Sessions were delivered at home with blinded outcome assessments. The primary outcome was a composite of attention measures jointly analysed via a multivariate ANCOVA with a combined effect size (ES) from coefficients at baseline, midpoint and endpoint (Registration: ISRCTN37683928). Uptake and compliance was good but intention-to-treat analysis showed no significant differences between 20 intervention and 23 control infants on primary  or secondary outcomes . There were no adverse effects on sleep but a small increase in post-intervention session fussiness. Although feasible, there was no support for short-term effects of gaze-based attention training on attention skills in early ADHD. Longer-term outcomes remain to be assessed. The study highlights challenges and opportunities for pre-emptive intervention approaches to the management of ADHD.Attention-deficit/hyperactivity disorder (ADHD) is first diagnosed during middle childhood, when patterns of difficulty are often established. Pre-emptive approaches that strengthen developing cognitive systems could offer an alternative to post-diagnostic interventions. This proof-of-concept randomised controlled trial (RCT) tested whether computerised gaze-based attention training is feasible and improves attention in infants liable to develop ADHD. Forty-three 9- to 16-month-old infants with a first-degree relative with ADHD were recruited (11/2015–11/2018) at two UK sites and randomised with minimisation by site and sex to receive 9 weekly sessions of either (a) gaze-contingent attention training (intervention;  Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by inattention, hyperactivity and impulsivity with an estimated prevalence of around five percent in the general population , 2. ADHDPreventative strategies offer an alternative to the non-pharmacological management of ADHD. The benefits of cognitive training could be increased and the likelihood of ADHD reduced through targeting brain systems during periods of increased plasticity in early development. Indeed, there is emerging evidence that ADHD-related atypicalities in attention systems may be present in infancy long before the emergence of the disorder . Could tOf note, full methodological details can be found in .INTERSTAARS was a blinded Phase 2 randomised controlled trial at 2 sites in the United Kingdom. Ethical approval was obtained from the London Central NHS Research Ethics Service (15/LO/0407). Parents of all participants provided written informed consent. A study Data Monitoring and Ethics Committee (DMEC) of an independent psychiatrist chair, statistician and ethicist was appointed, and convened three times during the setup and course of the trial.Forty-three 9- to 16- month-old infants with a first-degree relative (parent or older sibling) with a clinical or probable diagnosis of ADHD were randomised .Inclusion criteria were (1) residence within a 2-hour travel distance from either London or Southampton, (2) at least one parent/caregiver who is fluent in English and, (3) a first-degree relative with a confirmed clinical diagnosis or research-probable diagnosis of ADHD. Where ADHD diagnosis had not yet been confirmed through clinical services, eligibility was confirmed using age appropriate standardised screening questionnaires to establish a probable research classification  web-based service with minimisation over trial site and infant sex. Allocation was performed and automatically emailed to a trained researcher when they logged into the KCTU system.Researchers who administered the baseline and outcome assessments were blind to treatment condition. To maintain parent blindness, the number of home visits, contact with trainers, and set-up procedures were the same in the intervention and control groups. Data processing from control/intervention sessions and for primary outcome metrics were processed and extracted by researchers blind to group allocation. Analysis was completed using uninformative treatment labels. Subsequent to unblinding, recovery of data from three baseline eye-tracking sessions required analysis scripts to be rerun; interpretation of results did not change.Study flow is shown in Fig. Each training/control session involved two trained researchers visiting the family’s home with the eye-tracking equipment (Tobii X2-60) Figure  – S5. AdSix training games per session were run using in-house software (built in MATLAB R2016a with Psychophysics Toolbox3). Each training game was played for a maximum of 300 seconds, or until the infant became fidgety and disengaged for 20 seconds or more. If the infant had engaged with the game for fewer than 240 seconds , the experimenters attempted to re-present the game again later in the training session. The software automatically recommended game order, which was pseudo-randomised across training visits (SM1.4). The games are described in full in Goodwin et al.  and SM1.Infants in the control group viewed infant-friendly but non-gaze contingent television clips under a similar procedure to the intervention and run using Task Engine 3 (built in MATLAB R2016a with Psychophysics Toolbox3 ). The seSustained attention: Infants watched five repetitions of each of two complex pictures each presented until the infant looked away for >1 second. The longest of the five individual looks towards each stimulus were averaged. A minimum of 4 ‘looks’ per infant (in either of the two blocks) was required.Disengagement: Infants were presented with a minimum of 48 trials in which a central stimulus was followed by a peripheral stimulus that either did (Overlap) or did not (Baseline) overlap in time with the central stimulus. Disengagement scores were computed as the logged difference between mean saccadic reaction times in the Baseline and Overlap conditions. A minimum of 5 valid trials for the baseline and overlap conditions was required.Cognitive control: Infants were presented with 18 trials in which after fixating a central fixation point, a pair of rectangles was presented. 2 seconds later or when a rectangle is fixated, a video appears on one side of the screen. After 9 trials, the location of the video was reversed. Cognitive control is measured as the percentage of trials in which infants correctly anticipate the location of the target stimulus across both phases. A minimum of 2 trials with anticipations (either correct or incorrect) per phase  per block was required.The pre-specified primary outcome was a composite of measures (SM1.6) assessed at baseline, intermediate and endpoint. Designed to assess changes in infant attention control, the components were selected based on their responsiveness to attention training in previous studies and their widespread use in infant attention research . BecauseFor all tasks, the software computed an initial rapid estimate of validity in real time. If the validity criterion was not met at the end of the planned presentation trials, further ‘catch-up’ blocks were presented until the criterion was met. Of note, validity was then re-computed offline with more time-intensive but accurate methods and additional data could be considered invalid at this stage (see SM1.6).Parent-report measures of infant executive attention were assessed by the Infant Behavior Questionnaire-Revised shortened version ; specifiObservational measures of infant attention to toys were assessed during the 3-minute task orientation episode from the Laboratory Temperament Assessment Battery, Lab-TAB . BehavioObservational measures of infant social attention skills were assessed using the Early Social Communication Scales . ResponGeneral inattentiveness was measured by proportion of missing eye tracking samples in the stimulus presentation area across the entire 20-minute eye-tracking battery.Individual components of the primary composite were analysed separately.The following secondary outcomes were selected to assess whether changes in infant attention control were seen in more naturalistic contexts.Infant sleep: Parents completed a Sleep Diary (SM1.9) the night before, and the night following each intervention session reporting the amount of sleep during the day and during the night (minutes), and the number of times the infant woke during the night.Infant fussiness: Parents completed a fussiness scale (SM1.10) rated on a 1 to 5 scale for the afternoon of each intervention session, and for the afternoon of the previous day.There have been no previous reports of any adverse effects of the training games. Though adverse effects were not expected based on previous studies using these training games, the monitoring of adverse events is important in early intervention studies . ThroughISRCTN37683928).The full Statistical Analysis Plan (SAP) was associated with Protocol version 3.0 and signed off by the DMEC and published online  approach, a multivariate analysis of covariance was fitted using maximum likelihood within the structural equation modelling (SEM) framework in Stata’s sem procedure. This allowed for an unstructured correlation matrix between the outcome components and was estimated by full maximum likelihood (Stata v15.1). Measures were assumed conditionally multivariate normal and missing values Missing-At-Random (MAR). Baseline and follow-up measures were treated as dependent variables with a design matrix of predictors that allowed factors for randomisation (sex and study site) and treatment group set to zero at baseline and a different error variance at baseline, midpoint, and endpoint with non-zero covariances over time and across indicators. Normal probability plots of residuals were examined. The model also provided correlation estimates of measurement reliability.The above model provided six parameter estimates for treatment effect . Using the baseline standard deviation of each component, effect sizes were combined using the lincom post-estimation command (which takes the correlation among estimates into account), equally weighted across components but on the assumption that for each component the effect by mid-point would be half that achieved by endpoint. The 95% confidence interval for this combined ES was calculated using 1000 bootstrap samples.The sign of the effect size for the disengagement component was reversed such that higher values denoted outcomes associated with older age, in line with the other two eye-tracking components. A Complier-Average-Causal Effect (CACE) analysis was conducted (SM1.11).All secondary outcomes were continuously scored and analysed using a SEM setup that assumed bivariate normality of baseline and endpoint measures. All treatment group effects were adjusted for sex and study site except for the two Early Social Communication Scales (ESCS) that were further adjusted for age at administration.For adverse events, averaged over sessions the before-minus-after difference scores were calculated for each participant for day and night sleep duration, and for fussiness. The group difference-score means were compared using t-tests.n = 23) and Training (n = 20) groups (see Table After an extended period of 36 months of recruitment (11/2015–11/2018) 43 . The additional unplanned instrumental variable analysis of the effect of duration of Active Training was also non-significant .The CACE estimates the effect of a satisfactorily completed treatment schedule while accounting for the fact that those who comply may be systematically different from non-compliers. The CACE composite was not significant . To assess whether there were any lasting effects on temperament, we conducted a DMC-approved non-prespecified examination of the IBQ-R Negativity composite  analysed in the same way as the other IBQ-R scales. No group difference was found .From the 17 controls and 15 training families who reported, hospital presentations were reported for three control  and two training infants . The change in day and night sleep durations before and after a session showed no group difference (SM2.6). However, the training group were reported as showing a relatively greater increase in fussiness from before to after a session  than the control group  that was significant but small . This resulted in a physical eye-tracking set-up that was acceptable to families and could be applied in the home to collect robust, high quality data. Indeed, the data we collected in the home was of sufficient quality to pass our strict quality assessment thresholds for selection as the primary outcome composite. We employed an active control arm that was matched in visit number, duration and protocol as closely as possible with the training arm, indicating that rigorous control designs are feasible in this population. Further, feedback questionnaires completed at the end of the trial indicated that families enjoyed participating in the study (SM2.7), with over 90% of respondents reporting that the visits were enjoyable or very enjoyable, 100% reporting that the sessions were of a suitable duration, and 100% reporting that the staff who visited their home were excellent. When asked what they found to be the most enjoyable part of the study, a key theme that emerged was seeing their infant’s behaviour. For instance, one parent reported that the most enjoyable part of the study was seeing their infant “learn how the sessions worked and remembering things”, while another reported that the most enjoyable part for them was “observing [their] baby’s reaction”. Another parent reported that their infant “really enjoyed the weekly visits” and that “watching his confidence grow was good.” This positive feedback provides strong encouragement for future home-based deployment of eye-tracking-based assessments and interventions for this population.M = 224.57 minutes of total training, compared to 77 minutes in [Despite these successes, we encountered a number of significant challenges. First, we targeted families for recruitment who had both a young infant, and also a parent or a child with ADHD. A proportion of families recruited were relatively poorly resourced . Around half of families additionally reported significant mental health or psychiatric conditions in a first degree relative. These factors can make recruitment and retention in trials difficult. Multiple recruitment methods had to be employed at both the London and Southampton sites. Additionally, matching rates of recruitment to home visit capacity (due to limitations of testing team time) was challenging. However, despite some cancelled appointments and re-scheduling, the protocol was successively administered to our cohort of 43 families. The total quantity of training (or control exposure) that infants received was greater than in previous studies ,nutes in , SM1.2).Overall, we conclude that pre-emptive technology-based interventions directed at infants at elevated likelihood for ADHD are feasible. Further, these studies can and should apply rigorous RCT designs with appropriately designed control conditions, an approach that hitherto has been rarely taken with such populations . As suchThis trial yielded null results for both primary and secondary outcome measures. Some of the effect sizes we observed (around 0.39) indicate that attention skills around the end of the first year may be malleable, and that variations on the procedures we used, perhaps delivered with greater intensity or over a longer time period, may still be worth pursuing. One area for future exploration concerns the degree of contingency needed for optimal learning. For the training tasks, our fidelity measures showed that, on average, the eye tracker detected the infant’s gaze 68% of the time that they were looking to the screen. Such tracking validity is common even in lab-based developmental eye tracking  but hereThe present RCT was designed with later emerging ADHD traits in mind, and the possibility of pre-empting some attention difficulties before they become embedded during the course of development. While the study is not sufficiently powered to address later clinical diagnosis of ADHD, scheduled assessments of the participants at 24 and 36 months will allow us to measure any longer term effects on traits, or on sub-clinical attention difficulties. Indeed, a recent pre-emptive trial of a parent-mediated intervention with infants with older siblings with autism showed a significant effect on symptoms over time despite no immediate post-training effect . CombiniA limitation of the study is the sample size. While the target sample size for this study was 50 infants, 43 infants were randomised. The trial was powered on the basis of findings from previous experimental studies that provided the best available evidence for the likely effect size (e.g. ). Our coAnother limitation of the study is that thus far, the infants have not been followed up into toddlerhood and preschool. In this study, we targeted infant attention skills. Infant attention skills in both screen-based  and natuA further limitation of the study is that the majority of families included in the trial were white . Under-recruitment of families from certain ethnic backgrounds may partly reflect a broader issue in the diagnostic process for ADHD, where ethnic and racial disparities have been shown , 45. FutIn conclusion, our study provides an important demonstration of a rigorously designed pre-emptive RCT at home for infants at elevated likelihood for ADHD. While the present study did not yield positive results, the feasibility of the intervention approach will provide an important impetus for paediatricians, ADHD researchers and psychologists to turn their attention to very early intervention in this population.Individual participant data that underlie the results reported in this article, after de-identification  will be made available through the data sharing procedures of the BASIS network (basisnetwork.org). This includes presentation of a methodologically sound proposal with appropriate data security and ethical clearances to comply with the terms of the original collection. The study protocol and statistical analysis plan are freely available through the ISCRTN page and in . Data wiSupplementary Materials


Results show that our method can successfully infer the ventricular activation properties in sinus rhythm from non-invasive epicardial activation time maps and ECG recordings, achieving higher accuracy for the endocardial speed and sheet  speed than for the fibre or sheet-normal directed speeds.The realisation of precision cardiology requires novel techniques for the non-invasive characterisation of individual patients’ cardiac function to inform therapeutic and diagnostic decision-making. Both electrocardiography and imaging are used for the clinical diagnosis of cardiac disease. The integration of multi-modal datasets through advanced computational methods could enable the development of the cardiac ‘digital twin’, a comprehensive virtual tool that mechanistically reveals a patient's heart condition from clinical data and simulates treatment outcomes. The adoption of cardiac digital twins requires the non-invasive efficient personalisation of the electrophysiological properties in cardiac models. This study develops new computational techniques to estimate key ventricular activation properties for individual subjects by exploiting the synergy between non-invasive electrocardiography, cardiac magnetic resonance (CMR) imaging and modelling and simulation. More precisely, we present an efficient sequential Monte Carlo approximate Bayesian computation-based inference method, integrated with Eikonal simulations and torso-biventricular models constructed based on clinical CMR imaging. The method also includes a novel strategy to treat combined continuous (conduction speeds) and discrete (earliest activation sites) parameter spaces and an efficient dynamic time warping-based ECG comparison algorithm. We demonstrate results from our inference method on a cohort of twenty virtual subjects with cardiac ventricular myocardial-mass volumes ranging from 74 cm •Estimation of the ventricular speeds and earliest activation sites from ECG and CMR.•Evaluation with twenty virtual subjects shows the effect of anatomical variability.•Bayesian-inspired simultaneous estimation of continuous and discrete parameters.•Efficient dynamic time warping-based comparison of electrocardiograms (ECG).•Changing fibre and sheet-normal speed does not affect healthy activation sequence. CardiacImaging and electrocardiographic datasets are commonly used for the diagnosis of cardiac disease. The electrocardiogram (ECG) is the most widely used clinical modality for cardiac disease diagnosis. Its interpretation is, however, confounded by anatomical and functional variability in the human population . Non-invRecent studies have shown the power of patient-specific image-based modelling and simulation for therapy guidance, arrhythmic biomarkers interpretation and patient's phenotypic variability interpretation . This teThis study investigates new computational techniques for the efficient quantification of subject-specific ventricular activation properties using CMR-based modelling and simulation and non-invasive electrocardiographic data. We present an inference method combined with fast Eikonal-based simulations and CMR-based torso-biventricular anatomical models to determine the accuracy in the estimation of activation properties  from the QRS complex of the 12-lead ECG or activation time maps (as obtained through electrocardiographic imaging). We conduct the simultaneous inference of endocardial and myocardial conduction speeds and the root nodes (i.e. earliest activation sites), as these properties determine the activation sequence in the ventricles . To addr22.11simulate the activation time maps from the new population of models;2calculate the predicted ECGs (unless when working directly on activation maps);3compute the discrepancies (distance) between each prediction and the target data (e.g. ECG);4evaluate the stopping criteria;5replace the parameter-sets corresponding to the top 12.5% highest discrepancies.The process depicted in 1all predicted data ‘match’ the target (using a threshold);2more than 50% of the parameter-sets in the population are duplicates.In Step-1, the Eikonal model (Appendix A.2) simulates an activation time map from each parameter-set in the population using the subject's torso-biventricular mesh. Next, Step-2 (not needed when inferring from activation maps) computes the ECG-QRS from each activation time map using the pseudo-ECG algorithm (Appendix A.4) . Then, S1sort the parameter-sets in the population according to the discrepancy values (decreasing order);2define a discrepancy cut-off to replace the parameter-sets with the top 12.5% highest discrepancies in the population;3for each parameter-set to be replaced (within the 12.5%), randomly select one to be kept and create two new copies from it;4‘mutate’ only one of each pair of copies using Markov Chain Monte Carlo (MCMC) ;5simulate the Eikonal model for the mutated parameter-sets and compute their discrepancies;6finally, replace each parameter-set in the top 12.5% by the mutated alternative (dotted line on the left), unless its discrepancy would also have been rejected by the cut-off, in which case, use the unmodified copy for the replacement (dotted line on the right).If the population does not fulfil any criteria, the iterative process continues. The following six substeps compose Step-5 (Section 2.6)   with eleFurthermore, a second set of ‘target data’ were obtained from bidomain (Appendix A.1) simulations without noise-contamination for comparison. The bidomain simulations were conducted using the Chaste software  and the 2.4Measuring differences between epicardial activation maps to capture differences in the source activation properties is simple due to the sheared spatial representation of the epicardial activation map data (epicardium) and the root node locations (endocardium). Consequently, we defined the discrepancy between ‘predicted’ and ‘target’ epicardial activation maps as the root mean square error between the two activation maps. On the other hand, capturing differences in activation properties from differences between ECG recordings is challenging. Therefore, we propose a novel extension of the dynamic time warping (DTW)  algorithDTW is a speed-invariant dynamic-programming algorithm for measuring differences between sequences. Hence, DTW can compare signals of different lengths, such as ECGs , by streWe assume that in healthy ventricles, the root node locations are primarily responsible for the QRS's morphology and that the conduction speeds mostly define the QRS's width, as demonstrated by We present an extension of DTW that prevents non-physiological ECG transformations. Our DTW discrepancy implements the warping-slope constraint, a modified version of the parallelogram constraint, and a common-end warping constraint to avoid non-physiological ECG transformations. The warping-slope constraint prevents more than two warping steps from occurring consecutively . The parallelogram constraint limits the amount of warping at the signals’ start and favours ‘diagonal’ warping such that one signal is transformed as the stretched or shrank version of the other. In other words, it rewards signals with physiologically similar morphology, namely, penalising non-monotonic warping, especially when occurring discontinuously or displaying ‘unwarping’ . These warping penalties within the parallelogram are more prominent at the start of the signals and decrease linearly, allowing for more flexible warping when comparing the end of the QRSs since differences in the activation sequence can have a cumulative impact on the QRS. The common-start and common-end constraints imply that both signals represent the same phenomena and should be entirely encoded into each other. Overall, our DTW method favours signals with similar morphologies, even if their source conduction speeds were scaled to fast-track the root nodes’ identification. Therefore, we implement an additional penalty based on the difference in QRS-width to identify the source model's correct speeds, which, combined with the DTW extension described, composes our DTW-based discrepancy.2.5Our approach aims to infer the root node locations and the four conduction speeds  that enable reproducing a subject's ECG recording . We considered three sets of possible root node locations: the low, high and hybrid resolution of the discretisation of the root node parameter space to expose the method's ability to represent root node locations from epicardial activation time map and ECG data modalities.In the low resolution of the root node discretisation, the possible root node locations were preselected as the centres of each endocardial section following the American Heart Association's segmentation guidelines , as in AA high resolution of the root node discretisation was also considered by uniformly sampling more root nodes such that the distance from each point to a root node was reduced to 1.5 cm. This high resolution produced 133 candidate root nodes (64 in the left and 69 in the right endocardium) for the largest anatomy and 98 (39 in the left and 59 in the right endocardium) for the smallest one.Finally, we considered a hybrid resolution that combined the low resolution for the right ventricle with the high resolution for the left ventricle since the latter is presumed to have a stronger influence on the QRS. We anticipate the inference from epicardial activation maps will work better from the symmetric root node distributions (low and high) than from asymmetric ones (hybrid) as the epicardial activation map equally represents both ventricles. On the other hand, the hybrid resolution should improve the inference from 12-lead ECGs since it emphasises the exploration of the root nodes on the left ventricle, which is known to have more influence on the ECG than the right ventricle given its larger myocardial-mass volume.These candidate root node locations were considered a binary parameter, with the inference yielding ‘in use’ or ‘not in use’ to obtain a good match between simulated and target electrocardiographic signals. We define the range of the number of root nodes as  as Finally, the conduction speeds were assigned to be within predefined physiological ranges . The end2.6The combination of conduction speeds and root nodes creates an inference problem with continuous and discrete mixed-type parameter space that challenges many parameter inference algorithms. We propose an SMC-ABC-based algorithm (Appendix A.5)  to efficIn a nutshell, SMC-ABC defines its intermediate distributions (SMC) as approximate posteriors with a series of decreasing cut-off discrepancy values (ABC). In our context, SMC-ABC serves as a parameter-set-based optimisation approach that solves a sequence of simplified optimisation problems  where each informs the next.As reviewed in the description of The SMC-ABC algorithm's iterative process considers that the current population is a solution to the inference problem when all discrepancies are smaller than a positive tolerance (Appendix A.5). This tolerance threshold can be set according to what level of discrepancy is judged to be acceptable. Here, we hypothesise that the analysis of the inferred population of parameter-sets will highlight the method's representation limit, for example, identifying differences in the position of the root nodes that are negligible from the algorithm's perspective. Therefore, we define a relatively small tolerance  to investigate how accurately the method can recover the activation properties from different data modalities.However, a too-small tolerance will lead SMC-ABC to converge to a single parameter-set, whereas our inference problem is known to have non-unique solutions. Thus, we defined a second stopping criterion relative to the percentage of duplicate parameter-sets to terminate the inference before the population collapses into a single parameter-set. In other words, this second stopping criterion informs the algorithm to terminate when the MCMC process fails to find new acceptable parameter-sets too many times  standard deviation of the (unsigned) distance between each target root node and the closest centroid from k-means and the mean ± standard deviation of the absolute error in the number of root nodes.We aggregate the inferred conduction speeds as the median of each speed in the population of parameter-sets. To illustrate the error, we propose a speed-normalised error metric so that we can jointly represent errors from different virtual subjects. This error was defined asWe adopted the mean ± standard deviation of Pearson's correlation coefficient  as a mea2.8We calibrated the algorithms presented in this study using general and physiological knowledge and adjusted their values to work in one of the 20 virtual subjects  in our twenty-subject cohort, we conducted inferences using epicardial activation time maps and 12-lead QRS complexes as the ‘target data’. Moreover, we considered three different resolutions of the root node parameter space . These combinations defined our 120 inference executions, each repeated three times to demonstrate the results’ consistency.These inference executions were conducted at Amazon Web Services and the Swiss National Supercomputing Centre. Each inference required about one hour to compute in a virtual machine emulating 18 2nd generation Intel Xeon Scalable Processors.https://github.com/juliacamps/Inference-of-healthy-ventricular-activation-properties. The torso-biventricular meshes are also available under request.The inference pipeline was developed in Python/Numpy and can be found in The illustrations featured in this manuscript were created using ParaView software , Python's Matplotlib library (Hunter 2007), and Matlab .33.1The inference method accurately replicated the activation maps from noise-contaminated epicardial data C, showin3.2Our method inferred more accurately root nodes in non-septal areas since septal activation times are not represented in epicardial maps D. The nu3.3The endocardial and sheet speeds in the inferences implementing the low or high root node resolution were recovered more accurately than the fibre directed speed A-B. Thro3.4Analogously to The inference of root nodes was more accurate on the anterior side of the heart than on the posterior A-C compa3.5Analogously to Similarly to the inference from the noise-contaminated Eikonal epicardial activation maps , the con3.6To further assess the performance of our inference methodology, bidomain ‘target data’ were generated and used as previously shown for ‘target data’ generated from the eikonal model. Increasing the root node resolution improved the accuracy to infer epicardial activation maps and ECGs generated with bidomain simulations . In contThe high resolution of the root node location discretisation also helped to recover root node locations closer to the ground truth from epicardial activation maps and ECGs . HoweverIn agreement with our previous findings , the end43 to 171 cm3) variability in the healthy human population on the performance of the inference process. We considered the noise-contaminated simulations as the ground truth for the inferences. The impact of the resolution of root node discretisation on the inference errors was also tested.This study presents an inference method combined with CMR-based torso-biventricular Eikonal models to estimate the root nodes and conduction speeds from 12-lead ECG or epicardial activation map data. Our approach aims to serve as an efficient tool for generating cardiac ‘digital twins’, which is of paramount importance for precision cardiology . We condIn addition to the novel methodology and its ability to simultaneously work with continuous and discrete parameters, the key findings of the study are as follows. Firstly, the method enabled finding populations of models that produced activation sequences with nearly identical electrocardiographic patterns to those observed from the subject's data  while reA key contribution of this study is the development of an inference method to estimate the two types of parameters, namely, the anisotropic conduction speeds (continuous) and the number and locations of the root nodes (discrete) in both ventricles simultaneously. Previous work considered either a known number of root nodes  or known locations. For example, The evaluation of the inference methodology was conducted using synthetic data to know the ground truth values for the ventricular activation properties, as these cannot be measured in healthy subjects. This allowed us to explore the effects of the variability in tissue conduction properties in the healthy human population. We mimicked clinical conditions by contaminating the ‘target data’ using noise to demonstrate the feasibility of our method for clinical environments, and we repeated the experiments using a biophysically detailed model (bidomain) to test the capability of our phenomenological models to perform the inference on realistic data. Moreover, we showed the physiological soundness of our modelling and simulation methods by replicating a clinical electrocardiographic imaging-derived epicardial activation time map (Appendix A.9). This ability to reproduce the physiological patterns demonstrates that our inference methodology is relevant for clinical applications such as the generation of cardiac digital twins  towards All our results for the inference of conduction speeds  demonstrThe inference of the root nodes from epicardial activation maps  demonstrated that the baseline ability to recover the conduction speeds is conditioned by the identifiability of the root nodes . In othe4.1We implemented the Purkinje network as an isotropic fast endocardial layer with root node locations that emulate the hotspots of Purkinje myocardial junctions. This strategy has been extensively used in previous studies  and showOverall, this study presented the foundations of a novel pipeline capable of non-invasively calibrating cardiac digital twins for healthy subjects from synthetic epicardial activation maps and 12-lead ECG recordings. Our approach was designed to easily accommodate disease conditions, such as pathological tissue heterogeneities (scars or fibrosis). Moreover, the results using bidomain-generated ‘target data’ (Section 3.6) and clinical ‘target data’ (Appendix A.9) to guide the inference suggest that the presented approach can be directly translated to work on clinical ECG recordings. Moreover, we anticipate that our methodology can be adapted to work with pathological data to generate cardiac ‘digital twins’ in daily clinical practice.Julia Camps: Conceptualization, Methodology, Software, Formal analysis, Validation, Writing – original draft, Visualization. Brodie Lawson: Methodology, Software, Writing – review & editing. Christopher Drovandi: Methodology, Writing – review & editing. Ana Minchole: Conceptualization, Writing – review & editing. Zhinuo Jenny Wang: Formal analysis, Writing – review & editing, Visualization. Vicente Grau: Resources, Writing – review & editing. Kevin Burrage: Methodology, Writing – review & editing. Blanca Rodriguez: Conceptualization, Formal analysis, Resources, Writing – original draft, Supervision.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Background: Secondary prevention with lipid-lowering medications in patients with atherosclerotic cardiovascular disease (ASCVD) is known to reduce the risk of clinical events and death. Current guidelines codify recommendations for implementing secondary prevention in appropriate patients. However, in real-world practice, secondary prevention is frequently initiated only after the patient experiences a cardiovascular-related hospitalization. The impact of these delays is not well known.Objectives: To estimate the effects of delaying treatment on the risk of cardiovascular-related hospitalization and on costs for patients who meet the criteria for secondary prevention as specified in the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.Methods: This is a retrospective cohort analysis using Humana data. Eligible patients were categorized by treatment group: (1) patients who initiated treatment before an ASCVD-related hospitalization and (2) patients who either did not initiate treatment until after an ASCVD hospitalization or never initiated treatment. The associations between the timely initiation of cholesterol-lowering medications for secondary prevention and (1) the risk for an ASCVD hospitalization and (2) health-care costs over one year, were estimated using multivariate regressions.Results: A total of 272 899 secondary prevention patients were identified who met study selection criteria. Early treatment was associated with significant reductions in the risk of an ASCVD hospitalization at any time following the identification of the patient’s eligibility for secondary prevention , but was significantly associated with higher total cost over the first post-index year . Patients whose low-density lipoprotein cholesterol (LDL-C) levels were >130 mg/dL experienced higher ASCVD hospitalization risks, and also larger risk reductions if treated before an ASCVD hospitalization compared to patients with lower LDL-C levels who were treated late or never treated.Conclusions: More widespread implementation of the treatment policies specified in the 2013 ACC/AHA Guidelines for secondary prevention should significantly reduce cardiovascular disease hospitalizations and reduce costs. Cardiovascular disease (CVD) is the leading cause of death in the United States, resulting in significant health and economic burdens.The purpose of this study is to document the potential harm done by the suboptimal implementation of the secondary prevention treatment policies, as detailed in the 2013 ACC/AHA Guidelines. This analysis estimates the impact of delayed initiation of secondary prevention, including delaying treatment for the newly defined  high-risk population specified in the 2013 ACC/AHA Guidelines. The study replicates methods used in our earlier analysis of delayed primary prevention.This was a retrospective cohort analysis using data derived from the Humana claims database, covering January 1, 2007, to June 30, 2013. The Humana claims database is a national and longitudinal database covering 22 million persons in the United States and includes Humana’s Commercial and Medicare Advantage enrollees and contains medical , pharmacy, and laboratory data (including test results).Data elements include administrative claims from medical encounters , pharmacy dispensing, demographics, enrollment eligibility, and laboratory test values (for a subsample of members). These data can be used to derive relatively complete diagnostic and drug utilization profiles for each patient that reflect the patient’s health status at the point in time when each patient becomes eligible for secondary prevention.Online Supplemental Material, Table S1. ASCVD diagnoses included: acute myocardial infarction (AMI), unstable angina, subarachnoid and intracerebral hemorrhage, stroke, transient cerebral ischemia, cerebrovascular disease, atherosclerosis, peripheral vascular disease, arterial embolism, and arterial disorder.Patients included in the analytic sample met the requirements for secondary prevention, as specified in the 2013 ACC/AHA Guidelines, based on a chronological assessment of their diagnostic and procedure history. Specifically, secondary prevention patients were identified once the patient was found to have ≥1 medical claim with a diagnosis of ASCVD or had a paid claim for a CPT-4/ICD-9-DM procedure service directly related to an ASCVD diagnosis.Once identified, study patients were screened to determine if there was a minimum of 6 months of continuous enrollment before their index date, with both medical and pharmacy coverage, and that their enrollment continued for 12+ months following their index date. This latter selection criterion allowed for the evaluation of first-year costs but also required that patients survived at least one year post-identification. These requirements limited the index dates included in the study to the period from July 1, 2007, to June 30, 2012. These data restrictions allowed the analysis to develop variables correlated with the baseline health status and follow-up outcomes for study patients. Patients who filled or refilled a prescription for any treatment for high cholesterol before their index date were excluded, as were patients younger than 21 years old on their index date.All-cause health care costs were measured for each patient over each patient’s first post-index year. The post-index ASCVD events were quantified by counting days to both the first ASCVD-related and non-ASCVD hospitalization, not restricted to the one-year post-index period. Those time-to-event outcomes were evaluated using Cox proportional hazards models.Patients were categorized as having received timely secondary prevention if they initiated cholesterol-lowering medication at any point following their index ASCVD event, but before experiencing any subsequent ASCVD-related hospitalization. Timely secondary prevention was entered as a dichotomous variable in the analysis. The comparison group consisted of individuals who did not fill any cholesterol-lowering prescriptions or who filled their initial post-index prescription only after experiencing an ASCVD-related hospitalization. All available cholesterol-lowering treatments were used to define secondary prevention status . Since PCSK9 inhibitors received FDA approval after the end of the study data period, they were not included.The covariates used to adjust baseline risk in the statistical models included: age, gender, race, region, benefit group, health plan type , diagnostic and prescription histories, prior hospital admissions, and baseline all-cause health care costs  as measured over the 6 months prior to the patient’s index date. The specific ASCVD diagnosis or event that triggered the index date was entered as a covariate in the analysis; a patient could have more than one type of “index” ASCVD diagnosis on the same index date. Baseline LDL-C levels were also collected for the subgroup of patients with available lab result data. The LDL-C record closest to the index date was selected as the patient’s LDL-C level at baseline.Online Supplemental Material, Table S1. Inpatient services were used to define outcome ASCVD events in order to more precisely distinguish new events from routine follow-up outpatient services related to the original index event that qualified the patient for secondary prevention. All-cause health care costs were measured as the combination of insurance payments and the patient’s out-of-pocket charges over the first year following the patient’s index date and were sub-classified by type of service .This analysis investigated three primary outcomes: (1) an ASCVD-related hospitalization and time from index date to this ASCVD hospitalization; (2) a non-ASCVD-related hospitalization and time from index date to this non-ASCVD hospitalization; and (3) all-cause health care costs measured over the first year following the index date. Follow-up data was censored either when continuous enrollment of both pharmacy and medical insurance ran out, or an outcome-defining event occurred. ASCVD-related hospital admissions were identified using the ICD9 and CPT codes specified in the Descriptive statistics comparing patients’ baseline characteristics across treatment status used either the Pearson’s chi-square test or Student’s t-test to identify significant differences as appropriate.Two sub-analyses were also performed to test the results from the Cox proportional hazard models. The first sub-analysis re-estimated the effect of timely secondary prevention on CVD and non-CVD hospitalizations using the subset of patients with baseline LDL data. This sensitivity analysis only included patients who had LDL levels at baseline and was used to test the association between treatment effect and baseline LDL-C. The LDL-C lab results collected closest to index date (either pre-index date or within 5 days following index date) was assigned as patients’ baseline LDL. The LDL levels were classified into four categories consistent with the 2011 Adult Treatment Panel Guidelines: LDL-C <101 mg/dL, 101-130 mg/dL, 131-160 mg/dL, and >160 mg/dL.The second sub-analysis further investigated possible differential treatment effects of on-time secondary prevention treatment variable and the patients’ baseline LDL levels. All analyses were performed using the SAS System for Unix, Version 9.3.A flow diagram outlining patient selection for the study is presented in Unadjusted comparisons of baseline characteristics between patients who did and did not receive timely secondary prevention are shown in For the subgroup of patients who had baseline LDL data available, early prevention patients exhibited higher LDL-C levels, relative to both untreated patients and patients who delayed secondary prevention. This is consistent with the ACC/AHA Guidelines prior to 2013, which recommended treatment of cholesterol-lowering medications mainly just for patients with elevated LDL-C levels.Online Supplemental Material, Table S2).Over 88% of patients who initiated treatment at any time in the post-index period used statins as their cholesterol-lowering medication of choice. Approximately 68% of statin patients were specifically prescribed moderate intensity treatment. In addition, 2.9% of treated patients used a combination of a statin and non-statin as their regimen for secondary prevention. , entering that LDL level into the Cox model as a covariate. Note that the relative risk of an ASCVD-related hospitalization increases monotonically with the patient’s baseline LDL level, whereas the risk of non–ASCVD-related hospitalizations was significantly higher , driven mostly by a higher risk only in the lowest LDL group.The absolute risk of an ASCVD-related hospitalization likely varies by LDL level, which implies that the effectiveness of primary prevention in reducing CVD-related hospitalization risk may also vary by baseline LDL. To investigate this possibility, the third analysis reported in The impact of secondary prevention on health care costs over the first post-index year was estimated using GLM  from guideline compliance; the size of the population affected by the guidelines (or guideline changes); and the completeness of their implementation. This study addresses the first two factors as they relate to the 2013 ACC/AHA Guidelines for Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.Using paid claims data for ASCVD patients from a data period before the publication of the 2013 ACC/AHA Guidelines, this study estimates that the new Guidelines increased the size of the population recommended for secondary prevention by nearly 69%, based on the data for the subgroup of patients with available lab results see . Our resHowever, this study also found cholesterol-lowering medication was associated with a higher annual cost of US $500 in the first post-index year, primarily due to increased prescription drug costs per patient. That result may not persist later, assuming that risk reductions accrue beyond the first year. Also, some of the lipid-lowering drugs remained on-patent during the study period. Generic versions are now available for many of these medications, which would reduce the estimated pharmacy cost differences reported here.The decision to initiate timely secondary prevention may have been correlated with important but unmeasured risk factors that preferentially assigned patients into these two treatment groups. The first line of defense against this threat to study result validity is to expand the analysis to include all important patient baseline characteristics. This study documented the existence of many significant differences in the observable characteristics of treated and untreated patients. While our statistical analyses used this extensive set of characteristics as covariates, it remains impossible to fully control for treatment selection using any non-randomized approach. However, it is encouraging that after adjusting for all available risk factors, the risk of non–ASCVD-related hospitalizations differed only minimally between the timely and late/no prevention groups.The number of patients receiving early or delayed secondary prevention may also be underestimated due to any missing statin prescription claims that were paid for using cash, rather than billed to insurance, given the relatively low cost of these medications. The implication is that some patients in the “no secondary prevention” group may have initiated cholesterol-lowering medications. The effect of that potential data gap would be to underestimate the effectiveness of treatment in reducing CVD-related outcomes, making the effect sizes presented here falsely too low.Sensitivity analyses that included different subgroups of patients were performed to confirm the robustness of the main results, and to more clearly understand both the relative risks of CVD hospitalizations and the associated treatment effects across each LDL-C level subgroup. Since lab results reporting LDL-C levels were not available in the data for many patients, those analyses were only conducted on the smaller subpopulation with available baseline LDL-C results. The overall secondary prevention effect on CVD-related hospitalization risk did not change in this subgroup analysis, at least partially validating the results from the whole-sample analysis.Patient adherence to cholesterol-lowering medications was also not directly considered in this analysis, only initial prescription fills. Again, to the extent that our early treatment population includes some nonadherent patients, this would tend to underestimate the effects of adherent early treatment. Future analyses should account for patients’ long-term adherence to medications, estimating the impact of duration of therapy rather than just the act of initiating treatment.Implementation of the 2013 ACC/AHA Guidelines is intended to expand secondary prevention treatment to all ASCVD patients with a prior CVD event, regardless of their LDL-C levels. In this study using pre-Guideline data, we found that this policy change could benefit patients significantly, if Guideline policy recommendations are implemented fully in the newly eligible population. While timely secondary treatment benefits all patients, timely treatment was found here to benefit high-risk patients the most, at least in terms of absolute risk reduction. Patients with higher LDL levels exhibit the highest absolute risk of experiencing CVD-related hospitalization, and also experienced the largest absolute risk reductions after initiating cholesterol-lowering medications. The extent to which these Guidelines have been implemented since 2013 was not assessed here. This study provides numerical estimates documenting the magnitude of benefits gained, per patient, from more fully implementing secondary prevention.There are no disclaimers.


Growth behaviors of GaN on patterned GaN substrate were studied herein. Spiral and nucleation growth were observed after miscut-induced atomic steps disappeared. The morphology of nucleation growth at different temperature is explained by a multi-nucleation regime introducing critical supersaturation. Simulated results based on a step motion model successfully explain the growth behaviors on stripes. These findings can be applied to control the surface kinetics of devices such as laser diodes grown on patterned substrate. Due to their outstanding characteristics such as tunable direct wide band-gap and high electron saturation velocity, III-nitrides are widely used in optoelectronic and electronic devices. An atomically smooth surface is crucial for obtaining high internal-quantum-efficiency quantum wells  and highPatterned substrates were firstly used to reduce the threading dislocation (TD) density of GaAs grown on silicon by the well-known epitaxial lateral overgrowth (ELOG) technology . This te6–107 cm−2 were chemo-mechanically polished into vicinal wurtzite (0001) c-plane with a miscut angle of about 0.35° towards GaN substrates with TD density of 10Afterwards, the samples were dipped into 25% tetramethylammonium hydroxide (TMAH) at 85 °C for 20 min to remove the etching residuals on the surface and make a smoother sidewall . About 1The surface morphology was studied by atomic force microscope  in tapping-mode. Large-scale AFM amplitude images were used to clearly show atomic step features on the surface with huge difference in height . The mis2 and become new step sources, resulting in a surface full of curved steps as shown in Both sample A and B show step-flow morphology with uniformly arranged straight atomic steps on the unpatterned area as shown in For stripes along the m-direction, miscut-induced steps move freely except for the area of the upstream 2) also show asymmetric kinetic behaviors. Its step edge in the m-direction moved very fast and almost caught up with the step of the lower layer. However, the step in the ₋m-direction was far behind. Hence, the step edge in the m-direction of the topmost island should be type B with two dangling bonds while that in the ₋m-direction is type A with one dangling bond.ng bonds . Step edng bonds . Taking 2) smooth surface is obtained on the left side of the 10 μm-wide stripe along the m-direction in Except for some pits, a large-area th steps. k+ and k− are the probability of adatoms incorporating to the upper and lower steps, respectively. The Ehrlich–Schwoebel barrier (ESB), which describes the difference of energy barrier between the upper and lower terrace, is taken into account. For a single step, if the energy barrier for incorporation of the upper terrace is larger than that of lower terrace (k+ > k−), a positive ESB exists; otherwise, it is a negative ESB. To make this model more applicable, the following issues are considered:(a)The probability of adatom incorporation for steps with type A and B edges is different;(b)When the distance of adjacent steps is shorter than a critical value, step bunching occurs and bunched steps will move with the same speed;(c)If the terrace width is larger than the atomic diffusion length, only adatoms near steps (the distance from the step being shorter than the diffusion length) can feed the steps.Here, C is a constant of the step motion which is equal for all steps at specific growth conditions, while sBased on the above considerations, we simulate the step kinetics on the upstream edge of the stripe along the m-direction without nucleation. As is shown in According to Equation (1), the velocity of the upmost miscut-induced step will not be slower than that of the lower steps. Therefore, steps shown in cri when the energetic barrier of nucleation is overcome [cri), multi-nucleation occurs and quickly coalesces to form a two-dimensional (2D) island of the size d2D. The growth condition at a high growth temperature promotes the lateral growth of the (11–20) sidewall [cri for sample A). When two samples both meet the conditions for nucleation, the size of the 2D island is larger for the sample with more uniform distributions of supersaturation (larger d2D for sample B).However, such ideal layer-by-layer growth did not occur. Multilayers of islands with gradually reduced terrace width near the edge came up instead. To explain this phenomenon, we introduce a critical supersaturation value σovercome . On the sidewall  and therSF) forms at the upstream of the stripes; (b) multi-nucleation occurs and coalesces to form a 2D island (of the size d2D) at the middle of the surface when LSF reaches a critical nucleation value (Rcri); (c) the 2D island laterally spreads based on the step motion theory; (d) another new layer starts to grow when the size of the first island reaches the critical nucleation value Rcri. Considering multi-nucleation processes, the simulated results are shown in In our model, we assume that the condition for nucleation is met when the size of the step-free area reaches a critical value. Therefore, the nucleation processes on stripes is described as: (a) miscut-induced atomic steps flow downwards and a step-free surface (of the size LWe have investigated the surface kinetics on stripes of patterned GaN substrates. Both spiral and nucleation growth occur when miscut-induced steps flow downwards. Multi-islands morphology is caused by the edge effect and a positive ESB on the stripes. Without the interference of screw TDs, the different morphologies at different growth temperatures are explained by a multi-nucleation growth regime under non-uniform distributions of surface supersaturation. Simulated results based on the step motion model further verify the growth process on stripes. These findings show the importance of controlling the surface kinetics in GaN growth and can be applied to control surface kinetics in devices such as laser diodes grown on patterned substrates.


Dystocia in labor is still a clinical challenge. The "contracted pelvis" is the absence of pelvic mobility, which leads to fetal-pelvic disproportion, obstructed labor, and operative delivery. Maternal pelvis biomechanics studies by high technological techniques have shown that maternal shifting positions during pregnancy and labor can create more room in the pelvis for safe delivery. The external and internal pelvic diameters are related. The present study aims to evaluate the external obstetric pelvic diameters in shifting positions using a clinical technique suitable for daily practice in every clinical setting: the dynamic external pelvimetry test (DEP test). Seventy pregnant women were recruited, and the obstetric external pelvic diameters were measured, moving the position from kneeling standing to "hands-and-knees" to kneeling squat position. Results showed modification of the pelvic diameters in shifting position: the transverse and longitudinal diameters of Michaelis sacral area, the inter-tuberosities diameter, the bi-trochanters diameter, and the external conjugate widened; the bi-crestal iliac diameter, the bi-spinous iliac diameter, and the base of the Trillat's triangle decreased. The test showed good reproducibility and reliability. Linear correlations were found between diameters and between the range of motion of the diameters. The maternal pelvis is confirmed to modify the diameters changing its tridimensional shape. The pelvic inlet edge's inclination is inferred to be modified, facilitating the fetal descend. The pelvic outlet enlarged the transverse diameter, facilitating birth. The DEP test estimates the pelvic diameters' modification with postural changes, as magnetic resonance (MR) and computational biomechanics studies have demonstrated. Childbirth is still a potentially complicated event for the woman and the newborn, with destructive health consequences in low-resource countries . It is mObstetric pelvimetry has been used to evaluate the birth canal's childbirth capacity's endopelvic spaces in static conditions. Clinical studies have correlated the external pelvic diameter's raw static dimension with the internal diameters and the risk of "contracted pelvis" and obstructed labor ,8,11-13.The present study in a group of pregnant women in their third trimester of pregnancy is part of more extensive research on osteopathy for pregnancy. It observes the external diameters of obstetric pelvimetry assessed in shifting positions using the DEP test and considers the biomechanical implications for the birth canal's pelvis mobility. The present paper is addressed to evaluate and analyze the modification of the external pelvic diameters' measurement with maternal position change and confront literature data results. Moreover, the study considers the accuracy of measurements from the intra-observer and interobserver agreement, the intra-diameter and inter-diameter measurements' linear correlation in different positions, and the intra-diameter and inter-diameter range of movement (ROM) relationship while shifting positions.The cross-sectional study was performed at the Obstetrics Department of San Paolo Hospital of Savona, Italy (EU) and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement checklist. Seventy low-risk pregnant women in their third trimester were recruited at the Clinic for Physiological Pregnancy of the Obstetrics Department between 10 January and 30 October 2020. They gave their informed consent before the study; the low-risk pregnancy condition was certified from the medical records. Only the subjects who did not report abdominal, pelvic, or vertebral surgical interventions, did not suffer from lumbopelvic pains, did not have previous obstetrics complications, and did not have abdominal-pelvic diseases at the clinical evaluation were accepted. The authors contributed to define the protocol from the previous study . Data weThe authors registered the patients' general characteristics and measured the external pelvic diameters in the three different postural positions using the DEP test . The firThe diameters were evaluated in shifting positions depending on the degree of hip flexion on the pelvis: p1 "kneeling erect" position (the erect straight-led position), p2 "hands-and-knees" position , and p3 "kneeling squat" position Figures , 2B, 2C. and F.D.M.) and intra-observer (M.S.) agreement from randomly selected diameters measured by direct finger contact on the bone landmark, starting from a known value. Each patient's diameter was randomly selected and measured in the different positions before and after each session to avoid bias.The study appraised the DEP test procedure reliability and reproducibility to steadily and firmly maintain the fingers’ contact on the diameter references during the patients’ movement. The ability to recognize the bone landmark was not a study's aim, but the operators' accordance in estimating pelvic diameters modification in shifting positions. The authors assessed the inter-observer  was used to register the handwriting recorded measurements' values. Data of the pelvic diameters are expressed in millimeters and reported as mean (M), standard deviation (SD), minimum and maximum value, standard error of the mean (SEM), and 95% confidence interval (95% CI). The Kolmogorov-Smirnov test evaluated the normality of the data distribution. The t-test for repeated measurements (paired t-test), the intraclass correlation coefficient (ICC) and the Bland-Altman analysis, and the intra-diameter and inter-diameter Pearson's correlation coefficient with Fisher's Z were performed with the open-source statistical software StatsToDo . A p-value <0.05 and an ICC >0.70 were considered significant.The patients' general characteristics are reported and described as mean and standard deviation Table . 100% diThe external pelvic diameters showed a gradual difference in dimension from the straight-leg position (p1) to the 90° bent-leg p2) and the kneeling squat position (p3)  Figure . The intThe Bland-Altman plot and analysis evaluated the DEP test measurement technique reproducibility and reliability from 648 paired pelvic diameters and ROMs' values Figure . The intPearson's correlation coefficient (with Fisher's Z) analyzed the absolute values between the pelvic diameters (inter-diameter correlation) in each different position Table . It geneThe external pelvic diameters evaluated through the DEP test on 70 pregnant women in their third trimester showed a statistically significant adaptation in the different positions studied, homogeneous with literature data -6. The tExternal obstetric pelvimetry was founded for the early diagnosis of mechanical dystocia. It is a clinical procedure for daily practice to detect the narrow pelvis and consequent fetal-pelvic disproportion implicated in labor arrest childbirth complications. Pelvimetry has been complemented and replaced by radiological pelvimetry, which closer evaluated the birth canal's diameters. Researches observed correspondence between the external and internal pelvic diameters Table  12,14,1,19. CompBiomechanical research has highlighted an appreciable movement of the sacroiliac joints, the lumbosacral junction, and the pubic symphysis, which justifies the pelvis's ability to modify three-dimensionally its diameters and internal spaces -21. It cThe MR study of Michel et al. on 35 non-pregnant women resulted in a slight modification of the pelvic diameters in shifting positions . The obsThe 3D computational reconstruction simulation research by Hemmerich et al. has reported a modification of pelvic diameters measured from the standing position to the squat position confronting Reitter and Michel's results ,5. The sMost obstructed labor and cephalo-pelvic disproportion are diagnosed during uterine cervix dilation in the first and active phase of labor, whilst the fetal head glides on the pelvic inlet for engaging in the pelvic midlet. Women often utilize the standing and kneeling "all-4" position during the first stage to release the uterine contraction pain and facilitate the fetal descend, but the squat positions are not recommended . The antThe sacral movement between the iliac bones is a composite question, not fully unfolded . The thoThe images obtained by MR allow the positioning of the digital calipers on the edge of the internal pelvis' bony surface. The external pelvimeter is joined with the tissues due to the spring's compressive pressure, resting firmly on the posterior bone surface with pelvic fascia and soft tissues' interposition, potentially affecting the measurement . BiomechThe internal and external conjugates were revealed to be well related . The obsAll posterior diameters increased the measurement from standing to "all-4" position in our study. The posterior diameters increased further in the squat position, except the iliac bi-crestal distance decreased significantly Figure , 6B. TheAccording to Deseaeuve and colleagues' paper on 20 pregnant women, as the hip joints gradually flex, the pelvis tilts, and the lumbar spine flexes, increasing its vertical measure and the Michaelis longitudinal hemi-diameter . From ouThe external diameters corresponding to the pelvic inlet, midlet, and outlet result in a direct linear correspondence in the discrete measurements obtained in the positions Table . The chaThe anterior pelvic diameters decrease in shifting positions, while the posterior diameters increase, showing an inverse direction of motion Figure , 6B. TheThe DEP test cannot measure the anterior diameters in the squat position: probably they further narrow, according to correlations with other diameters and the direct anatomical connection between them and the bi-crestal diameter Table . The intThe iliac bi-crestal and the bi-trochanters diameters are well correlated in shifting positions. They demonstrated to mediate the relationships between diameters related to the pelvic inlet, midlet, and outlet Table . FurtherThe iliac bi-crest distance decreased from the "all-4" to the squat position correlating its motion significantly with the bi-trochanteric and the Michaelis rhombus' transverse diameter’s ROM, which coupled with the external conjugate's ROM Table . ConsequThe study admits some limitations. The study group is large enough to draw general statistical conclusions, but each diameter has different movement patterns, some homogeneous and others non-homogeneous. The joint anatomy of the various pelvic types can justify such variability in pelvic mobility . PreviouThe study shows that the external pelvic diameters modify their space in shifting positions. Maternal posture is related to the birth canal's internal pelvic diameters allowing more room in the pelvis for safe childbirth. The Dynamic External Pelvimetry test could quickly assess pelvic mobility, has excellent reproducibility and reliability, and potentially is a screening test for the "contracted pelvis" and mechanical dystocia. The test is suitable for the daily obstetric clinical practice in any socio-economic and health resource environment. Further studies are needed to relate pelvic mobility to obstetric outcomes and to delve deeper into the physiology of pelvic biomechanics and biodynamics during pregnancy and childbirth.


During COVID-19-related public health non-pharmaceutical prevention measures, such as social distancing, lockdown periods and use of face masks, a decrease in viral respiratory and gastroenterological infections was observed worldwide. Following discontinuation of preventative measures, a potential increase of respective infections outside of their usual seasons was a matter of concern.We aimed to illustrate annual distribution of confirmed viral infections between 2017 and 2021 based on 32,506 clinical samples in a German pediatric tertiary care center and to explore the impact of the COVID-19 pandemic on the epidemiology of these infections in children.While a decrease in overall viral infections was observed during the first and second lockdown period, an extraordinary increase in the number of viral respiratory infections, predominantly caused by human Rhino-/Enterovirus and respiratory syncytial virus (RSV), was observed after relaxation of preventive measures. Notably, Rhino-/Enterovirus infections increased 4-fold (2020 vs. 2019) and 16-fold (2021 vs. 2019). The occurrence of RSV was observed beginning from June to August 2021 and reached an all-time record with a 25- to 50-fold increase in numbers in September and October 2021 in relation to previous pre-pandemic years (2017–2019). In contrast, for non-respiratory viruses (i.e. Rota-/Norovirus), the effect on respective seasonal patterns was only minimal compared to previous years.The observed increase in respiratory infections in children is worrying and is already causing hospitals to become overburdened. Enhanced vigilance will be key to face clinical challenges due to these epidemiological changes in viral disease patterns in the months to come.The online version contains supplementary material available at 10.1007/s15010-022-01756-4. Following the two lockdown periods  in Germany, a joint statement of the German Society for Pediatric Infectious Diseases (DGPI) and the Society for Pediatric Pneumology (GPP) warned of a possible RSV and Influenza wave outside the usual season and suggested appropriate preventive interventions including administration of Palivizumab for children at risk, in Germany [A recent report noted the potential impact of clustered infections from RSV on the health care system and vulnerable patient populations . HoweverBesides the current dramatic increase in the number of COVID-19 patients (primarily adult cases) leading to a massive workload for the health system, there is also a concerning shortage of capacities in children’s hospitals. However, in the latter, other viral diseases seem to play more prominent role than SARS-CoV-2  yielded a positive  yielded a negative viral result (Supplementary 1). Until 2020, all tests were carried out in patients with corresponding clinical symptoms following clinical guidelines. In the case of RSV/Rhinovirus, these were presence of an upper and/or lower respiratory-tract infection, age of < 1 year, or presence of a lower respiratory-tract infection with pronounced symptoms in children aged > 1 year. Swabs for Noro-/Rota-virus were taken in case of gastrointestinal infections with severe symptoms that usually required inpatient care. All patients presenting as outpatients or inpatients in the defined study period and receiving a virological test were included in the analysis. The decision as to whether a virological diagnostic test was necessary was made by the attending physician, who followed in-house guidelines. Patients aged 0–18 years were included in the analysis, if they had a positive test result at the in-house microbiology laboratory for at least one of the following viruses: RSV, Rhino-/Entero-, Noro-, Rota-, Adeno-Virus, and Influenza A or B. In cases where two viruses were detected in the same clinical sample, respective viruses were counted individually. With the onset of the COVID-19 pandemic, multiplex-PCR testing  was performed on any patient admitted to our hospital, regardless of clinical symptoms. Therefore, we also calculated the proportion of negative test results on a yearly basis (Supplementary 1). Samples were taken by nasal or pharyngeal swabs  or via stool sample (Noro/Rota). All samples were tested by immunofluorescence assay .At the Hauner Children's Hospital, a large tertiary care university hospital, the number of accident and emergency (A&E) visits for respiratory or gastrointestinal infections as well as the number of microbiologically detected viral infections in patients between 2019 and August 2021 were investigated. Our analysis is based on results from a total of 32,506 routine clinical specimens of both outpatients and inpatients seen at our hospital between 2017 and 2021. Of these, 3086  and second lockdown (December 2020–March 2021) in Munich, a decrease in the number of emergency visits and detected viral infections was observed (data not shown). However, after relaxation of NPIs following the first lockdown, numbers of microbiologically confirmed viral infections increased from July 2020 to October 2020 compared to 2017–2019 , a significant increase in positive results over all months was observed for RSV, Rhino-/Enterovirus, Noro-virus, and Influenza A, while Influenza B and Rota-virus were not detected more frequently. In 2021 (even when only accounting for the months January–October), the detections of Rhino-/Enterovirus, and Influenza A and B were significantly elevated compared to 2017–2019. Virus detection numbers also varied from 2020 to 2021 showing a significant increase for RSV, Rhino-/Enterovirus, and Influenza A and B. Gender distribution was equal in all viruses between 2017 and 2021. Mean age for RSV and Rhino-/Enterovirus was higher in 2021 compared to 2020, but otherwise stable for other viruses and time points  .While the epidemiological patterns of respiratory viruses showed impressive changes compared to previous years, number and distribution of gastrointestinal viruses varied only slightly (data not shown). From February to November 2020, hardly any cases of Rota-virus infections were observed at our clinic. However, following the end of the second lockdown, an increase in Rota-virus cases outside the usual season was noted. This was comparable to the number of virus detections in 2019 though.Noro-virus infections, on the other hand, occurred a bit more frequently in the summer of 2021 compared to previous years.n = 3), November (n = 9), and December (n = 9), and 58 children were tested positive until October 2021, with highest numbers in April (n = 10) and September (n = 14). Thus, SARS-CoV-2 had no significant impact on the observed increase in respiratory-tract infections and played only a minor role in pediatric patients until the end of this analysis  had an immense impact on the occurrence of viral infections during and after the lockdown periods. While respiratory-tract infections were barely observed during the first and the second lockdown, our data show an overwhelming increase in virus detections particularly for RSV and Rhino-/Enterovirus after relaxation of NPIs. Seasonal patterns of some viruses changed significantly.Of note, up until August 2021, no off-season peaks of influenza A/B have occurred in our hospital. This might be due to the fact that these infections are vaccine-preventable, so that the impact of SARS-CoV-2 on these viruses may have been limited.Point-of-care diagnostic tests (POCT), including both antigen-based assays and rapid PCR methods, have been extensively used in pediatric settings . Rapid mThe increase in microbiologically confirmed RSV and Rhino-/Enterovirus infections since May 2021 was impressive  and illustrates the dramatic impact of public health measures on this epidemiology.Since the onset of the COVID-19 pandemic and the resulting non-pharmaceutical preventive measures, the epidemiological picture of non-SARS-CoV-2 viral infections has changed fundamentally. The overall rise of old foes—the increase in “non-SARS-CoV-2” viral infections—has a very concerning immediate impact on the care of pediatric patients with a shortage of hospital capacities. More importantly, it may also have long-term consequences on child health in the years to come, since it is still unclear whether the significant increase in Rhino-/Enterovirus infections observed now will lead to an increase in future asthma and wheeze exacerbations. Thus, the observed increase in microbiologically confirmed viral infections following both the first and second lockdown should trigger further investigations and highlights the importance of acquiring natural immunity against common viral infections for children and the collateral effects of the introduction of infection control and social distancing measures.Supplementary file1 (PDF 340 KB)Below is the link to the electronic supplementary material.


Genomic prediction of complex traits across environments, breeding cycles, and populations remains a challenge for plant breeding. A potential explanation for this is that underlying non-additive genetic (GxG) and genotype-by-environment (GxE) interactions generate allele substitution effects that are non-stationary across different contexts. Such non-stationary effects of alleles are either ignored or assumed to be implicitly captured by most gene-to-phenotype (G2P) maps used in genomic prediction. The implicit capture of non-stationary effects of alleles requires the G2P map to be re-estimated across different contexts. We discuss the development and application of hierarchical G2P maps that explicitly capture non-stationary effects of alleles and have successfully increased short-term prediction accuracy in plant breeding. These hierarchical G2P maps achieve increases in prediction accuracy by allowing intermediate processes such as other traits and environmental factors and their interactions to contribute to complex trait variation. However, long-term prediction remains a challenge. The plant breeding community should undertake complementary simulation and empirical experiments to interrogate various hierarchical G2P maps that connect GxG and GxE interactions simultaneously. The existing genetic correlation framework can be used to assess the magnitude of non-stationary effects of alleles and the predictive ability of these hierarchical G2P maps in long-term, multi-context genomic predictions of complex traits in plant breeding. The genHierarchical G2P maps provide a multi-trait context for investigations into the importance of interactions in genomic prediction. Complex trait phenotypes, such as grain yield, can be viewed as the product of multiple component traits. The hierarchical structure allows intermediate processes , such asIn quantitative genetics, hierarchical G2P maps have been developed based on path analysis . The speIn plant science, decades of experiments led to the development of hierarchical G2P maps for plant breeding that allow predictions across a wide range of growing conditions . Crop Gra priori or from simulation  and the environment changes. These non-stationary effects of alleles are determined by interactions between genetic loci, traits, and the environment. Non-stationary effects of alleles result in low prediction accuracy across breeding cycles, populations and environments. As discussed above, the development of hierarchical G2P maps has been shown to improve the genomic prediction of non-stationary effects of alleles across breeding cycles and environments. The simultaneous specification of GxG and GxE interactions in hierarchical G2P maps may help to more thoroughly explore the impact of non-stationary effects of alleles on the long-term response to selection of plant breeding programs.The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.OP and MC conceived and designed the perspective. OP wrote the first manuscript draft and developed the supporting simulations. MC, KV-F, DJ, and GH helped to refine the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Artificial resonant metamaterial with subwavelength localized filed is promising for advanced nonlinear photonic applications. In this article, we demonstrate enhanced nonlinear frequency-agile response and hysteresis tunability in a Fano-resonant hybrid metamaterial. A ceramic cuboid is electromagnetically coupled with metal cut-wire structure to excite the high-Q Fano-resonant mode in the dielectric/metal hybrid metamaterial. It is found that the significant nonlinear response of the ceramic cuboid can be employed for realization of tunable metamaterials by exciting its magnetic mode, and the trapped mode with an asymmetric Fano-like resonance is beneficial to achieve notable nonlinear modulation on the scattering spectrum. The nonlinear tunability of both the ceramic structure and the ceramic/metal hybrid metamaterial is promising to extend the operation band of metamaterials, providing possibility in practical applications with enhanced light-matter interactions. Beginning of metamaterial refers to a class of artificial structures that possess properties unattainable in nature materials. These structures usually consist of subwavelength-sized metallic particles (known as meta-atoms) –4. In sp3 (BST)] on a teflon substrate. Peng et al.  is a level of power in decibels referenced to 1 mW by the definition P [dBm] = 10 log10(P[mW]/1[mW]).In the experiments, the sample was placed in a WR-90 rectangular waveguide and was measured by a vector network analyzer. The cuboid is placed at a distance away from center of substrate along the


Albeit the effort to develop targeted therapies for patients with high-grade gliomas (WHO grades III and IV) is evidenced by hundreds of current clinical trials, radiation remains one of the few effective therapeutic options for them. This review article analyzes the updates on the topic “radiotherapy of high-grade gliomas” during the period 1 January 2021–30 June 2021. The high number of articles retrieved in PubMed using the search terms (“gliom* and radio*”) and manually selected for relevance indicates the feverish research currently ongoing on the subject. During the last semester, significant advances were provided in both the preclinical and clinical settings concerning the diagnosis and prognosis of high-grade gliomas, their radioresistance, and the inevitable side effects of their treatment with radiation. The novel information concerning tumor radiosensitization was of special interest in terms of therapeutic perspective and was discussed in detail. The earliest surgical interventions for high-grade glioma (HGG) date to 1884 and resulted in the patient’s death less than a month after surgery . The HGGAccording to the Oxford Centre for Evidence-based Medicine, there is level 1 evidence for the use of RT in previously unirradiated HGG patients, with numerous randomized controlled trials showing a clear survival benefit C] pyruvate for differentiating radiation necrosis from brain tumors has been investigated in vivo by Park et al. . ConventElderly patients (defined as age ≥ 65), patients with poor performance status (defined as Karnofsky performance status (KPS) < 60 or Eastern Cooperative Oncology Group Performance Status (ECOG PS) > 2), regardless of age and those where brainstem infiltration occurs, all have worse outcomes . AdditioThe mutational spectra following RT in 190 paired primary and recurrent gliomas and 3693 post-treatment metastatic tumors were analyzed by Kocakavuk et al. . RT was A mechanism-based, mathematical model that characterizes glioma cells’ temporal response to single-dose RT in vitro by explicitly incorporating time-dependent biological interactions with IR was developed by Liu et al. . The proThe neurovascular units responsible for functional connectivity may persist in the HGG tumor albeit with altered magnitude . It has HGGs are made up of multiple populations of tumor cells, among which those with the ability to initiate tumor development, herein referred to as glioma initiating cells (GIC), are of utmost importance. GICs often exhibit stem cell properties and may be constitutively less sensitive to radiation than the tumor mass, thus leading the tumor relapse after the end of the radiotherapy cycle. It is unclear by which mechanisms GICs resist the toxic effects of radiation, although DNA repair is probably one of the mechanisms involved . To idenPARK7 is a ubiquitous human protein involved in many cellular processes including cell proliferation, transcriptional regulation, cell differentiation, protection from oxidative stress, and maintenance of mitochondrial function. Its possible effects on the stemness and radioresistance of GICs has been studied by Kim et al. . PARK7 wHGG tumor recurrence occurs mainly in the peritumoral brain zone . The mRNBoth the perivascular niche and the integration into multicellular networks by tumor microtubes extension may be associated with resistance to therapies in HGG . By longProhibitin regulates mitochondrial ROS production in GICs, thus facilitating their RT resistance . ProhibiThe interaction between the SP1 protein and the pyrine domain of the NLR family (NLRP6) and their role in glioma cell activity has been studied by Yu et al. . SP1 andIrradiation of the brain can lead to the onset of a tumor-friendly microenvironment. Astrocytes, when pre-irradiated, increase the stemness and survival of co-cultured glioma cells , and mic2 partial pressure lower than 10 mmHg) is a possible radioresistance factor in HGG . Si. Si68]. Mice were transplanted with HSC transduced with lentiviral vector expressing the soluble fusion protein of the TGFβ receptor II-Fc under regulation of the MMP14 promoter. This TGFβ inhibitory therapy was compared with tumor irradiation, the combination of the two therapies and control. The survival of the mice was monitored to assess the long-term benefits of the therapy. The combination therapy resulted in a significantly longer survival time with respect to the control group and TGFβ blocking monotherapy a. In addFL/+), and defective (nPAFL/FL) tumors were irradiated with three daily fractions to the brain, each of 10 Gy. The high radiosensitivity of glioma cells in nPAFL/FL mice resulted in a tripling of median survival after RT (FL/FL) did not translate into improved survival after RT in vivo  technology was used to investigate whether the deficiency of the ataxia telangiectasia mutated (ATM) protein in mouse models of DIPG may allow increasing the sensitivity of the tumor to radiation  69,70].,70.69,70FL/+ mice retaining Atm expression. While the survival of mice with p53-deficient tumors tripled after irradiation , the survival was augmented 12-fold in mice carrying p53 wild-type tumors   on the radiosensitivity of glioma cells has been investigated by Zhao et al. . ImmunohNile et al. have studied the radiosensitization of glioma cells by inhibitors of glycolysis (2-DG) and mitochondrial function (metformin) . The radThe radiosensitizing effect of olanzapine has been evaluated in U87 GB cells . OlanzapPorphyrins such as 5-aminolevulinic acid-induced protoporphyrin IX selectively accumulate in neoplastic cells and are currently used for the fluorescent-guided surgical resection and photodynamic therapy of HGG. Overall, 5-aminolevulinic acid has been suggested as a radiosensitizer by increasing the oxidative stress in neoplastic cell mitochondria and enhancing the host immune response .A complex consisting of two different nanoparticles, Au-OMV (gold nanoparticles) and OMV (membrane vesicles of E. coli) in combination with RT, produced radiosensitizing and immunomodulatory effects that inhibited the growth of both subcutaneous and orthotopic G261 tumors in C57BL/6 mice . Longer The RT minibeam is a type of fractional RT that uses submillimeter beams of radiation . An incrCurcumin has been proposed as a therapeutic agent with radiosensitizing potential in brain tumor therapy . No inteUpdated guidelines for the diagnosis and management of adult patients with diffuse gliomas have been recently provided by the European Association of Neuro-Oncology (EANO) . The diaThe hypothesis that the time at which the HGG treatment is carried out may influence the efficacy and/or toxicity of RT has been studied by Sapienza et al. . The timThe recommended phase II dose, safety/tolerability, and preliminary efficacy of combining pembrolizumab, an anti-PD1 monoclonal antibody, with hypofractionated stereotactic irradiation and bevacizumab in patients with recurrent HGGs have been investigated . The comMagnetic hyperthermia is a treatment modality where tumor sensitization to RT and CT is explored by heating up tumor cells to 40–45 °C . HGG tumHyperbaric oxygen therapy increases the oxygen tension in tissues and, theoretically, it should enhance the efficiency of RT. This subject was recently reviewed by Fernandez et al., who found grade B and C evidence that at pressures of 2 absolute atmospheres, hyperbaric oxygen therapy increased the effectiveness of IR in head and neck tumors and achieved promising results in the local control of HGG .Animal brain-tumor models have demonstrated a synergistic interaction between RT and a ketogenic diet. Metformin has in vitro anti-cancer activity through AMPK activation and mTOR inhibition  and hypo-FRT (25–40 Gy in 5–15 daily fractions) . Hence, The incidence and risk factors associated with IR-induced leukoencephalopathy in long-term survivors of HGG have been investigated by Terziev et al. . A retroThe incidence and risk factors associated with IR-induced leukoencephalopathy in long-term HGG survivors were studied by Terziev et al. . PatientPatients with HGG treated with low-activity temporary iodine-125 stereotactic brachytherapy who also had external beam RT were investigated for radiation necrosis side effects . RadiatiRadiosurgery may offer potential for improving the toxicity profile of IR by focused and precise targeting of well-defined tumors under stereotactic immobilization and image guidance . The dosInhibition of neurogenesis due to IR-induced damage in neural stem cells (NSCs) is an important mechanism underlying long-term radiation-induced cognitive impairment ,96. AfteRecent data have shown that single-fraction irradiation delivered to the whole brain in less than tenths of a second using FLASH radiotherapy (FLASH-RT) does not elicit neurocognitive deficits in mice ,98. The Proton RT has been compared to intensity modulated RT in 90 patients with newly diagnosed HGG by Brown et al. . There wThe clinical and therapeutic factors associated with the long-term risk of secondary neoplasm (SN) of the CNS after cranial irradiation in childhood or adolescent cancer survivors have been quantified . After aUsing a tumor registry, Rodrigues et al. sought to characterize the risk of secondary tumor (SN) development after external beam RT (EBRT) of pediatric low-grade gliomas . A totalEpilepsy is a common complication in HGG patients after undergoing tumor surgery combined with chemotherapy and/or RT. A model for predicting the risk of epilepsy occurrence in such patients has been provided: a total of 219 patients with gliomas were reviewed. Multivariate analyses revealed that age, WHO glioma classification, CD34, EGFR, O6 methylguanine DNA methyltransferase, and vimentin were predictors of risk of epilepsy occurrence . A nomogDue to unacceptable side effects and limited efficacy, escalating RT doses for HGG may be not a viable strategy. To improve the overall effectiveness of currently employed RT toward HGG, several tumor-specific radio-sensitizing drugs are under development . However