see Eq. a. Furthals Fig. b. SimilCurve-fitting analysis: shape of the developmental progression. Such analysis indicated that development of sensorimotor-matching abilities with age is best approximated by the inverse-root model . The resulting curves of the inverse-root fitting for Matching Error and Variability  and the less variable (lowest Variability) for children at every age. No predominant trend resulted between FE and PS. This is confirmed by results of one-way ANOVA test, performed for each for each group to investigate the effects of the DoF. Results revealed statistical significance of the Normalized Matching Error (MEi%), for wrist proprioception anisotropy in all groups unless for groups eleven and fourteen years, while the Normalized Variability (Vi%) results to be significance among all the groups.To more completely understand the nature of proprioceptive developmental changes across childhood and adolescence we measured proprioceptive acuity in 49 children and adolescents (8–15 age). Data collected from young adults served as reference to assess at what age adult levels of proprioceptive acuity were achieved. The main findings of the study are threefold: 1) The robot-aided task proved to be an easy and reliable method for measuring proprioceptive sensitivity in both children and adult populations. 2) Based on our empirical data we derived a mathematical model that best described the development of proprioceptive acuity from middle childhood to adolescence, and we identified that proprioceptive acuity continued to develop throughout middle childhood and early adolescence following an inverse-root law. Additionally, we found that this development plateaued and reached adult levels at approximately twelve years of age. 3) Wrist/forearm proprioception emerged to be anisotropic across the three DoFs with the abduction/Adduction exhibiting the highest levels of acuity.The finding of a consistent refinement of wrist position sense with increasing age is in line with previous reports that focused on the assessment of age-related changes of proprioceptive acuity and sensorimotor ability , 27–29 aThe age-related improvements in wrist position sense are related to several physical and physiological changes that occur during development. Proprioceptive percepts are based on the integration of signals from multiple peripheral receptors such as muscles spindles, tendon organs and or cutaneous receptors . During A further aspect to be considered is the gradual recalibration of the internal body schema in response to physiological and physical growth which may have an impact in proprioceptive matching accuracy of body in space . It appeFinally, given that sensorimotor integration can be understood as a cognitive process, another interpretation for the improvement in the ability to integrate information from the proprioceptors can also be related to changes in cognitive functions from childhood through to adulthood, reflecting maturation of the central nervous system –43. ThesAt last another result emerging in our study concerns the anisotropy of wrist perception across its three DoFs. Outcomes showed the proprioceptive acuity of AA is significantly higher than the remaining DoFs (FE and PS). This anisotropy might be explained by differences in receptors, responsible of conveying sensory signals on joints’ movement , 48. IndGiven that mechanoreceptors in ligaments are largely sensitive at the ends of the range of motion, rather than providing much information throughout the range of motion, one could claim that the improved performance for abduction\adduction is due to the lower distance of proprioceptive targets. However, even if the absolute location of the targets was different, their relative position, with respect to the amplitude of the range of motion, was the same for each DoF. Targets in the three DoFs were located at the 80% of the active RoM of each DoFs.In conclusion, it could be argued that performance was influenced by fluctuation of subjects’ attention and by memory components. Attention and perception are certainly related process but this protocol, consisting in an active phase in which the subject has to move his/her wrist by him/herself, was developed also to keep the participant constantly focused on the task.In conclusion, this study showed the feasibility of a robot-aided assessment of the limb position sense in children that yields objective data of proprioceptive acuity. The proposed robotic implementation of the JPM presents several advantages respect to the regularly administered proprioceptive assessment by a human therapist: a more reliable control on the stimulus, a higher accuracy and precise sensing of joints position and consequently an easier post processing of the results. The wrist robotic device allowed to deliver a rigorous and precise test, where each proprioceptive target associated to each stimulus was presented to the subject in a repetitive and accurate location consistently across repetitions. High resolution encoders, provide with the possibility to extract a reliable measure of performance and subjects’ proprioceptive acuity.At present, there is no established objective method for clinical assessment of proprioception, and the few existing clinical rating scales such as the Nottingham Sensory Assessment  or the RThe absence of a learning trend through time indicate the test is robust and not influenced by fatigue or subjects’ familiarization with test and device.The robotic JPM test revealed that wrist proprioceptive acuity continues to change throughout childhood with a developing trend that follows and inverse-root law, and it reaches adult levels in early adolescence. While mapping the developmental time course of the wrist limb position sense contributes to our understanding of perceptual development, the methodology offers the opportunity to assess proprioceptive function in pediatric populations, which in turn may aid to improved therapeutic approach.


Cerebral hydatid disease is very rare, representing only 2% of all cerebral space occupying lesions even in the countries where the disease is endemic. Intracranial hydatid cysts are more common in children and occur more frequently in the supratentorial space. The aim of this paper is to describe the characteristic features of computed tomography (CT) and magnetic resonance imaging (MRI), and to determine the clinical presentation and surgical outcome of cerebral hydatid disease. A 7-year-old girl was admitted to the emergency department because of an epileptic attack. On radiological examination a round, cystic lesion appeared in the parietal lobe and caused shift of the midline structures. The cyst was successfully removed using the dowling technique. The postoperative period was uneventful and seizures were not seen during follow up. Hydatid cyst of the brain presents clinically as intracranial space occupying lesion and is more common in children, it is well demonstrated by CT and MR examinations, and Surgery is the treatment option with affordable morbidity and low mortality. Hydatid disease (echinococcosis) is a worldwide zoonosis produced by the larval stage of the Echinococcus tapeworm . This isHistory and examination: This 7-year-old girl, previously healthy, was admitted to the emergency department for an epileptic attack, she described four episodes of partial seizure secondary generalized. Neurological examination revealed postictal confusion, hemiparesis and bilateral papilledema. Headache and vomiting were not experienced. An anticonvulsant therapy was administrated. Magnetic resonance images (MRI) demonstrated well-defined round  entirely surrounded by brain parenchyma hypointense lesions on T1-weighted images  and the lung (8.5-43%) are the organs most commonly involved. The remaining lesions may involve any organ in the body, including cerebral involvement in approximately 2% of patients infected with the parasite . They maIn cystic echinococcosis, the parasitic cyst consists of an inner germinal layer (endocyst) and an outer laminated layer (ectocyst). The host reacts to the cyst by forming a fibrous capsule (pericyst), which contains blood vessels that provide nutrients for the parasite. From the germinal layer, scolices, brood capsules, and daughter cysts are formed by endoproliferation  .Cerebral cystic echinococcosis is most commonly seen in children and young adults (approximately 50–70%) . El- ShaThe lesions may remain asymptomatic until they are quite large. Headache and vomiting were the most commonly reported symptoms in other series. Other symptoms such as hemiparesis, seizures, visual field alteration and gait disorders, may vary with the location of the cyst . PapilleLesions of cerebral hydatid disease are usually distributed in the territory of the middle cerebral artery, especially in the parietal lobe. Most of the cysts are located in the supratentorial regions , 6, and Multiple cerebral hydatid cysts are rather rare and result from spontaneous, traumatic or surgical rupture of a solitary primary cyst or as a consequence of a cyst rupture elsewhere and embolization of hydatid to the brain , 10. ThePatients with cerebral hydatid cysts may have hydatid cysts in other organs. In recent studies, hepatic, pulmonary and other locations were found in 10% of the cases . In the Both CT and MRI demonstrate a spherical and well-defined, smooth, thin walled, homogeneous cystic lesion with fluid density similar to the cerebrospinal fluid, with or without septations or calcification. On unenhanced CT, the cyst wall was isodense or hyperdence to brain tissue. The cyst wall usually showed a rim of low signal intensity on both T1- and T2-weighted images. Calcification of the wall was rare, being less than 1%. The presence of daughter cysts is considered pathognomonic but has been rarely reported . ObviousThe differential diagnosis of intracerebral hydatid cysts includes cystic lesions such as porencephalic cyst, arachnoid cyst, cystic tumor of the brain and pyogenic abscess. In contrast to hydatid cysts, porencephalic cyst and arachnoid cysts are not spherical in shape and not surrounded entirely by brain substance. Arachnoid cysts are extra-axial masses that may deform adjacent brain. Porencephalic cysts result from insults to normal brain tissue and are lined by gliotic white matter that could easily be demonstrated with MR imaging. Cystic tumors of the brain could be differentiated by the enhancement of the mural nodule, if any, and periphery of the tumor. When a pyogenic abscess shows a cyst-like central necrotic area; peripheral edema is almost always present, the rim enhances intensely following contrast administration and satellite lesions are commonly present, all of which could be demonstrated on both CT and MR images. Clinical and laboratory findings could also aid in the differential diagnosis of the patients with cerebral abscess formation.The diagnosis should be suggested by evidence of a primary hepatic focus, appropriate clinical history, high prevalence of the infection in the host’s geographic location, and laboratory findings . CerebraIn conclusion, CT and MR imaging, alone or in combination, are helpful in the diagnosis of cerebral hydatid disease. Although CT is superior in detecting calcification of the cyst wall or septa, when present, MR is better in detecting multiplicity and defining the anatomic relationship of the lesion with the adjacent structures and helps in surgical planning. MR provides additional information and details that cannot be seen by CT. It provides additional information in the exact localisation of the cyst. When present, in complicated or recurrent disease, surrounding edema can better be demonstrated with MR imaging owing to the inherent capability of the imaging modality in revealing subtle differences in the tissue content. When a well-defined spherical cystic intracerebral lesion with obvious mass effect, but no surrounding edema and no contrast enhancement following contrast administration is detected on CT and MRI, hydatid disease should be taken into consideration in countries where the disease is endemic. If perilesional edema and thin rim enhancement are observed either complicated hydatid cyst or other cystic lesions of the brain should be considered in the differential diagnosis.The treatment of cerebral hydatid cysts is principally surgical. The primary goal of the operation is total cyst extirpation without rupture to prevent anaphylactic reaction and local recurrence . Many diDespite the advancements in microsurgical operative techniques and instrumentation, cerebral hydatid cysts pose a challenge for the surgeon because of the following characteristics: they are usually diagnosed when they are large in size; they have a very thin cyst wall; the neurological deficits are often minimal in their presentation despite the location and the large size of the cyst; and they are sometimes located deep or near the ventricular wall and require retraction of vital structures or meticulous cortical dissection. There are many reports suggesting that the Dowling technique is the most effective surgical procedure for the removal of cerebral hydatid cysts. However, some pitfalls exist with this technique concerning surgical methods, instruments, and cyst location. The best operative approach to a cystic lesion in the brain should be based on the site and the size of the cyst, and the relationship of the lesion with the other neural and vascular structures.Few reports mention the efficacy of drug therapy with albendazole in the cure of cerebral hydatid cyst . HoweverWe concluded that hydatid disease is not uncommon, affects pediatric age group and is usually located supratentorially. The clinical features are those of intracranial space occupying lesion. It can safely be removed intact with the dowling technique.


Hemangiopericytoma and solitary fibrous tumor are considered related variants on the same spectrum and both may essentially be the same tumor. They are infrequently encountered in the orbital region while the zygomatic bone is an extremely rare location for these neoplasms to occur.A 14-year-old boy presented with complaint of deformity of left infraorbital area and a firm, regular mass in the region. Orbital CT scan revealed a well-defined round isodense intraosseous lesion in the lowermost portion of the lateral orbital wall (zygomatic bone), expanding the bone and protruding anteriorly and medially. MRI showed the mass to be heterogenous and strongly enhancing with contrast medium. Inferior transconjunctival orbitotomy was performed and the mass was removed. The histopathologic examination and immunohistochemistry staining results  and desmin) confirmed the diagnosis of hemangiopericytoma. The postoperative course was uneventful, with no evidence of recurrence after 5 years follow up.This case represents the second hemangiopericytoma reported in the zygomatic bone. Although extremely rare, hemangiopericytoma/solitary fibrous tumor might be considered in the differential diagnosis of intraosseous lesions of the orbital and zygomatic region. Vascular tumors of the bone are uncommon, accounting for 1–2% of bone tumors . OccurreA 14-year-old boy was referred with complaint of deformity of left infraorbital region. There was fullness in the inferolateral orbital and periorbital areas  by a rare tumor (HPC/SFT) is reported and the relevant literature is reviewed. Complete surgical excision provides the most effective treatment, although postoperative follow up is required for a long period of time.


The authors present a case of an 80-year-old Caucasian male with multiple gastric and rectal metastases from malignant melanoma presenting with hypochromic anemia as the sole symptom of disease without evidence of cutaneous and ocular tumor localization. The patient had a medical history positive for malignant lentigo melanoma of the occipital region of the scalp and early stage laryngeal squamous cell carcinoma and prostatic carcinoma treated with radiation therapy. The authors make some considerations on intestinal involvement by metastatic melanoma and discuss the choice of not treating with endoscopic procedures the gastric metastatic lesions most likely responsible for the clinical sign present at diagnosis. The patient was referred to clinical oncologists and received immunotherapy with ipilimumab and pembrolizumab. Metastatic involvement of the gastrointestinal tract by epithelial malignancies is a rather infrequent event as opposed to malignant melanoma, which appears to have a particular trend towards metastasis to the gut . In factThe objective of this paper is to present a case of an unusual clinical presentation of metastatic melanoma with hypochromic anemia refractory to iron therapy treated with endoscopic procedures and systemic immunotherapy. Review of the literature is also reported below.In 2004, an 80-year-old Caucasian male underwent bilateral cordectomy for Tis carcinoma in the left cord and microinvasive T1 carcinoma at the right one. In the same year, he was diagnosed with prostatic carcinoma (Gleason score 3 + 3) which was treated with radiation therapy for a final total dose of 64 Gy. Since then, he has been controlled regularly on a 6-month basis. His family history was negative for cancer, but he suffered from mild hypertension that has been treated with a sartan drug for 17 years, and he also suffered from mild dyslipidemia without any medication besides dietary control. lentigo maligna melanoma in the occipital scalp, while the ulcerated lesion at the temporal region was classified as an actinic keratosis. Full skin and ocular examinations, chest X-rays, and abdominal sonogram excluded the presence of clinical detectable neoplastic deposits. Due to his medical history, the patient was admitted to a three-month follow-up program. In January 2015, for the appearance of a swelling in the left parotid gland, he received an MRI and a subsequent biopsy, which led to a diagnosis of pleomorphic adenoma.In January 2014, he was admitted at the dermatologic unit of our institution for a pigmented cutaneous lesion at the occipital region of the scalp and an ulcerated lesion in the left temporal region, which were both radically excised. The pathologist reported a BRAF, c-KIT, and N-RAS wild-typeIn May 2014, he was diagnosed with hypochromic, iron-deficiency anemia in the absence of overt clinical signs of bleeding and normal urine analysis. Fecal occult blood test was strongly positive. The patient was put on oral iron therapy without positive results for three months and therefore was referred to the endoscopy unit for upper and distal gastrointestinal tracts examination. Esophagogastroduodenoscopy showed the presence of several nonbleeding, bluish to black, gastric lesions of a few millimeters in diameter . The median overall survival with ipilimumab alone was 10.1 months . No difference in overall survival was detected between the ipilimumab groups . At progression after ipilimumab treatment, the patient was offered to start second-line therapy with the anti-PD-1 monoclonal antibody pembrolizumab according to the results of the Keynote-002 trial [Medical oncologists choose systemic immunotherapy with the monoclonal anti-CTLA4 antibody ipilimumab, which has been proven to be effective in the treatment of metastatic melanoma. In fact, ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma . The med02 trial . This ph02 trial . Only 14This case is intriguing for both clinical presentation and treatment challenges. In fact, occult gastrointestinal bleeding as the first clinical presentation of metastatic melanoma is relatively unusual, especially in the absence of other symptoms of disease. Gastrointestinal metastasis, especially of the small intestine, always represents an advanced stage of the disease even in the absence of other evidence of disease and should be always suspected in patients with gastrointestinal symptoms and history of cutaneous melanoma. The massive involvement of the stomach and the coexistence of rectal lesions as well as the simultaneous presence of bone metastasis are suggestive for metastatic spread rather than a primitive gastrointestinal melanoma. Therefore, after intensive workup, we concluded that gastrointestinal metastatic lesions detected in this case may be secondary to the excised malignant lentigo at the occipital region of the scalp even if this neoplastic malignant disease is reported to have a low metastatic potential.


The IMPAKT 2015 Breast Cancer Conference was designed for researchers and clinicians by the Breast International Group (BIG) and the European Society for Medical Oncology (ESMO). The event was held on 7–9 May in Brussels, Belgium, bringing together approximately 525 participants with a special interest in translational science and state-of-the-art applications in the clinical setting. Oncologists, pathologists and scientists collaborated to develop innovative ideas about breast cancer research and to enhance its relevance to patient care. This report highlights the most recent discussions in fundamental research and future clinical perspectives presented by professionals from around the world. It also covers the important issues regarding new technologies for biomarker discovery and the actual path to clinical utility. In recent years, there has been rapid progress in fundamental research followed by an increasing development of new strategies for clinical applications . The IMPThe conference introduced a series of talks that looked beyond the ‘well-known’ gene expression profiling. Using high-throughput sequencing analysis, Serena Nik-Zainal  exposed genome-wide mutational signatures and hypermutated regions in human breast cancers . The genOne of the recent topics of the conference was the discussion of which mutations are clinically relevant, how to identify them and what the therapeutic implications are. The systematic analysis of mutation frequencies and sequence contexts using whole-exome mutation data from The Cancer Genome Atlas (TCGA) revealed the importance of the APOBEC family of cytidine deaminases as a chronic source of DNA damage in breast tumors. Increased mutation frequencies induced by APOBECs, with emphasis on APOBEC3B, was also highlighted by Reuben Harris  ,6. InterOn the basis of these studies, thousands of somatic mutations identified across many samples have uncovered molecular signatures underlying the breast cancer history. Therefore, additional investigation of the APOBEC-mediated mutagenesis is required to comprehend major regulations and dependent mechanisms affecting the cell phenotype. This knowledge will further delineate the disease landscape with regard to the patient's clinical outcome. The main challenge, however, is to situate the mutation readouts in the context of anticancer therapies. In the view of future medicine, large-scale molecular profiling will be applied to clinical testing for diagnosis, prognosis and therapy in a complementary and more precise and individualized way than current methods.Integrated biology approaches involving both the genome and proteome are essential for addressing system-wide biological questions . CompareThe new proteomics technologies are in high demand and will remain so for at least the next decade, generating data that are complementary and, in some aspects, unique compared with other ‘omics’ approaches . AdditioCirculating tumor cells have potential as a ‘liquid biopsy’ to evaluate cancer in both the metastatic and early stage setting. There is a need for novel biomarkers with greater sensitivity and specificity to define disease prognosis, and to delineate the benefit of new and emerging therapies as well as treatment response. Bram De Laere  conducted research to determine the PIK3CA genotype in circulating tumor cells, at the single cell level. In the noninvasive evaluation of blood, PIK3CA was frequently mutated across patients with metastatic hormone receptor-positive breast cancer. The analysis revealed the PIK3CA mutations in both homo- and hetero-geneity in circulating tumor cells, which suggested the presence of subclones with both mutant and wild-type variant in the population.The PIK3CA status assessed in circulating tumor cells and cfDNA of liquid biopsies paves the way towards novel method for the management of patients with metastatic cancer. A critical question to be answered is how this status changes over time or is influenced by treatment in a larger cohort and real clinical trials ,10. The in vitro and in vivo.The explosion of molecular profiling assays has increased the pressure to identify novel markers for clinical implementation. Due to the lower risk of adverse treatment events, some researchers rely on defining more selective inhibitors rather than pan-inhibition agents which affects spread targets. Following this idea, Ian Krop  showed the mechanisms involved in PI3K/AKT/mTOR pathway inhibition and the increased drug sensitivity of ER-positive breast cancer cell lines. The pathway inhibitor also suppresses cyclin D1 expression thereby affecting the CDK4/6, responsible for mediating cell division and proliferation . The comIn tests with palbociclib, an inhibitor of CDK4/6, Maria Teresa Herrera-Abreu  showed that cell lines acquired resistance following chronic exposure to the drug. The mechanisms underlying resistance may involve the adaptive loss of cyclin D1 dependence or the acquired loss of RB1 phosphorylation. Agents that work synergistically with palbociclib may increase the drugs activity and improve the patient's clinical outcome. Rational drug combinations, however, may increase sensitivity in preclinical tests and further support medical development and cancer care innovation. Large prospective clinical trials to better assess the patients’ outcome is therefore essential in evaluating the drug efficacy and effectiveness.The conference provided a stimulating environment for discussing translational research in breast cancer via relevant updates and new insights for understanding the disease. The conference encouraged team integration and enhanced networking opportunities among specialists and early career professionals. The high-level scientific overview and exchange of opinions promoted the latest advances in molecular biology that can be exploited for clinical purposes. Despite the clear impact molecular profiling  has made in improving our knowledge of breast cancer history, there is still a great deal of work ahead. The findings need to be transformed into clinical applications, either for early diagnosis or effective treatments, in the sphere of personalized medicine.


There will be a lack of 18 million healthcare workers by 2030. Multiplying the number of well-trained healthcare workers through innovative ways such as eLearning is highly recommended in solving this shortage. However, high heterogeneity of learning outcomes in eLearning systematic reviews reveals a lack of consistency and agreement on core learning outcomes in eLearning for medical education. In addition, there seems to be a lack of validity evidence for measurement instruments used in these trials. This undermines the credibility of these outcome measures and affects the ability to draw accurate and meaningful conclusions. The aim of this research is to address this issue by determining the choice of outcomes, measurement instruments and the prevalence of measurement instruments with validity evidence in randomised trials on eLearning for pre-registration medical education.We will conduct a systematic mapping and review to identify the types of outcomes, the kinds of measurement instruments and the prevalence of validity evidence among measurement instruments in eLearning randomised controlled trials (RCTs) in pre-registration medical education. The search period will be from January 1990 until August 2017. We will consider studies on eLearning for health professionals’ education. Two reviewers will extract and manage data independently from the included studies. Data will be analysed and synthesised according to the aim of the review.Appropriate choice of outcomes and measurement tools is essential for ensuring high-quality research in the field of eLearning and eHealth. The results of this study could have positive implications for other eHealth interventions, including (1) improving quality and credibility of eLearning research, (2) enhancing the quality of digital medical education and (3) informing researchers, academics and curriculum developers about the types of outcomes and validity evidence for measurement instruments used in eLearning studies. The protocol aspires to assist in the advancement of the eLearning research field as well as in the development of high-quality healthcare professionals’ digital education.CRD42017068427PROSPERO The online version of this article (10.1186/s13643-018-0739-0) contains supplementary material, which is available to authorized users. The world is short of 7.2 million healthcare workers, and this will increase to 18 million by 2030 [Multiplying the number of well-trained healthcare workers through various means and making learning accessible and affordable through innovations and eLearning can potentially solve the shortage of health professionals. The World Health Organisation (WHO) and the United Nations (UN) consider the use of highly innovative, flexible, interactive and adaptive technologies in learning, herein referred to as eLearning, as one of the possible solutions to these problems . eLearniRandomised controlled trials (RCTs) are considered to be the gold standard research design when evaluating the effectiveness of eLearning educational interventions in improving knowledge, skills, attitudes, competencies and learning satisfaction of healthcare professionals. Systematic reviews provide the best quality evidence synthesis from the RCTs. However, there is a pool of measurement instruments which are used to evaluate the findings of these eLearning trials . HeterogThe choice of eLearning outcomes can be influenced by traditions, types of eLearning intervention or the curriculum , 11. MeaThe intended use of the data collected using the measurement instrument requires sufficient validity evidence. However, two systematic reviews identified scarce reports of validity evidence of measurement instruments used in medical and health profession education. Cook et al. found that only 64% of the 417 studies presented any form of validity evidence in technology-enhanced simulation in health professionals . RatanawThe current study is the first step toward ensuring the use of a set of reliable, standardised and validated outcomes and measurement instruments in studies on eLearning for health professionals’ education. The focus and the objective of this review are to determine and map the choice of outcomes, outcome measurement instruments and the prevalence of measurement instruments with validity evidence in eLearning research for pre-registration medical education.This study aims to systematically map and review the outcomes and measurement instruments and to report the prevalence of validity evidence for these measurement instruments in RCTs of eLearning interventions for pre-registration medical education.We hypothesise that there is a shortage of measurement instruments which provides validity evidence that support learning outcomes such as knowledge, skills, attitudes, competencies, learning satisfaction and patient outcomes in RCTs in eLearning pre-registration medical education. The shortage undermines the credibility of eLearning research leading to the unwarranted interpretation of the results.What type of outcomes  and measurement instruments are used in RCTs of eLearning for pre-registration medical education?What proportion of RCTs on eLearning pre-registration medical education presents validity evidence for the measurement instruments used and how is this evidence reported?In particular, the broad research questions that we aim to answer are:In response to the research questions, we will perform a systematic mapping of research evidence including the types of outcomes, outcome measurement instruments and the proportion of RCTs reporting validity evidence for the measurement instruments used. As part of this systematic mapping review, we will develop a database of eLearning outcome domains and the types of measurement instruments used in relation to each respective domain. We will also search the references of the included RCTs for relevant articles that present validity evidence including psychometric properties of the employed measurement instruments and report their findings. However, in-depth analyses of the quality of validity evidence and synthesis of validity evidence will be performed in another systematic review.(i)RCTs;(ii)Involve students participating in pre-registration medical education in any geographical setting or educational setting;(iii)Evaluate any type of blended or full eLearning method, including a range of eLearning modalities, for example, mLearning, massive open online course (MOOC), online learning, offline learning, virtual reality simulations and digital game-based learning;(iv)Employ a type of control intervention such as traditional learning, no intervention, other types of eLearning and blended learning.We will consider the studies eligible for inclusion if they fulfil the following criteria:We adopted the meaning of pre-registration or undergraduate medical education from World Health Organisation by which it means “any type of initial study leading to a qualification that (i) is recognized by the relevant governmental or professional bodies of the country where the study was conducted and (ii) enables its holder primary entry into the healthcare workforce” (p. 11) . StudiesThe search strategy of this review aims to find both published and unpublished studies. No language restrictions will be applied. The search for eligible studies will involve both electronic sources and non-electronic sources.○ MEDLINE (Ovid)○ EMBASE (Elsevier)○ Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley)○ PSYCINFO (Ovid)○ Educational Resources Information Center (ERIC) (Ovid)○ Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO)○ Web of Science Core Collection (Thomson Reuters)For the electronic search, the following databases will be searched from January 1990 until August 2017:We will use the MEDLINE strategy and keywords presented in Additional file EndNote (X7.2.1) or Covidence. Duplicate records of the same report will be removed. Two reviewers will independently examine the titles and abstracts of the records retrieved from the search. The full-text versions of the potentially relevant studies will be retrieved and assessed against the eligibility criteria. Multiple reports of the same study will be linked together, in order to determine if the study is eligible for inclusion. Both the initial screening and the full-text screening will be done independently by two reviewers. Reviewers will correspond with each other to make final decisions on the study eligibility and resolve any disagreements by a discussion with a third reviewer acting as an arbiter if needed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram will be used to report the selection and inclusion of studies [Search results across databases will be merged using the reference management software  studies .Two reviewers will independently extract and manage the data for each of the included studies using a structured data recording form. It will include information such as reference of the study, country of the study, the WHO region of the study, name of measurement instrument, description of measurement instrument, types of outcome, assessment category of measurement instruments , assessm(i)Ascertain the types of primary and secondary outcome measurement instruments(ii)Classify and map the data according to types of outcome ; intervention (e.g. online versus offline computer-based eLearning); healthcare profession ; types of measurement instruments (e.g. multiple choice questionnaires versus structured direct observation with checklists for rating); and discipline (e.g. anatomy or physiology or pathology)(iii)Determine the proportion of eLearning RCTs employing measurement instruments with adequate validity in relation to the goal of the measurements Data will be analysed and synthesised as follows. We will:The significance of this systematic mapping review is multifold. First, it will reveal the choice of outcomes, the type of measurement instruments and the proportion of RCTs on eLearning for pre-registration medical education which use measurement instruments with evidence for validity. It will reveal the current state of efforts in this area and advise areas of improvement. Second, our review aims to contribute to the improvement in the quality of reporting, assessment and interpretation of the findings from eLearning research for medical education. eLearning will grow significantly in medical and healthcare education and will in future account for a substantial share of such programmes globally . An undeWe will conduct this review according to the PRISMA standards of quality for reporting systematic reviews.Additional file 1:Search strings. (DOCX 16 kb)


The term optical coherence tomography angiography (OCTA) comprises different OCT-based technologies which all allow noninvasive assessment of retinal perfusion, based on moving red blood cells. The main areas where OCTA is currently used are investigation of perfusion and vascular structure of the macular retina  and the disk and peripapillary retina (in glaucoma and other optic disk diseases). The current editorial provides a brief overview on the potential of OCTA and its use to measure perfusion in the peripapillary retina in glaucoma.Holló G. Optical Coherence Tomography Angiography to Better understand Glaucoma. J Curr Glaucoma Pract 2017;11(2):35-37. Thus, in contrast to fluorescein angiography, information in OCTA arrives from the red blood cells and not the plasma; this may result in differences in clinical interpretation, mainly when the macula is investigated. It is important to note that lack of perfusion with OCTA does not necessarily mean missing or obstructed vessels, or lack of capillary perfusion; in contrast, it simply means that at the time of image acquisition, no moving red blood cell was present in the location of the low perfusion or nonperfusion OCTA areas.The term optical coherence tomography angiography (OCTA) comprises different OCT-based methods, which all offer noninvasive and cross-sectional assessment of the perfusion in the retina or other eye tissues . Various OCTA instruments manufactured by several manufacturers are currently used in clinical practice. All systems offer perfusion images, however, currently not all instrument and software versions provide numerical measurements. Due to the technical differences, no conversion of the measured results between the different systems is possible. Most commercially available OCTA systems are based on split-spectrum amplitude-decorrelation algorithm.2 Though OCTA of the disk area is technically available in all systems, the presence of the large vessels, and the variability and complexity of the three-dimensional structure of the disk makes it difficult to interpret the measurement results. In OCTA, both the perfusion and the corresponding structural information (en face OCT) of the different retinal layers are imaged and measured respectively, on the same image , OCTA of the radial peripapillary capillaries layer provides the most useful information. This layer is identical to the retinal nerve fiber layer on the structural (en face) OCT image.For glaucoma research and glaucoma practice, the most informative parameters are peripapillary angioflow density  and whole image angioflow density .me image . This al1 In the radial peripapillary capillaries layer, peripapillary angioflow density shows strong correlation with the retinal nerve fiber layer thickness.3 The measurement reproducibility is favorable and independent from the severity of glaucoma. This means that measurements made in advanced glaucoma are as reliable as those made on healthy and early glaucoma eyes.3 The perfusion of the peripapillary OCTA sectors shows strong relationship with the sensitivity and defect values of the spatially corresponding visual field areas.5 Recently, in a proof-of-concept study, it was shown in untreated high pressure open-angle glaucoma and ocular hypertensive eyes that at least 50% intraocular pressure (IOP) reduction to IOP of less than 18 mm Hg causes a significant increase of the peripapillary angioflow density.6 This means that there is a relationship between IOP and peripapillary perfusion. However, the detailed evaluation of the relationship and its potential applicability for glaucoma care remains to be specified.It has been shown that the diagnostic accuracy of peri-papillary and whole image angioflow density for separation of glaucoma eyes from normal eyes is similar to that of the retinal nerve fiber layer thickness.The OCTA entered clinical glaucoma practice 3 years ago. Thus, the time elapsed since its introduction was too short compared to the time necessary for the development of glaucomatous progression. Therefore, currently no information is available on the long-term changes of peripapillary angioflow density in treated glaucoma. It is also unknown whether OCTA can provide better or additional information on progression of glaucoma compared to the currently established structural OCT parameters . This limitation, however, is temporary. In the following years, we will see if OCTA can be usefully applied to detect glaucomatous progression earlier, to measure glaucomatous progression more reliably, or to find markers which differentiate eyes with optimal and suboptimal pressure control. Since OCTA is one of the most exciting and promising new technologies in glaucoma, it desires attention from both glaucoma specialists and general ophthalmologists treating glaucoma patients.


A research has been conducted in the present study to investigate the effect of hole configuration on tensile strength of lontar fiber-reinforced composites. The lontar fiber-reinforced composites used in this study were produced by hand lay-up process. The lontar fiber-reinforced composites consist of short random fiber of 5 cm that contains 32% of nominal fiber volume as the reinforcement and unsaturated polyester as the matrix. The results show that the differences of hole configuration have an effect on tensile strength of lontar fiber-reinforced composites. It is found that the specific area of four-hole specimens experiences smaller strain propagation due to the redistributed stress and no stress passes through the hole. The damage of lontar fiber-reinforced composites with different hole configurations in tension is fairly straight and transverse to the loading axis, where the initial damage occurs in the form of matrix cracking, propagates into interfacial failure in form of delamination, and ultimately failed mainly due to the fiber breakage. Nowadays, the weight of an automotive transportation has a large effect on its energy consumption and weight saving technology in transportation is crucial to reduce both the energy/fuel consumption and emissions substantially .2 emissions, and saving nonrenewable resources. Two other issues driving the transportation industry to seek new materials are cost-effectiveness and the capability of material.From the material use point of view, there is a need for developing new material that can be used to replace conventional material in automotive application according to the weight reduction issues and environmental aspect. In this regard, there are six main issues that are driving material development in the automotive application. The first four issues are the development and use of lighter weight material which correlates with the issue of fuel efficiency, reducing CO2 emissions but also save nonrenewable resources by substituting conventional mineral and petrochemical (fossil) materials. Indonesia is one of the countries with the largest potential of natural resources in the world. Natural fiber of lontar fruit (Borassus flabellifer) is one of those potentials which are produced from plant that thrives in the region of East Nusa Tenggara.According to this present scenario, composite materials based on renewable and natural resources have excellent potential to not only reduce CO go green and back to nature concept. Furthermore, the economic impact of natural fiber cultivation and beneficiation is well established and recognized as a key driver for sustainable growth through agricultural and industrial revolutions, particularly for developing countries [With this potential, natural fiber could be used for replacing the domination of synthetic fiber in composite field for transportation industry, thus opening opportunities and challenges for developing natural fiber composite according toountries .Previous work in the field of lontar fiber-reinforced composite, as summarized by Boimau et al. –5, invesThe influence of hole size on tensile strength and damage mechanisms of flax yarn composite was investigated by Gobi Kannan et al. . This woIn the present study, research has been planned to investigate the effect of hole configurations on tensile strength of lontar fiber-reinforced composites. To do so, a series of tests were conducted to establish the tensile strength of an open hole and multiple holes of lontar fiber-reinforced composites. In addition, postobservation of microscope was used for mapping damage mechanisms. Analysis of lontar fiber-reinforced composites is a challenge, since the material has limited information compared to other natural fiber composites materials.A plan view of hole patterns is shown in The composite specimen used in this study was reinforced by lontar fiber with 5 cm of fiber length. In order to consider the interface problem between fiber and matrix, lontar fibers were initially washed with distilled water and dried for 24 h. Then the lontar fibers were treated with 4% NaOH for 2 h at the room temperature. The treated fibers were washed with distilled water and dried at ambient conditions till the moisture was removed from the fiber by natural means and showed no residual NaOH. The composite specimen was produced by hand lay-up process that contains 32% of lontar fiber volume. The percentage of lontar fiber volume was obtained from the rule of mixture model of weight fraction from each constituent. The unsaturated polyester was used as the matrix throughout 4 mm of specimen thickness. The orientations of fibers occurred randomly against each other. In order to investigate open-hole tensile strength, five configurations of hole patterns were studied. Configuration I contains an open hole and configurations II and III have two holes with parallel and perpendicular patterns to loading direction. Configurations IV and V have four holes with diamond and square patterns.Test was carried out with a servohydraulic testing machine with a capacity of 100 kN. The machine was equipped with a standard load cell and mechanical grips. Specimens were aligned and mounted first in the lower and afterwards in the upper grips of the test station. After mounting the specimens, any loading due to the gripping was minimized through controller panel. A unit of dial indicator was used to record all the test results such as load and displacement. Then, the tests were considered to begin. Static tensile tests were performed under a constant cross-head speed of 1 mm/min. The test procedure was based on standard ASTM D5766 which consists of five specimens of each test for, respectively, each type of hole configuration. The tensile behavior of lontar fiber-reinforced composites was investigated. Tensile test has been performed on all test samples until final fracture. Three specimens for each type of hole configuration were tested. These curves show the effect of varying the hole configuration on the tensile behavior of the test specimens. Each curve exhibits a typical brittle behavior with sudden failure. The highest ultimate tensile load of 2400 N is shown in configuration III. The curves indicate the stress versus strain curve obtained from tensile test in which stress is resulting from given load and strain is derived from global displacement. The stress-strain curve shows linear relationship. This is typical brittle material with a sudden failure of composite material under tensile loading in static condition. There was no clear evidence of nonlinearity in the stress-strain curves, except at the beginning of the test which was possibly caused by the realignment of the fibers and could be corresponding to grip movement. To calculate the stress, two approaches reported by previous study can be used . The firσHS is the stress of specimen with hole area and σWHS is the stress of specimen without hole area, while p is tensile loading, w is the width of the specimen, d is the hole diameter, and t is the specimen thickness.The second calculation without a hole isCombine two approaches to calculate the stress; locally, the presence of the hole gives the lower area on specimen around the hole area. Therefore, the stress calculation increases and results in local stress between areas under different hole configuration. Specimens with four holes (diamond and square pattern) have smaller area compared to other hole configurations consisting of one or two holes. At the same time and load period, the area that contains more holes causes smaller area, thus increasing the stress. It is indicated in The highest UTS for this lontar fiber-reinforced composites specimen is around 44 MPa, resulting in highest modulus measurement of 1.5 GPa as seen in It can be noted that the differences in tensile modulus may also be originated by different local strain variations occurring at the surface of the specimen, as indicated in From From this condition, we can assume that area containing more holes (four-hole pattern) will experience lowest stress areas compared to specimen containing less holes (one or two holes). As a result, specific area of four-hole pattern experiences smaller strain propagation due to the lowest stress areas. These different conditions of stress-strain for different hole configuration ultimately have an effect on tensile modulus measurement.In addition, different tensile modulus also possibly indicates the highly nonhomogenous substructure derived from fabrication process of hand lay-up method. It means that the fabrication defects such as void, resin-rich areas and fiber kinking through the entire thickness of the specimen dictate the surface strain behavior of lontar fiber-reinforced composites. These specimens fail in a brittle type as seen in The brittle failure of lontar fiber-reinforced composites specimens with different hole configurations in tension is fairly straight and transverse to the loading axis at the edge of the hole, as shown by the black arrow in The differences of hole configurations have an effect on tensile strength of lontar fiber-reinforced composites.The stress of lontar fiber-reinforced composites is influenced by local area that results from the existence of hole (holes).The differences in tensile modulus possibly originated by different local strain variations occurring at the surface of the specimen.The specific area of four-hole specimens (diamond array and square pattern) experiences smaller strain propagation compared to specimens containing one-hole or two-hole pattern due to the redistributed stress and no stress passes through the hole, thus resulting in the lowest stress and strain at the area along the hole location.The tensile modulus indicates the nonhomogenous substructure derived from fabrication process of hand lay-up method. It means that the fabrication defects such as void, resin-rich areas and fiber kinking through the entire thickness of the specimen dictate the surface strain behavior of lontar fiber-reinforced composites.The appearance of the interfacial failure in form of delamination is in fact a result of initial damage propagation of matrix cracking along with the increase of tensile load.The damage of lontar fiber-reinforced composites with different hole configurations in tension is fairly straight and transverse to the loading axis, where the initiation damage occurs in the form of matrix cracking and ultimately failed mainly due to the fiber breakage.In our future work we will focus on the investigation of lontar fiber-reinforced composites as mechanical joint.This paper presents experimental results of different hole configurations of short random lontar fiber-reinforced composites under static tensile loading. The following conclusions have been generated:


Freezing of gait (FOG) is a gait disorder featured by recurrent episodes of temporary gait halting and mainly found in advanced Parkinson's disease (PD). FOG has a severe impact on the quality of life of patients with PD. The pathogenesis of FOG is unclear and considered to be related to several brain areas and neural circuits. Its close connection with cognitive disorder has been proposed and some researchers explain the pathogenesis using the cognitive model theory. FOG occurs concurrently with cognitive disorder in some PD patients, who are poorly responsive to medication therapy. Deep brain stimulation (DBS) proves effective for FOG in PD patients. Cognitive impairment plays a role in the formation of FOG. Therefore, if DBS works by improving the cognitive function, both two challenging conditions can be ameliorated by DBS. We reviewed the clinical studies related to DBS for FOG in PD patients over the past decade. In spite of the varying stimulation parameters used in different studies, DBS of either subthalamic nucleus (STN) or pedunculopontine nucleus (PPN) alone or in combination can improve the symptoms of FOG. Moreover, the treatment efficacy can last for 1–2 years and DBS is generally safe. Although few studies have been conducted concerning the use of DBS for cognitive disorder in FOG patients, the existing studies seem to indicate that PPN is a potential therapeutic target to both FOG and cognitive disorder. However, most of the studies have a small sample size and involve sporadic cases, so it remains uncertain which nucleus is the optimal target of stimulation. Prospective clinical trials with a larger sample size are needed to systematically assess the efficacy of DBS for FOG and cognitive disorder. Freezing of gait (FOG) is a gait disorder featured by recurrent transient gait retardation and interruption. FOG commonly occurs in Parkinson's disease (PD), primary progressive freezing gait, parkinsonism-plus syndromes and vascular parkinsonism. FOG is a major disabling feature of PD and usually occurs in late-stage PD with a severe impact on life quality of patients. FOG refers to the feeling of having the feet stuck to the floor and struggling to take a step. Most FOG episodes are related to the OFF state in PD, but severe cases begin to suffer from ON state freezing of gait (On-FOG)  to generate effective stepping in the absence of any known cause other than parkinsonism or high-level gait disorders. It is most commonly experienced during turning and step initiation but also when faced with spatial constraint, stress, and distraction. Focused attention and external stimuli (cues) can overcome the episode”  FOG occurs predominantly in the OFF state. The risk of FOG is higher if the PD patients present with abnormal gait but no tremor at an early stage  is most commonly used for PD patients. The score of the item related to FOG (item 14) is widely used to determine the severity of FOG. Gliadi et al. established the freezing of gait questionnaire (FOG-Q) in 2000, which is highly reliable in clinically assessing FOG  can lead to FOG in PD patients  is an important part of the midbrain motor area and projects to the basal ganglia, thalamus, cortex, brainstem, cerebellum and spinal cord. PPN has intimate fibrous connections with the basal ganglia and plays a role in regulating the gait and postures. FOG is considered relevant to the abnormalities in the functional connectivity of PPN and to the microstructural anomalies of the subcortical region  and substantia nigra pars reticulata (SNr) via the subthalamic nucleus (STN), thus inducing extensive inhibition of the excitability of the cerebral cortex. STN is considered as an important node in immobilization. Fling et al. found through resting-state functional MRI and DTI that the functional connectivity between STN and supplementary motor area (SMA) in PD patients with FOG decreased significantly as compared with the PD patients without FOG. It was inferred that the loss of functional connectivity of the STN-SMA circuit caused the loss of the ability in inhibiting competitive activity and initiating the right motion (gait), thus leading to FOG . In summary, it starts with stereotactic localization of the target nucleus. Pre-operative stereotactic computed tomography (CT) scan fused with a cerebral MRI and microelectrode recording  are performed to confirm accuracy of lead positioning. After the lead and microelectrode are secured, its position is then checked with postoperative MRI/CT scan. Microstimulation with the DBS lead is then performed with clinical observation. After DBS, the stimulation parameters and dopaminergic therapies are adapted postoperatively by a neurologist periodically. A schematic visualization of DBS on STN and PPN in a PD patient is shown in Figure The current study about the treatment of cognitive disorder by DBS shows that fornix and nucleus basalis of Meynert (NBM) are two main DBS targets which can improve the learning and memory capacities . Moreover, those patients with lower pre-dose item-scores also showed lower post-dose outcome scores  Large sample size, multicenter, randomized, blind, controlled trials; (2) To determine which frequency is optimal without aggravating other symptoms of PD; (3) To determine different stimulation parameters for each of the two sides and to discuss whether stimulation at different time for different sides produces a better effect; (4) Long-term follow-up to assess the efficacy; (5) To assess the outcome of FOG using different methods, subjective and objective. (6) To further investigate whether it can improve cognition.As mentioned above, PPN, also known as PPTg, is related to gait and gesture regulation and plays a key role in axial deficits such as FOG and postural instability in PD patients. It is also significant for the cognitive circuit. PPN stimulation to 6-OHDA lesioned rats affects neuronal activity in both the STN and SNr, suggesting PPN-DBS has potential effects to alleviate gait and motor symptoms in PD  associated with standard STN-DBS (130–185 Hz) improved gait and postural items of UPDRS-III (Stefani et al., Studies concerning the effects of DBS on FOG and cognitive impairment displayed safety of this treatment. The side effects of STN-DBS mainly resulted from the switching of stimulation frequencies. In one study that assessed the effects of DBS on FOG, 1 out of 20 patients dropped out due to a severe freezing episode when switching from HFS to LFS (Phibbs et al., FOG is closely related to cognition in the pathogenesis. These are both common symptoms in the late stage of PD, which are difficult resolve and severely affect physical coordinate ability of the patients. DBS proves effective for FOG symptoms in PD patients, especially those with a long disease course and poorly responsive to medication. Considering the “cognitive model” as one of the underlying mechanisms of FOG, we speculate the effect of DBS to alleviate FOG may be associated with cognitive functions improvement. As shown in Figure Based on the above hypothesis, this article reviewed relevant studies over the past 10 years and found that bilateral LFS of STN is a preferred option and that the treatment effect can last for at least 1 year. Although the overall safety of LFS stimulation of STN is high, there is still risk of aggravating other symptoms of PD. PPN stimulation is recommended for patients poorly responsive to STN stimulation. LFS is a preferred approach for PPN-DBS, and either unilateral or bilateral LFS can improve the symptoms of FOG with the efficacy lasting for at least 2 years. In theory, combined stimulation may achieve a better effect as it can improve various symptoms. The most intensively studied are the combined stimulation of PPN plus STN, PPN plus GPi, and STN plus SNr, all of which can achieve a satisfactory effect for FOG. Meanwhile, due to the close relation in mechanism, it is speculated that the mechanism of DBS treating FOG may be related to cognitive improvement. Given results of the current studies, PPN has greater potential to become the target of treating FOG and cognitive disorder. However, most of the existing studies have a small sample size and cannot reflect the real efficacy of DBS stimulation for FOG and cognition. It is also difficult to determine which nucleus can perform the optimal effect. Moreover, these studies only demonstrated the effects of DBS on FOG and cognitive impairment in PD patients through the clinical observations, lacking discussion of the mechanisms. Therefore, this review mainly summarizes the effects rather than the mechanisms. Large samples, multicenter, randomized, blind, controlled trials are needed to determine the optimal frequency and approach of stimulation and the optimal combination of nuclei to be stimulated through subjective and objective assessment of FOG and cognition as well as investigating the effect of DBS on the two. Long-term follow-up should be performed to assess the efficacy and to formulate the individualized DBS regimen for the patients. In addition, thorough investigation of the involved mechanisms may be another relevant research topic.CH, HC and YZ wrote and edited the manuscript. XW revised the review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.