Direct time-of-flight (DTOF) is a prominent depth sensing method in light detection and ranging (LiDAR) applications. Single-photon avalanche diode (SPAD) arrays integrated in DTOF sensors have demonstrated excellent ranging and 3D imaging capabilities, making them promising candidates for LiDARs. However, high background noise due to solar exposure limits their performance and degrades the signal-to-background noise ratio (SBR). Noise-filtering techniques based on coincidence detection and time-gating have been implemented to mitigate this challenge but 3D imaging of a wide dynamic range scene is an ongoing issue. In this paper, we propose a coincidence-based DTOF sensor architecture to address the aforementioned challenges. The architecture is analyzed using a probabilistic model and simulation. A flash LiDAR setup is simulated with typical operating conditions of a wide angle field-of-view (FOV = 40 Time-of-flight (TOF) has become a key depth-sensing technique in a wide range of light detection and ranging (LiDAR) applications spanning across consumer, automotive and industrial fields. Advancement in semiconductor miniaturization has led to compact solutions at smaller form factors, thus, making integrated TOF sensors almost natively available in mobile phones today. Automotive LiDAR, undoubtedly, is progressing at a rapid pace with growing interests in autonomous cars. With increasing range of applications, TOF sensors are only becoming increasingly relevant.TOF sensors are basically categorized into their direct (DTOF) and indirect (ITOF) forms. ITOF sensors have been implemented in a number of consumer applications for ranging and depth mapping. Recent ITOF sensors have demonstrated high spatial resolution with increased ability to detect multiple objects over a large field-of-view (FOV) . HoweverThis paper focuses on single-photon avalanche diode (SPAD) based DTOF sensors for LiDAR. DTOF image sensors based on time-correlated single-photon counting (TCSPC) are actively explored for their high speed and accurate ranging capabilities. Depth sensing in DTOF is achieved by transmitting a periodic light source  to a target and detecting the arrival of the reflected photons by high performance photodetectors such as avalanche photodiodes (APDs), SPADs or silicon photomultipliers (SiPMs). A supporting electronic circuitry then measures the arrival time of these photons. In DTOF sensors, time-to-digital converters (TDCs) are typically used for this purpose ,12,13,14Depth sensing in LiDAR systems is a complex process due to a number of challenges. High background noise from ambient light is one of the primary challenges. LiDARs can be implemented in scanning or flash modes of operation. Scanning LiDARs usually benefit from an increased signal-to-background noise ratio (SBR) due to higher achievable optical power while scanning over only sections of the target FOV. However, the presence of moving mechanical parts in conventional scanning systems introduces long-term reliability concerns. Recent advancement in solid-state scanning LiDARS with MEMS-based mirrors are achieving smaller form factors with better design and fewer optical components. Flash LiDARs benefit from a much simpler system by illuminating the entire FOV simultaneously, the drawback however being lower achievable SBR at longer ranges. Recent developments in illumination and optics have offered innovative solutions through VCSEL  array technology and laser diode arrays which circumvent this issue to some extent.At the sensor-level, ambient light suppression has been addressed by coincidence detection on chip ,12,16, aWe will address the challenge of imaging in a high background noise scenario with particular emphasis on wide dynamic range targets based on coincidence detection and time-gating.We propose a coincidence-based shared-DTOF sensor architecture to operate in a Flash LiDAR scenario. The architecture is analyzed using a probabilistic model simulated on MATLAB.We outline a framework for the integrated implementation of the sensor based on simulations of the proposed architecture.The main contributions of this paper are as follows:The paper is organized as follows; Illuminating every point on a target scene using patterned light source allows us to mitigate the effects of global components, thus minimizing errors in range estimation and target recovery by primarily using only direct illumination ,18. Howed. The target is assumed to be Lambertian in nature, thus, reflecting photons over a diffuse sphere with diameter, d  is an object with 60% reflectivity  at about 5 m and the desired target, labelled [2], situated at 20 m with 10% reflectivity. This target is reconstructed by the proposed DTOF model with 1024 pixels (32 × 32); the parts of this target as seen by different subgroups is highlighted in The histogram is then calculated for all the pixels in The average photon rate from object (1) is much higher than object (2) and therefore, the subgroup combination tree will propagate more events from object (1) compared to object (2) for a given measurement time, which can potentially mask the desired target photons from a target which may reflect fewer photons (as object (2) in this example). Without gating results in a histogram with two peaks, with a dominant one at 5 m as seen in Gating will thus, allow us to select and propagate only “desired timestamps” within a gating window, in that way we can mitigate situations as in this example case.In Given that depth sensing involves a number of interdependent challenges, it is imperative to visualize the entire LiDAR system as a closed-loop system wherein, there is a continuous feedback from the sensor to the illumination control logic and/or the optics. Therefore, we proposed an alternative DTOF sensor model in this article, with an architecture suitable for such an implementation. The sensor (or subgroup) is modeled to estimate the returning photon activity from different parts of the scene. This information can then be used to select an appropriate coincidence threshold as seen in The feature of subgroup clustering into multiple minigroups enabled with independent timestamping increases the overall timing throughput (up to number of minigroups). This has a direct implication on the histogram processing as well, especially in long distance ranging, by providing multiple depth estimation simultaneously. Additionally, this feature also decreases the timing uncertainty within a detection window (coincidence or gating), the absence of which can otherwise lead to large depth errors, particularly when windows become longer than ≈2–10 ns (≈0.3–1.35 m position error). Multi-pixel timing, counting and ID information as proposed preserves multiple pixel-data even in a shared architecture, which otherwise is typically lost due to the way they are combined ,11. FurtThe analytical model and simulations in this article provide an early validation and aid conceptual understanding of the sensor architecture. The next step will involve transforming this analysis into a SPICE-compatible model to support actual design of the sensor in an integrated circuit. A parallel future work will also involve building ray-tracing models to predict the photon behavior realistically in the light propagation path within the LiDAR system.Direct time-of-flight depth sensor architecture and method for operating of such a sensor .


J-wave pattern has been recognized as an arrhythmic risk marker, particularly in myocardial infarction patients. Mechanisms underlying J-wave development in ischemia remain unknown. In myocardial infarction model, we evaluated activation time delay as a prerequisite of J-wave appearance and predictor of ventricular fibrillation. Body surface ECGs and myocardial unipolar electrograms were recorded in 14 anesthetized pigs. 48 intramural leads were positioned across ventricular free walls and interventricular septum. Myocardial ischemia was induced by ligation of the left anterior descending coronary artery and the recordings were done during 40-minute coronary occlusion. The local activation times were determined as instants of dV/dt minimum during QRS complex in unipolar electrograms. During occlusion, ventricular local activation time prolonged in the middle portion of the left ventricular free wall, and basal and middle portions of septum, while J-waves appeared in precordial leads in 11 animals. In logistic regression and ROC curve analyses, activation time delay at a given time-point was associated with J-wave development, and a longer activation time was associated with ventricular fibrillation appearance. In experimental coronary occlusion, activation delay in ischemic myocardium was associated with generation of the J waves in the body surface ECG and predicted ventricular fibrillation. Originally, this phenomenon was regarded as a normal variant, especially in young subjects9, but subsequently has been considered as presenting a risk marker for malignant idiopathic ventricular tachyarrhythmias5. Recent evidence suggest that appearance of the J-wave pattern in patients with acute myocardial ischemia indicates the presence of arrhythmic substrate thus further increasing arrhythmic risk15. In an experimental setting, we have recently shown the appearance of J-wave during the progression of acute ischemia, which was highly predictive for ventricular fibrillation (VF)16, however the exact mechanisms underlying J-wave development could not be elucidated from the study based on close-chest myocardial infarction model.J-wave pattern is recognized as an electrocardiographic phenomenon manifesting as an additional low-frequency wavelet during the terminal part of QRS complex or QRS/ST junction17. The direct reason for the J-wave formation has been reported to be a transmural difference in a transient outward current density. This ECG phenomenon has been shown to be accentuated by increased vagal tone and bradycardia18, an observation supporting the suggested repolarization-related mechanism for the J-wave. However, a different mechanism could operate in ischemic conditions characterized by a conduction delay in the affected regions. The study by Nakayama et al.19 demonstrated that in patients with an acute ST-elevation myocardial infarction the J-wave amplitude was augmented in tachycardia, which supported the conduction delay-related mechanism of the early repolarization pattern. Meijborg et al.20 demonstrated that reduction of sodium current led to development of the J-wave pattern. Simulation studies22 demonstrated that prolonged activation in ischemic conditions produces an “overlap” of depolarization and repolarization potentials manifesting as the J-wave pattern. However, there is a lack of evidence for this concept based on direct measurements in the in vivo whole heart.The mechanism of the J-wave genesis in acute ischemia remains controversial. There are two main lines of evidence suggesting repolarization or depolarization abnormalities to underlie this phenomenon. The first line was suggested on the basis of studies of the distribution of electrophysiological properties on a transmural axis of the canine left ventricular (LV) wedge preparationThus, contribution of abnormal depolarization to J-wave generation and VF development in the ischemic conditions is unclear. In the present study, we aimed at evaluating activation time delay as a prerequisite of J-wave appearance and predictor of VF in open-chest porcine model of myocardial infarction.Guide for the Care and Use of Laboratory Animals, 8th Edition published by the National Academies Press (US) 2011 and were approved by the ethical committee of the Institute of Physiology of the Komi Science Centre, Ural Branch of Russian Academy of Sciences. Animals were anesthetized with zoletil , xylazine  and propofol . The animals were intubated and mechanically ventilated. The thorax was opened by a midsternal incision and the pericardium was cut. In order to prevent hypothermia-related phenomena including J-wave generation and slowing of activation spread, the temperature in pericardial cavity was maintained at 37–38 °C by irrigation with warm saline and heating the room air.Experiments were performed in 14 domestic pigs . The procedures conformed to the Body surface ECGs were recorded in 6 limb leads and 6 precordial leads. The latter corresponded to the standard V1-V6, but the leads V4-V6 were shifted downward to the level of xiphoid basis in order to minimize possible thoracotomy effects. This modification also took into account the vertical position of the pig heart in the thorax.16. At the end of each experiment, the animals were euthanized by an intracardiac injection of potassium chloride overdose, the heart was excised and Evans blue dye  was injected into the LAD, left circumflex and right coronary arteries with LAD ligated. The dyed zone identified the perfused or nonischemic area  free wall, interventricular septum (IVS) and right ventricular (RV) free wall at the apical, middle and basal levels of ventricles Fig. . The eleth minute until the end of 40-minute coronary occlusion. Local activation time (LAT) in each myocardial lead was measured from the QRS onset to the instant of a minimum of dV/dt during QRS complex25. For each recording, a maximal LAT was determined as the longest LAT throughout myocardium irrespective of a lead where it was observed. The presence or absence of J wave in the body surface ECGs was checked in the same time-points. According to the consensus document6, the J-wave presence was confirmed when there was a terminal QRS notching or slurring in two or more contiguous leads except V1-V3 with J-peak ≥ 0.1 mV and no QRS prolongation in leads free of the supposed J wave.Unipolar electrograms in a total of 48 myocardial leads were continuously monitored and recorded simultaneously with body surface ECGs by means of a custom-designed high-resolution system . At least 10-seconds duration recordings were done at baseline and at 1, 2.5, 5, 10, and then every 5Data are expressed as medians and interquartile intervals. Statistical analysis was performed with SPSS 23 . Kolmogorov-Smirnov test was used to validate application of ANOVA post-hoc tests; otherwise, Wilcoxon and Fridman tests were applied for paired and multiple comparisons, respectively, within the same groups of animals. Logistic regression analysis and receiver operating characteristics (ROC) curve analysis were used to assess relationship between intramural LATs and appearance of J-waves on the surface ECG and VF development. The differences were considered significant at P < 0.05.At baseline, we observed an expected activation pattern with relatively early LATs in subendocardial and intramural myocardial layers and relatively late LATs in subepicardial layers. Rapid intramural spread of activation resulted in a nearly simultaneous excitation of different parts of ventricular myocardium [median LAT ranged from 18 (IQR 17–22) ms in the LV apex to 20 (IQR 17–22) ms in the basal IVS and 20 (IQR 19–24) ms in the middle RV] with the only exception of the RV base that was activated later than the rest of myocardium .Coronary occlusion induced typical changes of ventricular electrograms in the affected regions, essentially in the anterior parts of basal and middle areas of LV free wall and IVS, observed as a prolongation of QRS complex duration and LAT delay. LAT prolongation was nonuniform across ventricular myocardium Fig. . While tth minute of occlusion. At this time-point, a marked prolongation of LAT medians as compared to the baseline state was documented in the middle portion of the LV free wall, basal and middle portions of IVS, while the rest of myocardial regions did not demonstrate statistically significant changes of LAT   in 11 animals . ROC curve analysis . Similarly, the ROC curve analysis  as predictors of VF. The logistic regression analysis demonstrated that only IVS LATs were the independent predictors of impending VF .The main findings of the present study are as follows: (i) LAD occlusion led to LAT increase associated with J-wave appearance on the body surface ECG; (ii) impending VF was predicted by LAT prolongation in ischemic regions; (iii) the LAT associated with impending VF was significantly longer than the LAT associated with J-wave development and confined to the IVS region.17. Presenting no objections against the role of repolarization in the J-wave pattern generation in a general sense, our experimental data suggest that in the acute ischemia setting, the J-waves were strongly associated with occurrence of abnormal depolarization and were likely to be the consequence of it. Several considerations support this hypothesis.There is a long-lasting debate on the origin of the J-wave pattern. Its alternative name “early repolarization pattern” implies its relation to the repolarization process, specifically to the potential difference during action potential phase 1et al.24. Using this method that provided the means for in vivo evaluation of activation wave spread across ventricular walls, we observed the expected activation slowing in the ischemic regions with the most pronounced LAT delay being associated with the J-wave pattern. This activation delay developed progressively in time and space with transition from the typical QRS morphology to the grossly distorted wide QRS complexes which were often attended by the change of initial portion of QRS (either loss or development of the q wave) (Fig. We measured LAT as an instant of the steepest downslope of the QRS complex of unipolar ventricular electrogram. This approach was validated in an earlier study by Kleber 26. Taken together, these findings suggest that the J wave can develop in conditions with prolonged activation of IVS and adjacent ventricular areas.J-wave formation was associated with LAT prolongation in specific ventricular areas. Since the site of occlusion was the proximal part of LAD artery, the areas demonstrating the significant ischemia-related activation delay were the anterior regions of the basal and middle part of IVS and middle part of LV free wall. These very areas demonstrated significant association between LATs and J-wave pattern. In previous studies, J-point elevation was reported to correlate with a thickness of IVS3. In the present study, we provided evidence suggesting J-wave association with depolarization abnormalities. Moreover, our findings suggest that further delay of LAT in the ischemia-affected myocardial region strongly predicts development of ischemia-induced VF.Whatever the cause of the J-wave pattern, this electrocardiographic phenomenon appears to be a risk factor for malignant ventricular tachyarrhythmiasLAT prolongation was associated with impending VF in a manner similar to LAT association with J-wave pattern. However, LAT predicting VF were longer than those predicting J-wave pattern for the similar levels of sensitivity and specificity Fig. . It coulIn the present investigation, only one locus of coronary occlusion was studied. It is plausible that different occlusion sites should have produced a different size and location of myocardial lesion, which could have resulted in a different electrophysiological and ECG manifestation. The positions and number of intramyocardial leads were limited due to technical reasons and could not ensure a complete “capture” of the ischemic area. This technical limitation at least partly explains the relatively low sensitivity of the LAT parameters. The limited number of animals and endpoints requires cautious interpretation of the data. However, our approach based on continuous multiple-lead potential recordings permitted relating electrophysiological events in the identified ischemic area to simultaneously recorded ECG phenomena that enhanced the quality of obtained results.The present study demonstrates that in experimental LAD occlusion model, activation delay in ischemic myocardium is associated with the generation of J-wave pattern. More pronounced LAT prolongation in the IVS expressed in J-wave pattern predicted impending VF. Abnormal depolarization in ischemic myocardium could present a “missing link” between J-wave pattern and arrhythmic risk in conditions of acute myocardial infarction.


Signal coverage of R-R intervals showed a very close overlay between the OMsignal system and Holter signals, mean difference in heart rate of 2 ± 5 bpm. The noise level of OMgarments was comparable to Holter recording. OMgarments provide high signal quality for adequate rhythm analysis, representing a promising novel technology for long-term non-invasive ECG monitoring.Diagnosis of arrhythmic disorders is challenging because of their short-lasting, intermittent character. Conventional technologies of noninvasive ambulatory rhythm monitoring are limited by modest sensitivity. We present a novel form of wearable electrocardiogram (ECG) sensors providing an alternative tool for long-term rhythm monitoring with the potential of increased sensitivity to detect intermittent or subclinical arrhythmia. The objective was to assess the signal quality and R-R coverage of a wearable ECG sensor system compared to a standard 3-lead Holter. In this phase-1 trial, healthy individuals underwent 24-h simultaneous rhythm monitoring using the OMsignal system together with a 3-lead Holter recording. The OMsignal system consists of a garment (bra or shirt) with integrated sensors recording a single-lead ECG and an acquisition module for data storage and processing. Head-to-head signal quality was assessed regarding adequate P-QRS-T distinction and was performed by three electrophysiologists blinded to the recording technology. The accuracy of signal coverage was assessed using Bland-Altman analysis. Fifteen individuals underwent simultaneous 24-h recording. Signal quality and accuracy of the OMgaments was equivalent to Holter-monitoring (84% vs. 93% electrophysiologists rating,  Arrhythmic disorders represent a common referral for cardiology consultations and have a strong impact on resource utilization of health care systems . As manyProlonged ambulatory rhythm monitoring is crucial for the diagnosis of intermittent arrhythmia and the correlation between rhythm and symptoms. Conventional technologies for noninvasive rhythm monitoring include Holter monitoring or external cardiac event recorders. Traditional Holter recording over 24–48 h provides excellent signal quality and high specificity, but is limited by low sensitivity and an overall low diagnostic yield in the vast majority of cases . ExternaAt present, implantable cardiac monitors (ICMs) represent the only technology for continuous ambulatory long-term monitoring . HoweverOther forms of wearable ECG sensors are already commercially available, but have been typically designed for recreational purposes. At present, clinical experience with those products is limited to pure, numerical detection of the heart rate and respiratory rate ,6,7,8,9.The OMsignal system represents a novel, alternative tool for non-invasive ambulatory rhythm monitoring with theoretically unlimited recording capacity and the potential of increased sensitivity to detect intermittent or subclinical arrhythmia. The aim of this study was to validate in a first step the signal quality of the OMsignal garments and signal coverage over 24 h against a standard Holter recording to demonstrate the general utility of the technology for advanced rhythm diagnosis.In this prospective phase-1 trial, healthy individuals underwent 24-h simultaneous rhythm monitoring wearing the OMsignal system together with a 3-lead standard Holter recording  with an ECG sampling rate of 200 samples per second. The study was approved by the local ethics and review board and written informed consent was obtained from all study subjects.The OMsignal system  consistsTo validate the overall suitability of the OMsignal system for rhythm analysis and monitoring, we assessed the signal quality and completeness of signal coverage  over a 24-h recording period. Signal coverage was assessed using automated algorithms and the accuracy compared to the Holter recording was verified using Bland Altman analysis (see below).R-R intervals were calculated using the built-in algorithms of each device. The OMsignal module embeds a modified Pan-Tompkins real-time QRS detection method with heuristic filtering for misdetections. The comparison of heart rates evaluated the difference between the OMsignal and the Holter recording for every second. This resolution of comparison is crucial to validate the capacity to measure physiological phenomena, such as heart rate variability. In this extent, heart rate was calculated over each R-R and interpolated second by second, which was the smallest time interval allowing accurate comparison. Signal temporal alignment between the Holter and OMsignal consisted of three components: (a) An offset, (b) a constant drift component, and (c) a variable drift component. The offset is to align recordings since they do not start at the same time. It is corrected using the best fit of a cross-correlation of the heart rate between the two signals. The constant time drift is due to hardware clock limitations, where 1 s on one device might correspond to 0.98 or 1.02 s from the other device. The drift between the two signals was calculated through cross-correlation for each hour. The time drift was calculated as the average slope of the 24 offsets. Those changes in time precision are also known to be affected by temperature such that the drift might change if the device is at room vs. body temperature. This phenomenon was taken into consideration by correcting time with the overall drift, but to the hour specific offset. Thus, the nonlinearity was partially compensated by having a specific offset per hour. To ensure maximal accuracy of the planned Bland-Altman analysis, all R-R intervals longer than 2 s without detection of an R-R interval in one device or the other were rejected.Signal quality of the OMgarments was qualitatively assessed regarding the adequate distinction of P-waves, QRS-complexes, T-waves, and noise levels . Among t2-test where appropriate. Continuous variables were tested for normality and are displayed as mean ± standard deviation (SD) or median with interquartile range (IQR) where appropriate. Continuous variables were analyzed using the Student’s t-test or Mann-Whitney-U test where appropriate. McNemar’s testing was performed for noninferiority analysis and the comparison of signal quality and noise level assuming a noninferiority margin of 15%. Bland-Altman analysis was used to compare the signal coverage between Holter recordings and the OMsignal system. The Bland-Altman comparison method was selected since both devices were assumed to have inaccuracies to a limited degree at some point of the recording. This method allows the comparison of measurements from two devices without the obligation of one owning the “true” value. The comparison is done by evaluating the relationship between the heart rate differences and the average heart rates of both devices at every second of the recording. The comparison was calculated at the second interval resolution to demonstrate the close beat-to-beat match between the 2 devices to provide the resolution expected from medical ambulatory devices. This metric can only be computed when both devices detected RRs simultaneously, which represented 91% of the recordings’ duration. These values can be summarized in distribution plots and agreement metrics . Interobserver agreement between the two blinded electrophysiologists was analyzed performing kappa and R statistics. A p value < 0.05 was considered statistically significant. All statistical analysis was conducted using Stata 14.1 Software .Qualitative and categorical variables were analyzed using the Fisher exact test or χp = 0.03).A total of 15 healthy individuals with a mean age of 41 ± 9 years  were enrolled and underwent simultaneous 24-h recording. Baseline characteristics of the study population are displayed in Representative examples of ECG recordings by Holter and the OMsignal system are shown in The distribution of R-R intervals over 24 h is shown in p = 0.06 [Wilcoxon] and McNemar’s chi2 = ). Details of the signal accuracy analysis are displayed in Overall signal quality of the OMshirt/-bra was noninferior B and sigThe interobserver agreement regarding the accurate signal quality of P-waves, QRS-complexes, and T-waves was excellent as shown in p = 0.26). Thus, the vast majority of the 24 h of recordings was rated as low to very low noise levels on both devices. Noise levels during Holter recordings were similar between males and females (p = 0.41) (p = 0.01) (Examples of intermittent noise are shown in  = 0.41) . However = 0.01) . The medExtended ambulatory rhythm monitoring is a key element for the diagnosis and management of various rhythm disorders ,12. HoweThe OMgarments represent a novel form of wearable ECG sensors providing equivalent signal quality and may be an alternative tool for ambulatory rhythm monitoring. The garments include bras for women and shirts for men that contain integrated electrodes detecting a real-time single-lead surface ECG. In the present study, we demonstrated that the OMgarments provide excellent signal coverage equivalent to standard Holter recording combined with a high signal quality. A particular strength of this phase-1 validation study was the direct, real-time head-to-head recording with OMgarments and a standard 3-lead Holter in each study subject–an approach that has been rarely performed in previous studies introducing novel non-invasive monitoring devices. Using this synchronized recording approach, we showed a very close overlay of R-R coverage (within 2 bpm over 24 h) between the OMgarments and the standard Holter. To the best of our knowledge, no previous study comparing non-invasive monitoring devices has ever reported such a close signal coverage. Excellent R-R coverage is a crucial element for reliable rhythm diagnosis and our study has shown that the OMgarments do not miss heart beats that might have otherwise been recorded by looping event recorders or standard Holter monitoring.The garments also provided high signal quality that was non-inferior compared to Holter recording. Accurate distinction of P-waves, QRS-complexes, and T-waves was present in most study subjects and based on a semi-quantitative evaluation by experienced electrophysiologists. The overall better signal quality in women is most likely related to a better skin contact of the bra electrode compared to the shirt electrode in men. Although the garment size was selected based on individual under-chest circumference and bust circumference, the overall fit was better in women. Those issues are currently being addressed in the design of the next generation of OMshirts. Changes of the electrode position and size as well as improved noise filter algorithms should overcome the observed differences in noise levels between bras and shirts in the future.An additional advantage of the garment in this study is the high wearing comfort and minimal risk of skin irritation (7% in this study) compared to conventional electrodes of Holter/looping external event recorders (47% in this study) or adhesive cardiac monitoring patches . Moreover, conventional looping external event recorders are cumbersome and interfere with showering, sports, and other daily life activities, resulting in poor patient compliance and reduced diagnostic yield , but hav3 [At present, implantable cardiac monitors (ICMs) represent the only device of ambulatory long-term monitoring beyond a period of 3 months. The utility and diagnostic accuracy of ICMs is well-established and the recent model of one manufacturer has been miniaturized to a volume of only 1.2 cm3 ,19. HoweThe potential spectrum of clinical applications for wearable ECG sensors, like the OMgarments, is broad, including diagnosis of unexplained syncope or palpitations, screening for subclinical atrial fibrillation, monitoring of heart rate variability and antiarrhythmic treatment effects, or screening for recurrent arrhythmia after ablation procedures. From a population health perspective, the screening for subclinical atrial fibrillation (AF) has gained wide interest, since two recent large-scale prospective studies have demonstrated that occult AF is a major source of cryptogenic ischemic stroke ,21. In tOne of the main challenges of wearable ECG sensors is the use of dry contact electrodes on a recording surface subject to movement artifacts. The current study demonstrates that OMsignal garments have a similar performance to a Holter monitor. As previously shown, such garments may have great potential in clinical settings. The cost of an OMsignal unit is quite low (180$ US), allowing a wider distribution of ambulatory monitoring. Patient set up and follow up are also simplified. Electrode placement is standardized using a sizing chart and once a patient is properly equipped, garments provide recordings of reproducible signal quality. The follow up is simplified as wireless transmission allows remote data transfer to a secured cloud and faster data processing. Combined with the rechargeable module, it would allow prolonged monitoring periods although this has yet to be demonstrated. Another challenge of prolonged recordings is the interaction between skin and the dry contact electrodes, which is minimized by the integrated electrodes of the garment. Wearable ECG sensors, like the OMgarments, are designed to integrate medical data acquisition into usual daily life activities. The emergence of artificial intelligence to monitor cardiac conditions opens the door for novel strategies of prolonged ambulatory monitoring ,26. BioiThis is a single-center study for a proof-of-concept that was conducted in healthy individuals. The sample size of this study is very modest, however, the crossover design with simultaneous Holter recording assured a true head-to-head design transforming each study subject into its own control. Performing a beat-by-beat analysis for signal coverage resulted in a large amount of quantitative data for the overall analysis. Therefore, we do not believe that the small sample size may have influenced the overall message of this study. All study subjects had a normal body mass index and there may be some uncertainty about the recording accuracy in individuals with extreme body weights. Overall signal quality was better in women, which is related to the better wearing fit of the OMbra. Despite that difference, the overall signal quality in men was still sufficient to establish a rhythm diagnosis in the vast majority of cases and there was no difference between males and females with regards to the accurate detection of heart rate and heart rate variability over 24 h. The present study was limited to a recording period of 24-h and a consistent signal quality over longer monitoring periods has yet to be demonstrated. An upcoming multicenter trial will address the utility of the wearable ECG sensors for mid- and long-term monitoring.In summary, the OMgarments (OMshirt and OMbra) represent a novel class of wearable ECG sensors characterized by its ease to use and a built-in capacity of short-term and long-term rhythm monitoring. Signal accuracy of the OMgarments is equivalent to standard Holter recording. The OMgarments provide high signal quality for adequate rhythm analysis and represent a promising technology for widespread use in ambulatory non-invasive ECG monitoring.


Three pathways are available to students considering a pediatric emergency medicine (PEM) career: pediatric residency followed by PEM fellowship (Peds-PEM); emergency medicine residency followed by PEM fellowship (EM-PEM); and combined EM and pediatrics residency (EM&Peds). Questions regarding differences between the training pathways are common among medical students. We present a comparative analysis of training pathways highlighting major curricular differences to aid in students’ understanding of these training options.All currently credentialed training programs for each pathway with curricula published on their websites were included. We analyzed dedicated educational units (EU) core to all three pathways: emergency department (ED), pediatric-only ED, critical care, and research. Minimum requirements for primary residencies were assumed for fellowship trainees.Of the 75 Peds-PEM, 34 EM-PEM, and 4 EM&Peds programs screened, 85% of Peds-PEM and EM-PEM and all EM&Peds program curricula were available for analysis. Average Peds-PEM EUs were 20.4 EM, 20.1 pediatric-only EM, 5.8 critical care, and 9.0 research. Average EM-PEM EUs were 33.2 EM, 18.3 pediatric-only EM, 6.5 critical care, and 3.3 research. Average EM&Peds EUs were 26.1 EM, 8.0 pediatric-only EM, 10.0 critical care, and 0.3 research.All three pathways exceed pediatric-focused training required for EM or pediatric residency. Peds-PEM has the most research EUs, EM-PEM the most EM EUs, and EM&Peds the most critical care EUs. All prepare graduates for a pediatric emergency medicine career. Understanding the difference in emphasis between pathways can inform students to select the best pathway for their own careers. Many physicians have elected to pursue career pathways focused on the care of children in the emergency setting. Focused training toward such a profession began in a non-accredited format in the early 1980s.All three pathways provide pediatric emergency care training in excess of what is required by the Accreditation Council for Graduate Medical Education (ACGME) training guidelines for both EM and pediatric residencies.Residency and fellowship programs are given autonomy by the ACGME to design their curricula in accordance with the resources of their institutions and the needs of their residents or fellows within approved training guidelines.We obtained a list of currently credentialed Peds-PEM, EM-PEM, and EM&Peds programs from the ACGME website in January 2018. Each program’s curriculum was obtained from its official website. Programs with insufficient curriculum or no curriculum posted on their websites were excluded. We analyzed dedicated educational units (EU) regarding time spent in the emergency department (ED) (adult or not specified between adult & pediatric), pediatric-only ED, critical care , and research. These were chosen as they are the most common for comparison purposes and make up the majority of EUs in each of the three pathways. The ACGME considers 12-month/year and 13-block/year EUs to be equivalent. EUs split between two experiences were assigned 0.5 EU to each area. Results were averaged for each of the three training pathways.What do we already know about this issue?There are three pathways toward a career in pediatric emergency medicine (EM), each with its own strengths and limitations.What was the research question?What are the differences between pediatric EM training pathways that students pursuing this career should understand?What was the major finding of the study?The curriculum of each pathway with their noted strengths can be used to guide students toward their ultimate desired careers.How does this improve population health?Students can identify their career path early in their training toward future careers focused on the care of children in the emergency setting.Peds-PEM and EM-PEM graduates were assumed to have fulfilled the minimum ACGME-required EUs during their primary residency and these were added to each fellowship’s totals prior to averaging. These include three EU pediatric-only ED and four EU critical care required to complete a pediatric residency, and five EU pediatric ED and four EU critical care required to complete an EM residency. Dedicated EUs spent in the ED for primary EM residents were assumed to be 21.8 based on the mean number for three-year EM residencies published in 2015 by Stowell et al.We identified a total of 113 active programs from the ACGME website . Of these, 64 Peds-PEM (85%) programs, 29 EM-PEM (85%), and 4 Peds-EM (100%) had published curricula on their official websites and were included. Results are tabulated in The EM-PEM training track demonstrated the most overall dedicated ED EUs (35.4) followed by EM&Peds (26.1) and Peds-PEM (20.4). Peds-PEM graduates have the most dedicated pediatric-only ED EUs (20.1) followed by EM-PEM (18.3) and EM&Peds (8.0). EM&Peds graduates have the most dedicated critical care EUs (10) followed by EM-PEM (6.5) and Peds-PEM (5.8). Peds-PEM graduates have the most dedicated research EUs (9.0) followed by EM-PEM (3.3), and EM&Peds (0.3).As all three pathways offer pediatric emergency training beyond what the primary residencies of EM or pediatrics offer, it is the route taken that will most affect the ultimate career options. The overlapping strengths of each provide an environment for the graduates of each training pathway to gain sufficient experience in both acute and critical care of the pediatric patient. The strengths and potential limitations of each pathway are highlighted in The Peds-PEM pathway offers the most overall training in pediatrics with a foundation of ambulatory and inpatient care in the primary residency followed by specialty training in pediatric emergency care during the fellowship. This requires both a residency and a fellowship match. The Peds-PEM route aims to train pediatricians first and then focus them into pediatric emergency physicians through a large amount of time spent in the pediatric ED with a targeted exposure to adult EM as required by the ACGME. There is a heavy focus on dedicated research time compared to the other pathways. Peds-PEM graduates are eligible for the PEM sub-boards co-sponsored by ABEM and ABP. The clinical scope of Peds-PEM is limited to patients <21 years of age, making children’s hospitals or EDs with a high pediatric volume the ideal career for these graduates. However, these age limits are noted to be arbitrary and 21 years is not a firm limit.4The EM-PEM pathway offers the most overall training in EM with a foundation of emergency and critical care in the primary residency followed by specialty training in pediatric emergency care during the fellowship. This requires both a residency and a fellowship match. The EM-PEM route aims to train emergency physicians first and then to focus them into pediatric emergency physicians through dedicated pediatric ED time and some subspecialty pediatrics. EM-PEM graduates are eligible for the PEM sub-boards co-sponsored by the ABP and the ABEM. The clinical scope of EM-PEM is all ages, although they are limited to an ED practice setting without the potential for pediatric ambulatory or inpatient medicine. EM-PEM duration of training is between five and six years. This is variable as students may choose to pursue a three- or four-year EM primary residency prior to their two-year fellowship.The EM&Peds pathway offers the broadest training of all pathways with complete training in both general pediatrics and emergency medicine. This requires only a residency match. The EM&Peds route aims to simultaneously train emergency physicians and general pediatricians, resulting in pediatric emergency physicians. Alhough this pathway has the least amount of pediatric-only ED EUs, the philosophy is to learn procedural skills and acute care principles through EM residency training and complete care of the pediatric patient through ambulatory and inpatient pediatric rotations. The result is not only an exposure to all aspects of pediatric and EM care but also a heavier focus on critical care compared to the other pathways.EM&Peds graduates are eligible for dual board certification in both EM and general pediatrics but have not been eligible for the PEM sub-board certification since 1998. Some centers, predominately freestanding children’s hospitals that care only for children, consider PEM sub-board certification a prerequisite which may be a limitation for EM&Peds graduates. However, the versatility of EM&Peds training may be a strength to centers that care for both adults and children. Many EM&Peds graduates work in academic, community, or rural centers.The EM&Peds physician and the Peds-PEM physician both share the primary pediatric board, allowing eligibility for additional ABP-sponsored fellowship training or shared time as a clinical pediatrician or pediatric hospitalist in addition to their EM practice. Similarly, the EM&Peds physicians and EM-PEM physician share the primary EM board allowing for EM fellowship training potential. Certainly, all of the pathways in pediatric EM provide a background for such physicians to take positions of advocacy and leadership in clinical and academic settings.10There are notable differences in the number of physicians trained through each pathway. A 2006 pediatric study referencing the Future of Pediatric Education II data revealed that at the time there were approximately 1300 ABP-certified Peds-PEM practitioners compared to only 170 ABEM-certified EM-PEM practitioners, a proportion that has likely continued to shift to less representation by EM-PEM physicians.13The reasons for this are not clear, although recently the ABEM EM to PEM taskforce has sought to address this difference. One possibility is that EM graduates do not seek to be further specialized as acute care of children is already within their scope of practice.Although possibly due to omission from their websites, PEM fellowship programs are not required to accept both pediatrics and EM candidates. This may indicate fewer available fellowship opportunities for the EM-PEM pathway compared to Peds-PEM or that EM-PEM trainees are required to complete three years at that fellowship instead of two.There were 48 postgraduate year 1–5 candidates enrolled in EM&Peds programs in the ABEM dataset, making it the second most common pathway chosen. Still the vast majority of pediatric emergency providers are Peds-PEM, making the EM&Peds pathway less well known by comparison. More research might reveal more subtle differences between the specifics of these training pathways as regards specific procedural experience, patient volume, or other metrics.What may be considered a limitation to one student may be a strength to another. An appropriate starting point may be whether the student wishes to care for adults or only children. Should students not wish to care for adults, a Peds-PEM pathway would be most suitable. If students would like to care for adults, the applicant would be directed toward either EM-PEM or EM&Peds. The difference here is eligibility for the PEM sub-boards and general pediatrics exposure for the EM&Peds graduate. EM-PEM graduates are eligible for sub-board certification, which may increase the likelihood for employment in some children’s hospitals or other centers that require subspecialty certification. EM&Peds graduates are no longer eligible for sub-board certification, which can be a deterrent to certain centers. However, EM&Peds graduates have a much broader scope of practice with the potential for more varied career paths including ambulatory and hospital pediatrics to which EM-PEM graduates do not have access. This may be attractive to centers looking to employ a provider in several clinical areas or departments. Students can certainly blaze their own trail within a given pathway but should be aware and well prepared for the path ahead of them.Data collected is limited to only those programs with a published online curriculum. By not polling programs directly, this does give an incomplete picture and may have failed to recognize more recent developments in certain programs. However, the authors felt that this approach was similar to that of a medical student researching future career options and was thus appropriately realistic with a relatively large sample size. Confirmation and clarification from programs would increase the overall accuracy of the available data by ensuring only the most recent/updated curriculum was used, and would add more data points by including programs without a publicly published curriculum.Longitudinal experience was not accounted for in the dataset as only dedicated EUs were included. Similarly, many training programs also incorporate clinical shifts into elective or research time. However, dedicated EUs are what is mandated by the ACGME as well as by the ABP and ABEM for board certification and thus are a better marker of the overall goals of training programs. The exact number of dedicated EUs that Peds-PEM and EM-PEM residents do during residency was estimated. However, all graduates from accredited pediatrics or EM primary residencies are eligible for the PEM fellowship, thus making the minimum number required a reasonable estimation. To our knowledge, a central resource with this depth of analysis and information was not previously available to medical students considering their career choices.Three training pathways lead to expertise in pediatric emergency medicine although with different career trajectories. Peds-PEM training is ideal for the student who does not wish to care for adults, although clinical career options may be limited to children’s hospitals or EDs with a high enough pediatric volume to sustain the narrower scope of practice. EM-PEM and EM&Peds pathways are similar, although the lack of sub-board eligibility for EM&Peds may be a limitation for clinical careers in centers that require the sub-board certification. The curriculum of each pathway can be used to guide students toward their ultimate desired career. Understanding the characteristics of current available paths will hopefully set students up for success in future careers focused on the care of children in the emergency setting.


Biro Psikologi (Psychology Bureau) UNY, amounting to 1046 students from Yogyakarta, Indonesia. Data were analyzed using item response analysis with the assistance of BILOG program.This article describes the item parameters analysis result of the space-relations subtest measurement. This subtest is part of the differential aptitude test (DAT) instrument. The item parameters are characteristic psychometric refer quality of the item. The Item parameters than analyzed in this instrument are item fit model, item difficulty, item discrimination, pseudo-guessing, item information curves, and test information function. The data was collected through documentation technique from the space-relation test conducted at  Specifications TableValue of the data•Presents item parameter of the space-relations subtest based on item analysis using item response theory.•The findings can be used as a reference for researchers or test developers in conducting item selection and creating question compilations, particularly that relates to space relations test.•This data can be used as a reference in making improvements for items that have inappropriate item parameters.1This research contains information on the psychometric characteristics of the space-relations sub-test items using items response theory. Item response theory is developed based on two postulates: (1) The examinee performance in a particular test could be predicted using a set of factors called latent traits, where traits are aptitude dimension of a person such as verbal ability, cognitive ability, and so on and (2) The relationship between examinee item performance and the traits that influence it is in accordance with monotonically increasing function called Item Characteristic Curve (1). These values consist of item difficulty (b), item discrimination (a), pseudo-guessing (c), item characteristic curve (ICC), item information function (IIF) and test information function (TIF). Based on the number of item parameter under the study for dichotomous data, there are three logistic models in the modern analysis that could be used; one-parameter (1-PL), two-parameter (2-PL), and three-parameter (3-PL) logistic model Standard Error of measurement (SEM) were representation the accuracy of test that explained latent variable Item information function (IIF) is a method IRT to explained the item representation, It shows the score accuracy of the items. Birmbaum 2This study aims to analyze the data documentation of psychological test results, namely space-relations. The findings could be used to evaluate existing measuring tools and developing it into a new format. Item parameter analysis of the instrument was done using a modern approach, namely item response theory (IRT). IRT is the analysis of characteristic instrument that focused on information item The research instrument is a space-relation test, part of a differential aptitude test (DAT). This instrument was adapted in Indonesia. The original instrument was composed by Bennet, Harold G. Seashore, & Wesman in 1947 1.A good level of item difficulty is at -2 to +2 2.A good item discrimination index criterion would be above 0 below 2 3.The pseudo-guessing index in the multiple-choice test is around one to the number of available answer choices An item is considered appropriate if it meets the item parameter criterion below:The analysis of test information function and the standard error of measurement (SEM) did by Matlab program. The information function of space-relations measurement test analyzed with 1, 2, and 3 logistic parameters. Test information function is described as having a low curve that initially increase, reaching the highest score in the middle before it goes down again away from the midpoint. The width of the curve shows the breadth of effective ability applied from the measurement results. TIF will be effective if the curve line extends above SEM line without having a cutoff point.


Electroencephalographic (EEG) activity in the gamma (30–80 Hz) range is related to a variety of sensory and cognitive processes which are frequently impaired in schizophrenia. Auditory steady-state response at 40-Hz (40-Hz ASSR) is utilized as an index of gamma activity and is proposed as a biomarker of schizophrenia. Nevertheless, the link between ASSRs and cognitive functions is not clear. This study explores a possible relationship between the performance on cognitive tasks and the 40-Hz ASSRs in a controlled uniform sample of young healthy males, as age and sex may have complex influence on ASSRs. Twenty-eight young healthy male volunteers participated (mean age ± SD 25.8±3.3) in the study. The 40-Hz click trains (500 ms) were presented 150 times with an inter-stimulus interval set at 700–1000 ms. The phase-locking index (PLI) and event-related power perturbation (ERSP) of the ASSR were calculated in the 200–500 ms latency range, which corresponds to the steady part of the response. The Psychology Experiment Building Language (PEBL) task battery was used to assess five cognitive subdomains: the Choice response time task, the Stroop test, the Tower of London test, the Lexical decision task and the Semantic categorisation task. Pearson‘s correlation coefficients were calculated to access the relationships; no multiple-test correction was applied as the tests were explorative in nature. A significant positive correlation was observed for the late-latency gamma and the mean number of steps in the Tower of London task reflecting planning and problem-solving abilities. These findings support the concept that 40-Hz ASSR might highlight top-down mechanisms which are related to cognitive functioning. Therefore, 40-Hz ASSRs can be used to explore the relationship between cognitive functioning and neurophysiological indices of brain activity. Accumulating evidence suggests that electroencephalographic (EEG) activity in the gamma 30–80 Hz) range is related to the information processing associated with a variety of sensory and cognitive processes such as perception ,2, atten0–80 Hz rThe auditory steady-state response (ASSR) is the electrical response of the brain to regularly repeating auditory stimuli  that is In line with the latter view, some evidence supports the link between gamma-range ASSRs and cognitive functions. First, the wide thalamo-cortical networks are involved in the generation of ASSRs –36, thouHowever, the analysis of the relationship between parameters of 40-Hz ASSRs and the basic cognitive abilities is limited to a few studies. Of those, several studies failed to show any correlation between ASSR and cognitive parameters in both patients and controls ,50 or thThe present study aims to explore the possible relationship between the complex information processing and the 40-Hz ASSRs in a uniform sample of young healthy males. The complex information processing refers to the most basic operations of the human mind that are essential both for higher cognitive abilities and in everyday living . The terThirty healthy non-smoking right-handed males  particiEach participant was given a brief description of the procedure prior to the testing. The Psychology Experiment Building Language  based taReaction times (RTs), number of errors and response efficiency (as a mean reaction time divided by the proportion of correct responses on the test) were used as the outcome measures in the Choice response time task and Stroop test in all three conditions . The CRT task was used to measure reaction time and psychomotor information processing speed ,63; SOO ®Arduino,https://www.arduino.cc/) and presented binaurally through Sennheiser HD 280 PRO earphones; sound pressure level was adjusted to 60 dB with a DVM 401 dB meter . Participants were asked to focus on stimulation and try to fixate their gaze at the fixation cross on the computer screen in front of them.The 40-Hz click stimulation trials lasted 500 ms and consisted of 20 identical clicks. Each 40-Hz trial was presented 150 times with an inter-stimulus interval set at 700–1000 ms. The auditory stimuli were generated by Arduino Uno microcontroller  and a 64 channel WaveGuard EEG cap  with Ag/AgCl electrodes. Mastoids were used as a reference; the ground electrode was attached close to Fz. Impedance was kept below 20 kΩ and the sampling rate was set at 2048 Hz. Vertical and horizontal electro-occulograms (VEOG and HEOG) were recorded from above and below the left eye and from the right and left outer canthi.The off-line processing of EEG data was performed in EEGLAB and ERPWAVELAB for MatLab ,63. The Epochs of 1200 ms were created starting at 500 ms prior to the stimulus onset and lasting for 700 ms post-stimulus onset; the epochs were further inspected for remaining artefacts. The data were baseline-corrected to the mean of the pre-stimulus period. A wavelet transformation  was performed.Phase-locking index (PLI), corresponding to the phase consistency over epochs, was calculated . The eveThe mean PLIs and ERSPs were extracted focusing on the frequency window of 35–45 Hz by averaging the data over 200–500 ms. Data were baseline-corrected by subtracting the mean of the pre-stimulus period of 200 ms prior to the stimulus onset. In the next step PLI and ERSP values were grouped for the left , central , and right  regions.Pearson‘s correlation coefficients were calculated to assess the relationship between mean PLI and ERSP values of the 40-Hz ASSR and measures of cognitive tasks. P values less than 0.05 were regarded as significant and no multiple-test correction was applied as the tests were exploratory in nature. The PLI and ERSP values between the regions (left vs. center vs. right) were compared by means of one-way ANOVA with subsequent post hoc tests. Statistical evaluation was performed using SPSSv20 .The topographies of PLIs and ERSPs in response to 40-Hz stimulation within 0–500 ms range in 100 ms windows are presented in Performance on cognitive tasks was similar to the results of previous research . Means aPearson’s correlation coefficients and corresponding p values for correlation between PLIs/ERSPs in response to the 40-Hz stimulation and cognitive indices are presented in The involvement of the gamma activity in various cognitive functions is a well-documented finding ,70 as arThe Tower of London (ToL) task reflects executive function, planning and problem-solving ,71. UnexCazalis et al.  have sugWe did not evaluate some domains that were shown to be correlated to 40-Hz ASSR measures before, like abstract verbal reasoning  or workiOnly young male subjects were enrolled in the current study, thus any potential gender-related aspects were avoided. Some of the employed cognitive tasks are known to be differently performed by males and females  and 40-HAuditory stimulation is frequently used to test gamma activity as it produces the strongest EEG responses in the gamma range –81. HoweFinally, ASSR assessment approach could influence the observed relationships. As detected in the current study, weak correlations between measures over the central locations  of the response and the mean number of steps on the Tower of London task was observed. This association potentially indicates that the late-latency gamma in response to auditory 40-Hz stimulation might index abilities for planning and problem-solving. The finding supports the concept that 40-Hz ASSR might highlight the top-down mechanisms which are related to cognitive functioning and can be a useful tool to explore the relationship between cognitive functioning and neurophysiological indices of brain activity.


Detection of biomarker genes and their regulatory doses of chemical compounds (DCCs) is one of the most important tasks in toxicogenomic studies as well as in drug design and development. There is an online computational platform “Toxygates” to identify biomarker genes and their regulatory DCCs by co-clustering approach. Nevertheless, the algorithm of that platform based on hierarchical clustering (HC) does not share gene-DCC two-way information simultaneously during co-clustering between genes and DCCs. Also it is sensitive to outlying observations. Thus, this platform may produce misleading results in some cases. The probabilistic hidden variable model (PHVM) is a more effective co-clustering approach that share two-way information simultaneously, but it is also sensitive to outlying observations. Therefore, in this paper we have proposed logistic probabilistic hidden variable model (LPHVM) for robust co-clustering between genes and DCCs, since gene expression data are often contaminated by outlying observations. We have investigated the performance of the proposed LPHVM co-clustering approach in a comparison with the conventional PHVM and Toxygates co-clustering approaches using simulated and real life TGP gene expression datasets, respectively. Simulation results show that the proposed method improved the performance over the conventional PHVM in presence of outliers; otherwise, it keeps equal performance. In the case of real life TGP data analysis, three DCCs  for glutathione metabolism pathway dataset as well as two DCCs (acetaminophen-medium and methapyrilene-low) for PPAR signaling pathway dataset were incorrectly co-clustered by the Toxygates online platform, while only one DCC (hexachlorobenzene-low) for glutathione metabolism pathway was incorrectly co-clustered by the proposed LPHVM approach. Our findings from the real data analysis are also supported by the other findings in the literature. We denote this average value by F for the convenience of further use. In toxicogenomic data the expression profile of a subset of genes is highly correlated across a subset of conditions/treatments |). If there are extreme values of |F| the logistic transformation bring them within the range of 0–1. The other transformation methods like Box-Cox family of power transformation returns unbounded value for the extreme one. The observed n×m (gene-DCCs) fold change gene expression data matrix consisting of G =  genes and C =  DCCs is transformed using logistic functionThere are two ways to obtain robust estimates in presence of outlying observations (1) applying the robust methods (2) applying conventional methods on the modified dataset. The modification of the outlier contaminated dataset can be done deleting the outlying observations from the dataset or applying transformation on the dataset. Nonetheless, application of robust methods is complicated than using the conventional methods and deletion of outlying observations loses the information of the dataset. Hence, transformation is the better option for reducing outlier effects. Several authors  as the count value for applying PHVM.Similar to other works  genes and C =  DCCs. LPHVM assumes that there prevail a certain number of unobserved hidden co-clusters or clusters underlying the gene-DCC count valued data matrix. We have estimated the number of co-clusters (k) in the dataset using gap statistic algorithm proposed by Tibshirani et al.  the model quantifies the relationships Pr(Gi|Hr), Pr(Cj|Hr), and Pr. The following are the probability definition and underlying assumptions of LPHVM accordingly: (1) Pr(Hr) is the probability of the rth co-cluster/cluster and Pr(Gi|Hr) is the probability of the ith gene over the rth co-cluster and Pr(Cj|Hr) is the probability of the jth DCC over the rth co-cluster and Pr is the joint probability of the ith gene and the jth DCC and Gi, Cj) considering hidden co-cluster Hr as follows:In order to perform robust co-clustering between genes and DCCs we propose LPHVM approach. We define LPHVM as the application of PHVM on the count valued dataset which is obtained transforming absolute value of the fold change gene expression data by logistic transformation. For this standpoint, let us consider i et al. . IntroduWhere,Pr can be written asApplying Bayes' rule, the gene-DCC joint probability So as to estimate the parameters of the model, we need to maximize the total likelihood of the observations:We have applied the widely used Expectation-Maximization (EM) algorithm  and Pr(Cj|Hr) have been estimated the genes and DCCs are clustered independently and co-clustered simultaneously. The gene (Gi) and DCC (Cj) will belong to co-cluster r ifOnce the parameters Gi) and the DCC (Cj) is grouped into a co-cluster (r) and this pair has the highest joint probability Pr in that co-cluster ) of gene-DCC within the co-clusters. The co-cluster having largest average joint probability contains most important biomarker genes and their regulatory DCCs and so on. The non-biomarker genes and non-regulatory DCCs in a dataset of a particular pathway are filtered in a co-cluster by LPHVM which have the smallest average joint probability. Except this co-cluster  others are the co-clusters of biomarker genes and their regulatory DCCs and we define these co-clusters as biomarker co-clusters. We extract the toxicogenomic biomarker genes and their regulatory DCCs from these biomarker co-clusters.As described in section “logistic transformation of gene expression data” the biomarker genes form co-clusters with their respective regulatory DCCs. Additionally, the non-biomarker genes in a pathway form another co-cluster with non-regulatory DCCs. The LPHVM grouped the genes and DCCs simultaneously to their respective co-clusters. Zhu et al.  has showlth dose level of the tth chemical compounds if Pr matrix. The biomarker gene regulatory DCCs are ranked according to their average joint probability value over all biomarkers. We also rank the relationships among biomarker genes and their regulatory DCCs based on their joint probability. The ranking is made considering the formula:The biomarker co-clusters consisting of biomarker genes and their regulatory DCCs are separated from the whole gene-DCC fold change data matrix which is discussed in the previous section. Within this co-clustering matrix a subset of biomarker genes may be upregulated corresponding to a subset of DCCs or downregulated corresponding to another subset of DCCs. These can be observed from the average fold change value Zj is the average joint probability of a DCC over the biomarkers or Zi, j is the joint probability of gene Gi and DCC Cj within the biomarker co-clusters.where We investigate the robustness of the proposed (LPHVM) algorithm and conventional PHVM using simulated datasets in absence and presence of outliers in the dataset based on the co-clustering /clustering error rate (ER). The genes and DCCs which are considered in one co-cluster/cluster in the simulated data are incorrectly assigned in another co-cluster/cluster by the PHVM or LPHVM is considered as the miss co-clustered/clustered observations. The ER is the percentage of miss co-clustered/clustered observations which is calculated as:For detecting the toxicogenomic biomarker genes and their regulatory DCCs from the pathway level toxicogenomic dataset using LPHVM the following steps are to be considered for desired outputs:Step 1: Obtain gene expression data of treatment and control group of animals from the toxicogenomic experiment  and D2(n = 50 × m = 60) imitating the toxicogenomic experiment given in Figure Ytlq) have been generated using the following model:To investigate the performance of the proposed LPHVM algorithm over the conventional PHVM we have simulated two sets of pathway level fold change gene expression data F11and +F21 represent the fold change expression values for upregulated genes under the DCCs group 1 and 2, respectively. Similarly, –F12, and –F22 represent the fold change expression values for the downregulated genes under the DCCs group 1 and 2, respectively. The 0s represent there is no compound effects on the respective gene group and N represents the random error term generated from normal distribution with mean 0 and variance σ2. Now if we take absolute value of the fold change gene expression data generated from the above data generating model (2), the fold change gene expression data +F11 and –F12 will merge into a single gene group-1 and make a co-cluster with their correlated DCCs group-1. Accordingly, +F21 and –F22 will merge into a single gene group-2 and make a co-cluster with their correlated DCCs group-2. The rest of the genes which are not regulated by any DCCs make a gene group-3 and the DCCs that do not regulate the expression pattern of genes make a DCCs group-3. The gene group-3 and DCCs group-3 together will make another co-cluster. These co-clusters can be retrieved by the LPHVM. In the simulated datasets n represents the number of genes  and m represents the number of DCCs . The data generation procedures for D1 and D2 datasets are given in the In the above model, +in vitro and in vivo experiment of human and rat model. Presently, pathway based analysis in cancer research has also advanced promptly since pathway level analysis able to produce more stable biomarkers . Because the compounds' toxicity at 24 h time point is more visible compare to other time points  and within co-cluster average joint probability of gene-DCC are given in Table D1. Similarly, for D2 dataset co-cluster-3 produces the smallest average joint probability of gene-DCC (Table D1 and D2 datasets.We investigate the performance of our proposed method (LPHVM) by comparing it with the conventional PHVM using simulated datasets d Figure . For calCC Table  for bothReactive oxygen species (ROS) are produced by living organisms as a normal product as a result of normal cellular metabolism. However, in presence of environmental pollutants or toxic chemical the production of ROS increased dramatically. It is highly reactive molecules and can damage cell structures such as carbohydrates, nucleic acids, lipids, and proteins and alter their functions. In the liver, glutathione is an important antioxidant; a major detoxification player which scavenges ROS. Thus imbalance in the abundance of ROS and glutathione/antioxidant in favor of ROS in the liver in presence of toxic chemicals/drugs causes' drug induced liver injury. Subsequently, gene expression changes occur simultaneously in response to the glutathione depletion or after the glutathione depletion   PPARIdentification of biomarker genes and their regulatory DCCs is one of the most important tasks in the toxicogenomics studies as well as in drug design and development as mentioned before. In this article, we have proposed a robust co-clustering approach based on logistic probabilistic hidden variable model (LPHVM) to detect important biomarker genes and their regulatory DCCs. The proposed LPHVM approach is robust against outlying gene expressions and more flexible and effective than the application of one-way classical clustering approaches  for co-clustering. The proposed method produces robust results by using the logistic transformation of fold-change gene expression data into the conventional PHVM approach. The logistic transformation reduces unusual/outlying observations into the reasonable space without changing the original hidden patterns of genes and DCCs in the dataset. Thus the proposed LPHVM approach produces robust results.We investigated the performance of the proposed LPHVM method in a comparison with the traditional PHVM and Toxygates online computational platform using simulated and real life TGP gene expression data, respectively. The simulation results showed that the proposed method improves the performance over the conventional PHVM in presence of outlying observations; otherwise, they perform equally. We also demonstrated the performance of the proposed method in a comparison with the online computational platform “Toxygates” using the real life pathway based fold change gene expression datasets collected from the “Toxygates” database. We observed that three DCCs  for glutathione metabolism pathway dataset as well as two DCCs (acetaminophen-medium and methapyrilene-low) for PPAR signaling pathway dataset were incorrectly co-clustered by the Toxygates online platform, while only one DCC (hexachlorobenzene-low) for glutathione metabolism pathway was incorrectly co-clustered by the proposed LPHVM approach. Our findings from the real life data analysis are also supported by the other findings in the literature (Kiyosawa et al., http://www.bbcba.org/softwares/rCoClust.zip.The demo data and R-code are provided at MH and MM worked together to develop the algorithm. MH analyzed the data and drafted the manuscript. MM coordinated and supervised the project. MMR, AB, and MR attended at the meeting regarding this article as well as read and approved the final version of 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.


Dysplastic gangliocytoma or Lhermitte-Duclos disease is a rare disorder characterized by a slowly progressive unilateral tumour mass of the cerebellar cortex. It is probably hamartomatous, although the exact pathogenesis remains unknown. Lhermitte-Duclos disease was recently encountered to be part of a multiple hamartoma-neoplasia complex (Cowden's syndrome). It typically presents in young adults, although it has been encountered at all ages. We present the case of bilateral cerebellar location of this pathology in a 50-year-old man presented with a progressive onset and worsening of headaches accompanied by nuchal rigidity, photophobia and nausea awakening each morning. Upon physical examination, the patient was awake with a discrete right vestibular syndrome made of positive Romberg without nystagmus. Magnetic Resonance Imaging (MRI) was performed and revealed salient “tiger stripe” appearance of the bilateral cerebellar cortex relevant to a Lhermitte-Duclos disease. Dysplastic gangliocytoma or Lhermitte-Duclos disease is a rare disorder characterized by a slowly progressive unilateral tumour mass of the cerebellar cortex. It is probably hamartomatous, although the exact pathogenesis remains unknown. Lhermitte-Duclos disease was recently encountered to be part of a multiple hamartoma-neoplasia complex (Cowden's syndrome). It typically presents in young adults, although it has been encountered at all ages. Interestingly the genetics of childhood-onset appears different to the more common adult onset form.It is about a 50-year-old man with no particular medical history who was admitted for a progressive onset and worsening of headaches over 4 months with by nuchal rigidity, photophobia and nausea awakening each morning without epilepsy or other localization signs. Upon physical examination, the patient was conscious with a discreet right vestibular syndrome made of positive Romberg without nystagmus or motor palsy. Cerebral MRI  was perfThe Lhermitte-Duclos disease, or dysplastic cerebellar gangliocytoma, is an unusual tumour arising from the cerebellar cortex. It most frequently presents in the third and fourth decades of life , 2 but tDysplastic gangliocytoma of the cerebellum is of benign behaviour and its incidence is extremely rare. Its origin is still debatable. This lesion is hypo intense on T1- and hyper intense on T2-weighted MRI. Recognition of the disease is of particular importance, as the frequent but under-reported coexistence with Cowden syndrome, should prompt thorough clinical and apparative investigation to detect or exclude concomitant malignancies.The authors declare no competing interests.


The results of recent diffusion tensor imaging (DTI) studies on amyotrophic lateral sclerosis (ALS) are inconclusive and controversial. We performed a voxel-based meta-analysis to identify a statistical consensus among published DTI studies of altered white matter (WM) microarchitecture in ALS.A systematic search was conducted for relevant studies that used voxel-wise analyses of WM microarchitecture in patients with ALS. Anisotropic effect size-signed differential mapping (AES-SDM) was applied to analyze fractional anisotropy (FA) differences between ALS patients and healthy controls. Meta-regression analysis was used to explore the effects of clinical characteristics on WM integrity in patients with ALS.A total of 14 studies with 16 datasets that included 396 patients and 360 healthy controls were identified. The pooled meta-analysis revealed that patients with ALS exhibited significant FA reductions in two clusters relative to healthy controls. The largest cluster exhibited a peak coordinate in the left corona radiata, extending to the body and splenium of the corpus callosum, left superior longitudinal fasciculus, posterior limb of the internal capsule, right corona radiata, and bilateral cingulate gyrus. The other cluster exhibited decreased FA in the right corticospinal tract that extended to the right cerebral peduncle. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score was positively correlated with the FA reduction in the left corona radiata. Mean age and illness duration were not linearly correlated with the FA reductions.This study provides a thorough profile of WM microarchitecture alterations in patients with ALS and further evidence that the neuronal degeneration is not limited to the corticospinal tract but also includes extra-motor areas, which supports the view that ALS is a multisystem degenerative disorder that involves the white matter. •To identify statistical consensus between published DTI studies in ALS•Two consistent clusters of FA reductions in patients with ALS.•ALS is a multisystem degenerative disorder involving the WM. ALS is a disease with an insidious onset, and there is a long period before typical symptoms begin appearing. The overall lifetime prevalence rate is 1:400, and most patients die within 3–5 years of symptom onset  is now the leading technique in the search for biomarkers  and currently assists with the diagnosis of ALS substantially.Amyotrophic lateral sclerosis (ALS) is a neurodegenerative, age-related and predominantly male disease that may result in the progressive loss of bulbar and limb function. om onset . The diaom onset . With thIn recent years, psychoradiology  which stA previous meta-analysis found FA reductions in the bilateral frontal WM and the posterior limb of the bilateral internal capsule . HoweverOur purposes in conducting this meta-analysis are as follows: first, to quantitatively summarize the 14 most relevant DTI studies (16 datasets met the inclusion criteria) concerning FA abnormalities in patients with ALS using a newly developed meta-analysis technique, anisotropic effect size-signed differential mapping (AES-SDM), which has the potential to quantify the reproducibility of neuroimaging findings and produce insights that are difficult to obtain from individual studies; second, to perform subgroup meta-analyses that include only studies with methodological homogeneity to avoid the potentially confounding effects of different methodologies; third, to use a meta-regression method to assess the potential effects of mean age, age at onset, duration of disease, and ALSFRS-R score on the reported WM abnormalities.22.1We searched PubMed, EMBASE, Web of Science, Cochrane Library and Science Direct to find relevant literature published articles between January 1994 and November 2016 and “in press” articles. All follow a systematic and extensive retrieval strategy. The search keywords were  and (“diffusion tensor” or “DTI” or “diffusion magnetic resonance imaging”). Additionally, the reference lists of both eligible articles and review articles were manually screened to avoid omitting.2.2All studies found in our search were assessed. The studies included in the meta-analysis met all of the following inclusion criteria: (i) original articles published in peer-reviewed English-language journals; (ii) studies comparing the FA values of WM areas between patients with ALS and healthy controls; and (iii) studies that detected FA alterations in whole-brain analyses and reported the results in Talairach or Montreal Neurological Institute coordinates. The corresponding authors of studies that met all of the above inclusion criteria but lacked global brain coordinates were contacted to obtain additional information.The exclusion criteria for this meta-analysis were as follows: (i) studies that were case reports or reviews; (ii) studies involving familial ALS patients; (iii) studies that lacked an health control group; and (iv) studies using overlapping research samples from different publications . Additionally, our meta-analysis also defers to the guidelines of Meta-analysis of Observational Studies in Epidemiology (MOOSE) .The three-dimensional coordinates in each study were also extracted for the meta-analysis according to the AES-SDM methods . Its main feature is the possibility of combining peak coordinates and statistical parameter map, and use of statistical data has been established and the differences between accounting research . The authors did this independently and based on the AES-SDM method , clinical data , data processing method, statistical thresholds. M method . Discuss2.3We performed a voxel analysis to identify FA differences between ALS patients and healthy controls, and AES-SDM software was used according to standard procedures. To examine the reproducibility, we performed systematic whole-brain voxel-based jack-knife sensitivity analysis. This method consists of iteratively repeating the pooled meta-analysis while discarding a different data set in each iteration to determine whether a discovery was replicable . We alsohttp://sdmproject.com/software/Tutorial.pdf) and previous literature , and the results were overlaid on a high-resolution brain image template created by the International Consortium for Brain Mapping. The WM bands were plotted with DTI query software (http://graphics.stanford.edu/projects/dti/) by displaying the brain regions with significant FA differences and by means of a map of the human WM anatomy  compared with 360 healthy controls . In one study , the ALS3.2The pooled meta-analysis revealed that patients with ALS exhibited significant FA reductions in two clusters relative to healthy controls, as illustrated in 3.3The whole-brain jack-knife sensitivity analysis of the pooled meta-analysis showed that the decreased FA in patients with ALS in the left corona radiata was highly replicable; this decrease was preserved throughout all 16 combinations of the datasets. The results regarding the right corticospinal tract remained significant in all but 4 combinations of the datasets .3.4The subgroup analyses revealed that the cluster in the left corona radiata remained unchanged in all of the subgroup analyses. In the SPM (n = 9 datasets) and TBSS (n = 6 datasets) subgroups, the cluster in the right corticospinal tract remained unchanged, but the FSL/TIFT (n = 7 datasets) and VBA (n = 10 datasets) subgroup analyses failed to detect this cluster.3.5p = 0.000023474; 349 voxels) as illustrated in Meta-regression analysis found a positive correlation between the ALSFRS-R score and FA reduction in the left corona radiata  is more helpful for illuminating alterations in white matter microstructure. Unfortunately, most of the studies included in the present meta-analysis did not report the alterations in other diffusion parameters. Finally, another limitation is related to document bias. Although we attempted to include as many studies as possible (even if they were negative), the possibility of publication bias could not be ruled out altogether.There are still some limitations in the current study. First, similar to previous voxel-based meta-analyses, small sample size limits the generalization of results, especially in subgroup analyses. 6In summary, this meta-analysis revealed two consistent clusters of FA reductions in patients with ALS. The largest cluster was located in the left corona radiata, extending to the body and splenium of the corpus callosum, left superior longitudinal fasciculus, posterior limb of the internal capsule, right corona radiata, and bilateral cingulate gyrus, as well as involving the left corticospinal tract, left superior longitudinal fasciculus and the interhemispheric fibers running through the CC. The other cluster of decreased FA was in the right corticospinal tract, extending to the right cerebral peduncle. Furthermore, the FA reduction in the left corona radiata can reflect the severity of the disease to some degree. This study provides a thorough profile of WM microarchitecture alterations in ALS and further evidence that the neuronal degeneration is not limited to the corticospinal tract but also includes extra-motor areas, which supports the view that ALS is a multisystem degenerative disorder involving the WM.The authors declare no conflict of interest.