Previous studies have reported correlates of bodily self-illusions such as the rubber hand in signatures of rhythmic brain activity. However, individual studies focused on specific variations of the rubber hand paradigm, used different experimental setups to induce this, or used different control conditions to isolate the neurophysiological signatures related to the illusory state, leaving the specificity of the reported illusion-signatures unclear. We here quantified correlates of the rubber hand illusion in EEG-derived oscillatory brain activity and asked two questions: which of the observed correlates are robust to the precise nature of the control conditions used as contrast for the illusory state, and whether such correlates emerge directly around the subjective illusion onset. To address these questions, we relied on two experimental configurations to induce the illusion, on different non-illusion conditions to isolate neurophysiological signatures of the illusory state, and we implemented an analysis directly focusing on the immediate moment of the illusion onset. Our results reveal a widespread suppression of alpha and beta-band activity associated with the illusory state in general, whereby the reduction of beta power prevailed around the immediate illusion onset. These results confirm previous reports of a suppression of alpha and beta rhythms during body illusions, but also highlight the difficulties to directly pinpoint the precise neurophysiological correlates of the illusory state. The rubber hand illusion serves as an important paradigm to investigate the neurophysiological processes underlying multisensory body perception and the sense of body ownership. During the rubber hand illusion (RHI) the synchronous stimulation of an artificial hand in view and of participants’ occluded hand lets participants feel the rubber hand as becoming a part of their own body –3. DespiOne group of neuroimaging (EEG) studies has focused on signatures of rhythmic, i.e. oscillatory, brain activity. These studies focused on classical versions of the illusion involving a rubber hand , 5, on iYet, given that individual studies used different experimental setups to induce the illusion, or used different control conditions to isolate those neurophysiological signatures related to the participant’s illusory state, the reliability and specificity of these results remain unclear. That is, the body of previous studies leaves it unclear whether the same electrode-frequency-wise pattern of oscillatory activity differentiates the illusory-state from non-illusory states regardless of the precise experimental conditions. Importantly, none of the previous studies directly probed whether the reported changes in alpha and or beta band activity indeed arise directly around the onset of the subjective illusion , 22. In We here address these questions in an explorative study  and quanThe data analysed here was obtained during a previous study, where we report the behavioural data and an analysis of evoked responses .Participants were informed about the details of the study and provided written informed consent prior to participation. All procedures were approved by the Ethics Committee of Bielefeld University. Experiments took place in a darkened and electrically shielded room . To ensure that participants in the main study were indeed able to feel and report the rubber hand illusion we conducted a pre-screening. For this, a group of 54 participants was invited, none of whom reported having participated in a study on body illusions previously. The screening session included the two Illusion conditions and the two Incongruent conditions, each presented in a pseudo-random order. Details of the experimental conditions are provided below. Note that in the following we use the uppercase term Illusion to refer to the experimental condition and the lowercase term illusion for the general phenomenon. Participants were not informed on the possible behavioural or phenomenological outcomes of the single conditions, the nature of the different Illusion and Control condition and the nature of the visuo-tactile stimulation. To determine whether and when participants felt the illusion we capitalized on the key item from the rubber-hand questionnaire  and instA total 24 participants were included in the main study. During the main study, the five conditions described below were each repeated 4 times, with trials administered in a pseudo random order for each participant. Each trial lasted for 3 minutes of visuo-tactile stimulation (180 stimulation events). We determined the onset of the subjective illusion as the time of the button press made by the participant on each trial. Administering the rubber hand questionnaire multiple times per experiment is unlikely to yield sensitive results, and hence we relied on the button press response as a test of the main item of the questionnaire pertaining to the embodiment of the rubber hand. We also administered the full questionnaire at the end of the first repeat of each of the two Illusion conditions . Electrode offsets were kept below 25 mV and the acquisition rate was 1028 Hz. The electrooculogram (EOG) was recorded using 4 additional electrodes placed at the outer canthi and below participants’ eyes. The data were analysed using Matlab  and the FieldTrip toolbox . The datThe time-averaged power in different frequency bands was extracted in Fieldtrip using discrete prolate spheroidal multi-tapers. We computed the time and epoch-averaged power at frequencies between 5 and 49 Hz . Power estimates were obtained for each electrode separately. Depending on the specific analysis, we either combined all Illusion epochs and all Incongruent epochs respectively, or we derived the power for Illusion or Incongruent conditions separately for each hand position. We then contrasted Illusion, Incongruent and Real epochs (see Statistics below).In a separate analysis we quantified the change in the power around the subjective illusion onset. For this, we derived the power in two shorter time windows: one comprised the 10 epochs prior to the button press in Illusion trials (from -12 to -2 relative to the epoch containing the button press) and one comprised the 10 epochs after this (+2 to +12). We avoided artefacts potentially arising from the button press itself by excluding the 4 epochs immediately around the button press , 43. TheWe also implemented a region of interest (ROI) based analysis. This was done for two reasons: first, to allow a confirmation of the results obtained using the unbiased approach, and second to allow a comparison to previous studies. These have reported significant effects across electrodes covering premotor and parietal sites , frontocentral and parietooccipital sites (5) and medial sensorimotor and premotor cortices (10). Hence, we chose the ROIs to cover the significant effects from the unbiased approach c.f.  and thos10.5281/zenodo.4849568) whereby we relied on the Jeffreys-Zellner-Siow (JZS), as recommended [a priori for these specific analyses. Still, we asked whether the sample of n = 22 would be sufficient to reproduce previous reports of changes in oscillatory activity associated with body-related illusions. From three studies we derived the effect sizes for the main contrast of interest from the numbers reported in the text, tables or figures : theses yielded values of Cohen’s D of 0.5, 0.89 and 1.2 respectively. For a paired two-sided t-test with an alpha level of 0.01 and a power of 90% our sample size would be sufficient to yield a significant effect for two of these three previous studies.The comparisons of interest were between the group-level average power contrasted between conditions, such as between Illusion and Incongruent, or between Illusion and Real, or between the epochs prior to and those subsequent to the illusion onset. To test for such differences across electrodes and frequency bands we relied on a cluster-based permutation procedure . Specifiommended . Bayes fommended , 46. Wheommended . TherefoThe main focus was to compare strength (power) of rhythmic brain activity between the illusory state and the different control conditions. To illustrate the overall spectral power of the EEG signals, In a first approach we quantified statistical differences between Illusion and control conditions across electrodes and frequencies. For this we relied on cluster-based permutation procedures to test for differences in the group-average power (paired two-sided t-tests), which also controls for multiple comparisons along frequencies and electrodes. When combining both hand positions, this revealed a significantly reduced power during Illusion compared to Incongruent epochs around the alpha and beta bands  is observed consistently in both arrangements of hands used to induce the illusion and between the different statistical contrasts used to isolate the illusion effect. If so, this would speak in favour of an effect that generalizes across statistical comparisons used to isolate an illusion correlate. Second, it allowed us to probe whether any reduction in power is comparable between hemispheres or whether this is possibly lateralized. The electrodes and frequencies of interest were determined based on the above results Click here for additional data file.


Prognosis of nephrotic syndrome has been evaluated based on pathological diagnosis, whereas its clinical course is monitored using objective items and the treatment strategy is largely the same. We examined whether the entire natural history of nephrotic syndrome could be evaluated using objective common clinical items.Machine learning clustering was performed on 205 cases from the Japan Nephrotic Syndrome Cohort Study, whose clinical parameters, serum creatinine, serum albumin, dipstick hematuria, and proteinuria were traceable after kidney biopsy at 5 measured points up to 2 years. The clinical patterns of time-series data were learned using long short-term memory (LSTM)-encoder–decoder architecture, an unsupervised machine learning classifier. Clinical clusters were defined as Gaussian mixture distributions in a two-dimensional scatter plot based on the highest log-likelihood.Time-series data of nephrotic syndrome were classified into four clusters. Patients in the fourth cluster showed the increase in serum creatinine in the later part of the follow-up period. Patients in both the third and fourth clusters were initially high in both hematuria and proteinuria, whereas a lack of decline in the urinary protein level preceded the worsening of kidney function in fourth cluster. The original diseases of fourth cluster included all the disease studied in this cohort.Four kinds of clinical courses were identified in nephrotic syndrome. This classified clinical course may help objectively grasp the actual condition or treatment resistance of individual patients with nephrotic syndrome.The online version contains supplementary material available at 10.1007/s10157-022-02256-3. Nephrotic syndrome is characteristic by massive proteinuria, edema, and hypoalbuminemia . NephrotThe overall prognosis of nephrotic syndrome has not been evaluated based on objective clinical items. Currently, key clinical information and decisions, such as prediction of the prognosis and determination of treatment strategy, rely on kidney biopsy, and pathological diagnosis has difficulty in eliminating subjectivity. The fact that kidney biopsy is rarely performed repeatedly, due to its risk and tendency to be procedurally cumbersome, also suggests that it is preferable to explore objective methods to monitor nephrotic syndrome. Usually, the clinical course of nephrotic syndrome is followed by physiologic findings and laboratory test values. The treatment strategy for nephrotic syndrome is often common and mainly utilizes immunosuppressive therapy . TherefoNephrotic syndrome is a representative rare and intractable disease. Rare and intractable diseases share common problems in research and development. Smaller patient populations yield limited information on diseases, and multifactorial pathogenesis may result in a complex set of symptoms. It is necessary to overcome this problem to elucidate the natural history of rare and intractable disease, including nephrotic syndrome. Deep learning is a method of artificial intelligence technology that may help to unravel potential patterns of multiple factors. Deep learning methods have been applied in the analysis of clinical patterns of several diseases from complex combinations of clinical parameters. Additionally, an autoencoder (self-encoder), an unsupervised machine learning method, is suitable for learning objectively and without bias, even with a small number of cases –15. A coIn this study, we aimed to mathematically classify the clinical course of nephrotic syndrome based on machine learning algorithms using clinical variables. The Japan Nephrotic Syndrome Cohort Study (JNSCS) aims to clarify the clinical course of nephrotic syndrome . ThroughThe JNSCS is a multicenter cohort study of primary nephrotic syndrome with a 5-year follow-up period. The main purpose is to elucidate the incidence rates of major clinical outcomes and to assess the effectiveness of immunosuppressive therapy in Japan. Details of the study design were previously described . BrieflyThe study protocol of JNSCS was approved by the ethics committee of Osaka University Hospital  and the institutional review board of each participating hospital. All procedures performed in the present study were in accordance with the Declaration of Helsinki.In this study, the long short-term memory (LSTM)-encoder–decoder architecture, an unsupervised machine learning classifier, was applied. To classify the severity of the clinical course of patients, an existing disease type classification is necessary as the objective variable in supervised machine learning. Since disease classification is generally based on clinical information at the time of initial diagnosis, the predicting of aggravation is not always accurate. Such teacher data itself can form a learning bias and may hinder the objective classification of clinical course variation patterns. The unsupervised machine learning-based time-dependent analysis has the advantage of objective classification of the clinical course.The first step of this architecture is to apply the LSTM neural network . LSTM lehttps://github.com/cran2367/understanding-lstm-autoencoder#readme.The second step is to apply an autoencoder. An autoencoder is a learning model that makes the input and output the same, and is a neural network widely used for dimensional compression and feature extraction. The compressed dimensions can be visualized as a scatter plot with one case as one point if the intermediate layer is two-dimensional or three-dimensional . This inFor the LSTM-encoder–decoder architecture, the input values of the encoder have 5 dimensions (5 items), followed by the output dimensions of 24 in the first layer of LSTM, 12 in the second fully bonded layer, and 2 in the third layer of LSTM. The decoder restores the input values in the reverse order of the encoder. The mean square error was used for the loss function. Learnings were performed in 5 sets with the conditions of 4 epochs per set, 1,000 learnings per epoch, and a batch size of 10 data points. Learning was not performed in more than the number of epochs where no significant reduction in loss was observed. The learning result was defined by the Gaussian mixture distribution in the cluster in the two-dimensional scatter plot . Each caThe background demographics of the participants are shown in Table Based on these data, we investigated the clinical time course of nephrotic syndrome. To learn the fluctuation pattern of time-series data consisting of multiple clinical items based on the relationship between measurement points, we utilized the LSTM neural network Fig. . LSTM haThe clinical parameters included serum creatinine, serum albumin, dipstick hematuria and proteinuria, and urine protein per creatinine ratio. This selection was based on the following concept; (i) fluctuating items, but not solid ones such as age and sex, which can parallelly change with the clinical course, and (ii) items used to monitor clinical course are selected. Treatment of steroid greatly affects the clinical course of nephrotic syndrome, and a fraction of patients with nephrotic syndrome is treated with steroid before the kidney biopsy. To avoid the treatment bias, analysis was performed using data after kidney biopsy. Both dipstick proteinuria and urine protein per creatinine ratio are included, since they occasionally show the discrepancy . Using uThe mean values of each clinical item for each cluster are shown in chronological order Fig. . Based oThe distribution of the original kidney diseases in each cluster is shown in Table The average blood and urine test values at the time of kidney biopsy for each group are shown in Table Out of 205 cases, 19 cases were not treated with steroids or immunosuppressive drugs during the observational periods Below is the link to the electronic supplementary material.


Yinlong and Hualianceratops from the early Late Jurassic of Xinjiang and Chaoyangsaurus from the Late Jurassic of Liaoning Province. By micro-computed tomographic analyses, our study has revealed significant new information regarding the dental system, including no more than five replacement teeth in each jaw quadrant; at most one replacement tooth in each alveolus; nearly full resorption of the functional tooth root; and occlusion with low-angled, concave wear facets. Yinlong displays an increase in the number of maxillary alveoli and a decrease in the number of replacement teeth during ontogeny as well as the retention of functional tooth remnants in the largest individual. Chaoyangsaurus and Hualianceratops have slightly more replacement teeth than Yinlong. In general, early-diverging ceratopsians display a relatively slow tooth replacement rate and likely use gastroliths to triturate foodstuffs. The difference in dietary strategy might have influenced the tooth replacement pattern in later-diverging ceratopsians.The dental system of ceratopsids is among the most specialized structure in Dinosauria by the presence of tooth batteries and high-angled wear surfaces. However, the origin of this unique dental system is poorly understood due to a lack of relevant knowledge in early-diverging ceratopsians. Here, we study the dental system of three earliest-diverging Chinese ceratopsians:  Protoceratops which retain single-rooted teeth which, although compacted rostrocaudally, have no more than 2 replacement teeth in each alveolus  imaging. Three earliest-diverging ceratopsians were studied: s youngi . Yinlongg, China . Yinlongividuals , whereasmandible . Chaoyanandibles . This stPremaxillary teeth. IVPP V18638 only preserves the right maxilla . All preThe digital reconstructions show that the second functional premaxillary tooth is larger than all maxillary or dentary teeth, and the third premaxillary tooth crown is quite short . The labAll well-developed roots of the functional teeth in the premaxilla are nearly conical and compressed labiolingually into an oval cross-section. Compared with other premaxillary teeth, the tip and root of the second premaxillary tooth curve more distally to appear arched in lateral view  and 3C,HLiaoceratops have cone-shaped crowns and are similar in morphology to their corresponding functional teeth  . In lingal teeth . In LiaoYinlong.Maxillary teeth. The incomplete right maxilla of IVPP V18638 contains 10 functional teeth and 3 empty alveoli . The lefThe maxillary tooth row is curved lingually  and 4B. Chaoyangsaurus, Psittacosaurus, Liaoceratops, and Archaeoceratops  has the most replacement teeth in the maxilla and CT data reveal 3 replacement teeth out of 10 functional teeth inside the right maxilla  preserves the 2 premaxillary teeth. The premaxillary teeth of Chaoyangsaurus are ellipsoidal in cross-sections and the crowns are not expanded mesiodistally at their base as in Yinlong. The apices of the crowns are missing  of Yinlong. Therefore, we conclude that the resorption rate may decrease through the ontogeny of Yinlong.Although the accurate ontogenetic stage of these 4 specimens is not clear, the ontogenetic variation of the tooth replacement pattern in this taxon can be discussed relative to the specimens’ size difference. Previous research suggests that the maxilla in 13 teeth . Our 3D ceratops . In largceratops . This phYinlong, Hualianceratops, and Chaoyangsaurus exhibit features that differ from neoceratopsians including small numbers of teeth in tooth rows, concave surfaces on the lingual side of the maxillary crowns and labial side of the dentary crowns, loosely packed tooth rows, and regular occlusal surfaces. There are also some differences between early-diverging taxa. The crowns of unworn teeth in Yinlong and Hualianceratops are subtriangular and bear primary ridges located at the midline of the crowns  exhibits similar concave surfaces on the occlusal surface of the crowns as in Yinlong, Chaoyangsaurus, and Hualianceratops. These early-diverging ceratopsians bear similar low-angled wear facets but the depression on the occlusal surface indicates a different occlusion from the shearing occlusal system as in neoceratopsians. In addition, the primary ridges are located at the midline of the crowns in P. lujiatunensis.Liaoceratops, Archaeoceratops, and Auroraceratops, the crowns developed slightly more prominent and narrow primary ridges and the teeth of Leptoceratops and Protoceratops developed the most prominent primary ridge outside of ceratopsids (Archaeoceratops (IVPP V11114) are located relatively mesial to the midline of the crowns in contrast to its maxillary dentitions and other neoceratopsians. Late-diverging neoceratopsians including Leptoceratops and Protoceratops have deeper indentations mesial and distal to the primary ridge, as in ceratopsids, than early-diverging neoceratopsians , and the root of the replacement tooth in Chaoyangsaurus is relatively vertical and is appressed to the functional tooth , an alveolus bears at most 2 replacement teeth with a relatively lower replacement rate , each alveolus bears at most 1 replacement tooth indicating lower replacement rates than late-diverging ceratopsians , IVPP V18636, IVPP V18637, and IVPP V18638.Three earliest-diverging ceratopsians eviously . Four skYinlong described here with the skull length  estimated to be about 13 cm. Only the right maxilla, jugal, squamosal, postorbital, quadratojugal, and pterygoid are preserved (IVPP V18638 (CT scanned). This is the smallest specimen of reserved . The rigIVPP V18636 (CT scanned). This specimen consists of a nearly complete skull with a mandible and partial postcranial skeleton . The skuIVPP V14530 (CT scanned). The holotype preserves a nearly complete skull with a mandible and nearly complete postcranial skeleton . The skuYinlong with a skull length measured as 23 cm. Only the premaxillary and maxillary dentitions are studied.IVPP V18637 (CT scanned). The preserved elements on this specimen consist of a nearly complete skull lacking a mandible . It is tChaoyangsaurus (IGCAGS V371) includes the dorsal part of a skull and a nearly complete mandible  was also CT scanned, but we were unable to study teeth due to poor preservation. An additional specimen, IVPP V28614 (field number WCW-05A-2), which only preserves the left dentary, is described here for comparison although it was not CT scanned  and strongly rugose sculpturing present on the lateral surface of the dentary  to render 3D models of bones and teeth. The program builds meshes based on density differences in each specimen and applies material properties to each mesh.Edmund, 1960 hypothesized that teeth in reptiles are replaced in an ordered, alternating segmented pattern called a Zahnreihe. Each Zahnreihe consists of a series of teeth, including unerupted teeth, where a rostrally placed tooth is more mature than a more caudal one along the same tooth row  no or slight wear on marginal denticles with an open pulp cavity; (F2) wear on marginal denticles and a slightly concave lingual wear facet with a large pulp cavity; (F3) extensive wear on marginal denticles and a concave lingual wear facet with the depression on the lingual surface of the roots or a bud of the replacement tooth; (F4) polished and greatly worn marginal denticles and a highly concave lingual wear facet with a broken pulp cavity or the emergence of a replacement tooth. Three stages of replacement teeth are recognized: (R1) small incipient tooth showing the tip of the crown; (R2) crown fully erupted; (R3) crown reaches the base of the functional crown.ooth row . The dis-spacing . Previou-spacing . Becausenosaurus , as wellZ-spacing and the Z-spacing of Yinlong is described by the mean of all measurements.Based on stage division, each functional tooth and replacement tooth was plotted on a graph whose vertical axis is the growth stage and the horizontal axis is the tooth position. In the graph, these teeth show a regular pattern that the growth stage decreases progressively and periodically over several tooth positions. Each degressive sequence represents a Zahnreihe indicated by a series of teeth linked with each other as black lines . The dis This paper employs virtual analytical methods to thoroughly examine the evolution of the dental system of Jurassic ceratopsian dinosaurs. The rich dataset and level of analytical detail on tooth development and replacement patterns are accompanied by careful interpretations of functional morphology and dietary adaptation, making the paper particularly valuable for main-stream paleontologists while still appealing to the wider evolutionary biology community. public reviews designed to be posted alongside the preprint for the benefit of readers; (ii) feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.Our editorial process produces two outputs: (i) Decision letter after peer review:eLife. Your article has been reviewed by 3 peer reviewers, including Yonatan Sahle as the Reviewing Editor and Reviewer #1, and the evaluation has been overseen by George Perry as the Senior Editor. The following individual involved in review of your submission has agreed to reveal their identity: Marcos Gabriel Becerra (Reviewer #2).Thank you for submitting your article "Computed tomographic analysis of the dental system of three Jurassic ceratopsians: implications for the evolution of the tooth replacement pattern and diet in early-diverging ceratopsians" for consideration by The reviewers have discussed their reviews with one another, and the Reviewing Editor has drafted this to help you prepare a revised submission.Essential revisions:1) To demonstrate that the conclusions in the article are supported by the data presented, the authors should add the raw metric data on the dimensions of each functional and replacement tooth.2) Raw micro-CT scans  must be made available via a suitable permanent archive. If this is not possible for any reason, the authors must discuss their justification with the Senior Editor.Reviewer #1 (Recommendations for the authors):AbstractThe last few sentences of the abstract focus exclusively on Yinlong and can benefit from a sentence on new information about the two other Ceratopsian genera that make up the focus of the paper.Materials and MethodsThe first paragraph can benefit from a revision in which only a quick summary of the type, size and preservation details of each studied specimen is presented, with the method of analysis saved for the respective subtitles. Also, a clearer mention how much dentition is preserved and studied for the respective genera will be helpful.The subtopic on micro-CT methods could use why the method was chosen over other approaches, especially since this is also reflected in the title of the paper.Line 90: Add the location of the laboratory .Lines 99-100: Be consistent with the use of "Zahnreihen" as the plural form of "Zahnreihe"Line 100: Previous researchers…Line 354: Replace "their" with "the specimens'" for clarityLine 453: Consider revising subtitle as "Implications for…"Reviewer #2 (Recommendations for the authors):The manuscript denotes not only excellent research but also effort and time well spent to perform the 3D reconstructions. The use of opened/closed pulp cavity and its relation with wear development is innovative evidence that supports the interpretations of stages of tooth replacement, and the discussion of the specific stage represented by Yinlong, Hualianceratops, and Chaoyangsaurus in the phylogenetic framework of ceratopsian dinosaurs opens the discussion of the similarities and differences with other ornithischian lineages that also evolved specialized herbivory.Reviewer #3 (Recommendations for the authors):Could you estimate tooth formation times and replacement rates based on tooth length? Essential revisions:1) To demonstrate that the conclusions in the article are supported by the data presented, the authors should add the raw metric data on the dimensions of each functional and replacement tooth.Thank you for pointing this out. We have provided each functional and replacement tooth’s total height, maximum mesiodistal width, maximum labiolingual width of all specimens presented in TABLE S1 classified by the specimen number. These data help to support our conclusions.2) Raw micro-CT scans  must be made available via a suitable permanent archive. If this is not possible for any reason, the authors must discuss their justification with the Senior Editor.We have uploaded the raw micro-CT scanning images of all scanned specimens  in Dryad as.TIF or.BMP file format and also the reconstructed 3D files (see the link https://doi.org/10.5061/dryad.9ghx3ffk0). The detailed information of all images is provided in a TXT file ‘README_file.txt’ saved in Dryad.Reviewer #1 (Recommendations for the authors):AbstractThe last few sentences of the abstract focus exclusively on Yinlong and can benefit from a sentence on new information about the two other Ceratopsian genera that make up the focus of the paper.Chaoyangsaurus and Hualianceratops in the abstract .Thanks for your suggestion. We have added more statements on the teeth replacement pattern of Materials and MethodsThe first paragraph can benefit from a revision in which only a quick summary of the type, size and preservation details of each studied specimen is presented, with the method of analysis saved for the respective subtitles. Also, a clearer mention how much dentition is preserved and studied for the respective genera will be helpful.Thanks for your suggestion. We have reorganized the materials and the methods and made a summary of each specimen with their preservation details, size, and preserved dentitions .The subtopic on micro-CT methods could use why the method was chosen over other approaches, especially since this is also reflected in the title of the paper.Considering the reviewer’s suggestion, we have supplemented the advantage of the micro-CT methods in the first paragraph of the computed tomography. The reasons for using the method are as follows: The main body of the functional teeth and the replacement teeth are usually encased in the tooth-bearing bones excluding the crowns. Micro-CT methods help us to study the internal structures and the tooth replacement progress through the bone and rock matrix .Line 90: Add the location of the laboratory .Added as suggested .Lines 99-100: Be consistent with the use of "Zahnreihen" as the plural form of "Zahnreihe"Corrected .Line 100: Previous researchers…Modified as suggested .Line 354: Replace "their" with "the specimens'" for clarityModified as suggested .Line 453: Consider revising subtitle as "Implications for…"Modified as suggested .Reviewer #3 (Recommendations for the authors):Could you estimate tooth formation times and replacement rates based on tooth length?Tooth formation times and replacement rate can be calculated in extinct animals by counting incremental lines of deposition in tooth dentin. However, more histological experiments need to be done to acquire the mean width of von Ebner incremental lines. These experiments require not only a large amount of time but also the permission of the museum. This will be our research focus of the next stage. The current focus of our study is the tooth replacement pattern of earliest-diverging ceratopsians.


The COVID-19 pandemic has weakened the health systems in many countries particularly putting at risk efforts on the Immunization Agenda to make vaccination available to everyone, everywhere, by 2030. Immunization Agenda 2030 reconfirms the importance of reducing the absolute number of zero-dose children and increasing the proportion of children who complete their vaccinations on time. Despite the gains in promoting equity in immunization services, many children missed vaccination because of the COVID-19 pandemic that disrupted well planned strategies. The cancellation of outreach services following the COVID-19-motivated lockdown meant many children missed vaccination. The situation was further worsened by vaccination related rumors and fears. The collapse of the Primary Health Care (PHC) service provision during the epidemic may lead to higher under-five mortality similar to the Ebola Virus Disease epidemic in West Africa. The post COVID-19 recovery strategy should include strengthening the service delivery systems to remain resilient when threatened by emergencies. The recovery must therefore focus on rebuilding trust as the foundation for vaccine acceptance and demand which can only be achieved by appropriate community engagement. African children are at the highest risk of dying from vaccine preventable diseases in the world. The pandemic disrupted public health and social services across the continent and efforts to restore routine immunization services have already started. The COVID-19 pandemic presents an opportunity to build a better and more equitable immunization service delivery system that will close the yawning vaccination gap in sub-Saharan Africa. The public support and political will for vaccination is an opportunity for sub-Saharan African (SSA) countries to close the immunization equity gap that leaves more than 6 million children unvaccinated each year in the region. African leaders, ministers of health, UN organizations and national and international immunization partners must make the most of this unique chance to ensure that the right of every child born in region to be protected against vaccine preventable diseases is realized during the IA2030 decade. It is time to start planning beyond the end of the COVID-19 pandemic for a more resilient, fair and effective immunization and primary health care services.Immunization is acknowledged as probably the most successful public health intervention . CountriIn 2020 various partners meetings, countries reported substantial reduction in coverage: relative difference in DTP3 coverage of around 15% between January and April 2020 compared to same period in 2019. Rapid assessments conducted at global levels and in the Eastern and Southern Africa Region on the impact of COVID-19 on continuity of essential health services confirm the disruption in provision of essential routine services, including immunization. Although most countries adopted and implemented WHO guidelines for maintaining routine immunization [The movement restrictions and the costs of accessing vaccination reduced the utilization of immunization services. Misinformation and rumours related to infection and vaccine trials have increased and constitute a barrier. Postponement and cancelation of supplementary immunization activities (SIAs) in Eastern and Southern Africa because of the COVID-19 pandemic have increased risks of vaccine-preventable disease outbreaks and reduced population´ immunity. At least 56 million targeted individuals in 2020 have missed at least one vaccination .Immunization outreach services are an entry point for Primary Health Care (PHC) services and an opportunity for a comprehensive package of basic services. It has been documented that the number of deaths caused by malaria, measles, tuberculosis, and HIV/AIDS, attributable to health system failures during Ebola Virus Disease (EVD) epidemic in west Africa (2014-2016) outnumbered the direct deaths from EVD . StrategAt onset of the spread of the COVID-19 pandemic, countries had to tackle the unprecedented level of misinformation about the disease, which caused public misunderstanding, fear and decline in utilization of essential health services including immunization. To rebuild trust and increase acceptance and demand for vaccination services mass media engagement and community engagement are essential .Immunizations are typically offered free-of-charge as part of the national Universal Health Coverage package and programs have an obligation to ensure access to vaccinations for all. The strategies employed over the last decade to improve coverage and equity have not been effective overcoming the barriers to vaccination faced by children from poor, uneducated and marginalized households.The need to catch-up missed vaccination services post-COVID offers an opportunity to build back more equitable vaccination services. The idea of providing fair services that reach all children must become mainstreamed in the planning and monitoring of immunization services. This demands better understanding of who the under-vaccinated groups and the zero-dose children are and where they live, and the implementation of effective pro-equity strategies for overcoming the barriers that prevent parents from vaccinating their children. Programs must improve monitoring of trends in inequality and the impact of pro-equity strategies as closely as they monitor changes in overall coverage. The Equity Reference Group has guidance on the most critical determinants of low vaccination uptake and the most promising pro-equity strategies for improving access . OvercomOther contexts where programs should expect high numbers of zero-dose and partially vaccinated children are urban poor communities, nomadic populations and families in remote rural areas, in areas where health services and families are affected by insecurity and conflict, including among internally displaced people and refugees. It is important that national programs identify and quantify the number of missed children in each of these contexts (and any other country-specific contexts) and design targeted strategies for reducing access to vaccines. The start for that process is to conduct a Coverage and Equity Assessment of the vaccination services, set targets, prioritize interventions and monitor outcome  as well as process indicators (implementation of pro-equity strategies). It is important to consider structural inequalities in the health system such as the health workers and health facility ratio per population, average distances to services and cold chain capabilities as these often are important determinants of inequities in access to services.The COVID-19 pandemic has caused major disruptions in immunization programmes: measles, polio and other preventive campaigns were suspended for several months and utilization of routine immunization services was reduced due to access challenges. Prior to the COVID-19 pandemic, over 6 million children in the region missed vaccination annually. COVID-19 impacts have uncovered gaps and challenges in the performance of the immunization programme. Catching-up on lost ground will require building better systems and enhancing the equity agenda for primary health care.


There is no consensus on the optimal duration of luteal phase support (LPS) in fresh IVF cycles. Although some clinicians withdraw LPS on the day of a positive pregnancy test, most clinicians continue its administration at least up to the 8th week of gestation. In this literature review, we included several randomized clinical trials comparing early and late cessation of LPS. Most studies have found no benefit in extended administration. These studies, however, were limited by their small sample size and selection bias. Until now, only a few attempts have been made to indicate when LPS can be safely stopped based on individual patient characteristics. In conclusion, the quality and quantity of the evidence regarding LPS duration in fresh IVF cycles is currently insufficient to justify early cessation in all patients. Individualization of LPS should receive high priority in future research. Luteal phase support (LPS) has a pivotal role in the establishment and maintenance of IVF pregnancies. This has been one of the earliest evidence-based subjects to become a consensus in assisted reproduction technology (ART) . FollowiIt has been clearly demonstrated that LPS is crucial in filling the gap between the disappearance of exogenously administered hCG for ovulation triggering and the initiation of secretion of endogenous hCG from the implanting conceptus. After implantation, embryonic hCG takes over pituitary LH in supporting the corpus luteum (CL) and maintains its function until the establishment of the luteo-placental shift, at around the 8th week of gestation .Early studies have estimated that exogenously administered hCG remains in the circulation for up to 7 days , and thaIn terms of duration, without clear evidence to support the administration of luteal support beyond the day of the first pregnancy test, it has become a common practice to administer LPS until the establishment of the luteo-placental shift, at 8, 10 or even 12 weeks of gestation .Several investigators have questioned the benefit of LPS administration beyond the point of pregnancy establishment. Retrospective as well as prospective studies have compared early cessation of LPS, either at the time of positive hCG test or early pregnancy ultrasound scan, to extended administration until 7–8 gestational weeks.Kyrou et al.  conducteOther researchers demonstrated similar outcome after early and late cessation of LPS in GnRH-agonist cycles. Nyboe Andersen et al.  randomizOnly one early RCT showed higher clinical pregnancy rate (CPR) in women treated with a long GnRH-agonist protocol and received extended LPS consisting of IM 17α-hydroxyprogesterone caproate and 10 mg estradiol valerate (PC/EV) in an oily vehicle up to the 12th week of gestation .It should be noted that in the majority of the previous studies patients were carefully selected for inclusion based on normally rising hCG levels , 14, absIn an editorial addressing one of the above-mentioned RCTs  George GDespite the heterogeneity of previous studies and the bias introduced by patient selection criteria, several meta-analyses were performed to investigate the impact of extended LPS duration. In 2012, Liu et al.  publisheWhile these meta-analyses provide some reassurance regarding early secession of LPS, clinicians must take into account the limitations of the included studies as mentioned above.LPS regimens harbor discomfort and side effects and increase the cost of treatment. Therefore, clinicians should aspire to reduce the duration of LPS to the minimum. This may improve patient's convenience and compliance with treatment.https://ivf-worldwide.com/survey.html) evaluating the practice of LPS. A close look at four such surveys conducted over the last decade (2009–2019) reveals that the majority (>60%) of clinicians world-wide administer LPS until 8 gestational weeks and beyond. This rate did not change significantly over the years.While most of the above RCTs were published more than a decade ago in the leading journals of our field, the scientific community has been very conservative and generally reluctant to adopt the practice of early cessation of LPS. This is evident in the methodology being used in recent publications from our discipline, as well as by examining the results of a series of web-based surveys . The luteal phase, however, has been neglected in this sense, and the practice of “one size fits all” has become the rule in the majority of ART programs, as most patients receive the same fixed regimen of LPS.Only a few efforts have been made to indicate when LPS can be safely stopped based on individual patient characteristics. In a retrospective cohort study, Segal et al.  reportedAnother available biochemical evidence for normal implantation and embryo development is a sufficient rise in hCG levels. In a previous RCT , doublinThere is a crucial need to develop advanced techniques to evaluate the function of the CL starting from the mid-luteal phase as well as the efficiency of CL rescue process by the ensuing pregnancy . This woAlthough the current review did not include a systematic literature search, it covered the leading publications in this subject. It can be concluded that the quality and quantity of evidence regarding early cessation of LPS in fresh IVF cycles is insufficient to justify a change in the current practice of continuation until the establishment of the luteo-placental shift. Better understanding of CL function following various COS regimens and ovulation triggering agents may allow individualization of LPS regimens according to specific patient's characteristics. Individualization of LPS should receive high priority in future research.All authors contributed substantially to the concept and design, analysis and interpretation of data, drafting, and revisions.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.


Coronary artery disease (CAD) represents a modern pandemic associated with significant morbidity and mortality. The multi-faceted pathogenesis of this entity has long been investigated, highlighting the contribution of systemic factors such as hyperlipidemia and hypertension. Nevertheless, recent research has drawn attention to the importance of geometrical features of coronary vasculature on the complexity and vulnerability of coronary atherosclerosis. Various parameters have been investigated so far, including vessel-length, coronary artery volume index, cross-sectional area, curvature, and tortuosity, using primarily invasive coronary angiography (ICA) and recently non-invasive cardiac computed tomography angiography (CCTA). It is clear that there is correlation between geometrical parameters and both the haemodynamic alterations augmenting the atherosclerosis-prone environment and the extent of plaque burden. The purpose of this review is to discuss the currently available literature regarding this issue and propose a potential non-invasive imaging biomarker, the geometric risk score, which could be of importance to allow the early detection of individuals at increased risk of developing CAD. Cardiovascular disease, including CAD, constitutes the first cause of mortality in developed countries and particularly societies with a western lifestyle. Reports show that approximately one third of all deaths in patients older than 35 years are attributed to chronic heart disease. It is also estimated that 4 million patients die in Europe every year, while in Greece CAD is characterized by a mortality of 110 deaths per 100,000 people and 16,000 new cases of stable angina present every year . These fCAD is primarily associated with the formation of atherosclerotic plaques along the course of coronary arteries, a phenomenon not yet fully understood but with many contributing pathophysiologic factors. The currently accepted mechanism for coronary atherosclerosis includes the following stages: an endothelial malfunction and the subendothelial deposition of low-density lipoprotein (LDL); the oxidization of LDL; the migration of monocytes towards the subendothelial level and their transformation to macrophages; foam-cell formation; the multiplication of smooth muscle cells; and finally the apoptosis of foam cells, leading to the creation of necrotic cores. There are many systematic factors contributing to this multi-faceted process of plaque development, including hyperlipidemia, hypertension, genetic factors, and vessel characteristics defining the wall shear stress and other blood flow hemodynamic factors ,4. The notion that vascular geometric characteristics influence atherosclerosis development and progression is not new but has still not been fully studied so far due to the complexity of the issue and the abundance of different vascular visualization techniques. The predisposing factors of atherosclerosis mentioned previously apply everywhere within the vascular network of a patient and would thus be expected to lead to a diffuse and uniform thickening of the vascular wall. Nevertheless, it has been long known that different vessels or segments of the same vessel are affected to a different degree by atherosclerotic plaque formation. Namely, atherosclerotic plaques tend to occur near the origins of arterial branches or in vascular bends, due to specific flow patterns observed in such vascular segments. Such geometric parameters create an atherosclerotic-prone environment favoring either high or low shear stress . InteresModalities traditionally used for the evaluation of CAD, including invasive coronary angiography (ICA) and ultrasound, are both limited by their two-dimensional nature, while atherosclerotic vessels represent a three-dimensional structure. The introduction of modern scanners and technologies rendered coronary computed tomography angiography (CCTA) a superb and widely available modality for the evaluation of coronary anatomy and disease . This teAs it was previously suggested, the relationship between vascular geometry and atherosclerosis could be mediated by analyzing the influence of geometry on hemodynamics and flow profile. Nevertheless, in the era of modern imaging, the geometry can be directly correlated with the extent of atherosclerosis using CCTA, and this is the current target of ongoing research . The cors), while the contour distance reflected the actual length of a vessel following a rounded course (termed as Dc). The tortuosity was defined as (Dc/Ds) − 1, so that a straight vessel would yield a value of 0 tortuosity. In this study, the curvature was determined from vector representation of the vessel axis [In an angiographic study of autopsy hearts, Brinkman et al. attempted to define the variability of the coronary tree by using specific geometric parameters . This stsel axis .The variation of the anatomy of the coronary tree was further studied and catalogued in living healthy subjects during clinical biplane cine-angiography by Zhu et al. in 2009 . This grOne essential confounding factor for the study of coronary arterial tree anatomy and geometry is the fact that coronary arteries exhibit a significant movement throughout the cardiac cycle. This can be studied using clinical biplane cine-angiograms, and data so far show that both the LAD and RCA show significant variation throughout the cycle for the measures of curvature and torsion. This continuous motion is thought to influence both vessel wall mechanics and fluid dynamics, thus having implications on atherosclerosis development. Significant coefficients of variation were noted using in vivo tracking of the coronary arteries motion, with individual vessels coefficients reaching 2.28. It was found that the LAD shows greater variability of its torsion, compared with the RCA but less displacement . The fea2 between 0.17 and 0.44). Both of the time-average values of curvature and torsion and their excursion throughout the cardiac cycle were positively correlated with maximum wall thickness and cross-sectional asymmetry [The observation that dynamic changes in coronary geometry throughout the cardiac cycle influence the atherosclerosis onset and progress was also confirmed by Zhu et al. in 2003. This study used biplane cine-angiograms to assess the right coronary artery, measuring vessel length, cyclic displacement, axial strain, curvature, and torsion. Intravascular ultrasound (IVUS) was performed to measure the vascular wall thickness. Although independent geometry parameters failed to correlate with wall thickness, the linear combinations of parameters did predict thickness with high confidence . Low ESS typically occurs at the inner areas of curvatures and upstream of stenoses (2) may occur concurrently at the “neck” of a stenosis, increasing in magnitude with progressive luminal encroachment. This enhances local thrombogenicity and triggers molecular pathways implicated in fibrous cap disruption, increasing the probability of clinical manifestation as acute coronary syndrome [Although the natural history of atherosclerosis is a complex and dynamic process determined by a variety of local and systemic biological and biomechanical factors, blood-flow-induced shear stress has emerged as an essential feature of atherogenesis. ESS is the tangential force exerted on the endothelial surface that results from the friction of the flowing blood. The pattern of blood flow through a vessel depends on the flow velocity and the presence of geometric irregularities or obstructions. Flow may be either laminar or turbulent . In relaotection ,21. In cstenoses . OscillaAn experimental study published in 1983 analyzed haemodynamic data in pulsatile flow through human aortic bifurcation casts . In thisThe relationship between the geometric features of coronary bifurcations and local haemodynamic parameters was studied in models of both healthy and stenotic vessels using CFD simulations. The study by Chiastra et al. focused on the LAD/diagonal angle and showed that the bifurcation angle mildly influences the hemodynamics in both stenosed and healthy vessels . On the Among its multiple benefits, modern CCTA can help the investigation of the influence of coronary geometry on atherosclerosis by providing accurate data for the production of models in order to perform CFD simulation using patient-specific models. Such a study was performed by Peng et al. . This stThe association between left coronary artery geometry and haemodynamic characteristics was addressed by Pinho et al., who used CTA data to perform CFD analysis of the left coronary circulation. This research group evaluated the vessel’s cross-section area; the proximal LAD length; and the angles between branches and the septum, curvature, and tortuosity. It was concluded that arteries with high caliber, high angles , and high tortuosity were significantly correlated with a haemodynamic profile favoring plaque formation within the LAD. In contrast to these findings, increased proximal LAD length, angle (LMS-LCx), tortuosity (LMS-LAD and LAD-LCx), and curvature of LMS and LCx lead to a more atherosclerosis-resistant haemodynamic profile . A similThe theory that arterial geometry affects atherosclerosis onset and formation is not new, with reports on pulsatile flow through vascular branches and the hemodynamics of atherogenesis dating back to 1975 . In a stIn an early study published in 1993, Friedman et al. investigated the correlation of coronary artery geometry with the distribution of early atherosclerotic lesions. The angle formed between LCx and LAD arteries in the bifurcation of LMA was measured based on the multi-plane angiograms of the left coronary artery in fifteen autopsy specimens. The images were digitized and computationally processed in order to generate three-dimensional models of the centerlines of the lumens. A normalized index of disease severity RPI  was used to isolate the effect of geometry on disease development  from other risk factors that would apply to the entire vessel uniformly. This index divided the percentage of atherosclerotic plaque burden seen in the first 1 cm post the bifurcation by the percentage seen in the first 5 cm. Interestingly, no correlation was found between the angle and the extent of atherosclerotic burden in either the first 1 or 5 cm of the vessels. This is why the authors used the RPI, in an attempt to eliminate the effect of systemic factors, applying to the entire vessel uniformly and only study the effect of geometry on the proximal segment of the vessel. It was concluded that the RPI was negatively correlated with the LM branch angle. As a result, a small angle would lead to proximal atherosclerotic disease, an observation stronger for LCX. This observation was in-keeping with the notion that atherosclerosis affects vessels with values of ESS near zero. The stronger correlation observed with LCX was attributed to the fact that LAD is usually a continuation with LM, while LCX is usually a side-branch, originating with a larger angle as measured by ICA . ContrarA multi-plane angiographic study performed on autopsy hearts, with histologic examinations of the vascular wall, investigated the relationship between the angle of origin of LAD branches and the structural asymmetry of the branch vessels. It was found that the angle of the branch origin was positively correlated with the maximum thickness of intima and media, as well as the branch’s circumferential asymmetry. This shows that branches originating with a larger angle from the parent vessel show eccentric intimal thickening and are thus prone to atherosclerosis formation . An atteIn a recent study, CCTA was used to quantify coronary geometry and correlate it with atherosclerotic burden . Coronarn = 163), using ICA to classify the RCA shape as C-shaped or S-shaped based on the left oblique position angiographic view [n = 124) were significantly more affected by atherosclerotic lesions in their proximal and mid regions. The TIMI frame count (TFC) was significantly higher in S-shaped RCAs [Altintas et al. examined a patient population with ST elevation myocardial infarction of the RCA (hic view . It was ped RCAs .n = 116) and propensity score-matched non-ACS controls (n = 116). Atherosclerotic plaques a short distance from the coronary ostium or located within vessel bifurcations or tortuous segments were more likely to develop into culprit lesions causing an ACS. The research group concluded that CCTA-derived AGCs capturing lesion location and vessel geometry are associated with the risk of future ACS-causing culprit lesions. In particular, it was suggested that adverse geometric features may provide additive prognostic information beyond plaque assessment in CCTA.The association between lesion-level adverse geometric characteristics (AGCs) and the risk of future acute coronary syndrome (ACS) was addressed by Han et al. , who use3/g) had four times more events than patients with high coronary artery volume index (CAVi), regardless of the presence of significant stenoses. Such a result supports the idea of a normalization of atheroma burden to the volume of the coronary arterial tree. Moreover, the same research group demonstrated that CAVi is independently associated with abnormal stress myocardial blood flow (MBF), as derived from 13N-ammonia positron emission tomography myocardial perfusion imaging [In another study published in 2020, Benetos et al. investigated the long-term prognostic value of coronary artery volume per myocardial mass as a potential new imaging biomarker . To stud imaging . More imFinally, the ongoing GEOMETRY-CTA study  aims to Coronary atherosclerotic disease represents an undeniable modern pandemic with important consequences in terms of morbidity and mortality, particularly in western societies. The pathogenesis of this disease has long been studied, with many factors identified as contributing to its multi-faceted nature. Such traditional factors include systemic conditions such as hyperlipidemia and hypertension, the effect of which on the vascular wall is expected to be uniform throughout the vascular tree. Nevertheless, the observation that atherosclerotic plaques tend to affect particular points of the vascular tree raised the effect of local geometric features to the occurrence and progression of atherosclerosis. The relationship between the coronary arterial tree geometry and atherosclerotic disease has gained interest over the past years, with several reports investigating multiple aspects of this interaction. It is clear that coronary geometry influences atherosclerosis, but several aspects still require definitive answers. Such pending questions include which modality should be used (ICA vs. CCTA), whether dynamic or static measurements should be made, which exact parameters among the numerous reported should be used, and to which exact points of the coronary tree the measurements should be performed. It is widely recognized that state-of-the-art CCTA, due to the three-dimensional imaging nature, offers an unparalleled technique for the assessment of coronary arterial geometry and is expected to further advance knowledge in this field.


Oropharyngeal dysphagia (OD) is a high impact morbidity in head-and-neck cancer (HNC) patients. A wide variety of instruments are developed to screen for affective symptoms and OD. The current paper aims to systematically review and appraise the literature to obtain insight into the prevalence, strength, and causal direction of the relationship between affective symptoms and OD in HNC patients. This review was conducted in accordance with the PRISMA statement. A systematic search of the literature was performed using PubMed, PsycINFO, Cochrane, and Embase. All available publications reporting on the relationship between affective conditions and swallowing function in HNC patients were included. Conference papers, tutorials, reviews, and studies with less than 5 patients were excluded. Fifteen studies met the inclusion criteria. The level of evidence and methodological quality were assessed using the ABC-rating scale and QualSyst critical appraisal tool. Eleven studies reported a positive relationship between affective symptoms and OD. The findings of this paper highlight the importance of affective symptom screening in dysphagic HNC patients as clinically relevant affective symptoms and OD seems to be prevalent and coincident in this population. Considering the impact of affective symptoms and OD on patients’ daily life, early detection and an integrated interdisciplinary approach are recommended. However, due to the heterogeneity of study designs, outcomes, and outcome measures, the generalization of study results is limited. Swallowing is a complex neurocognitive process. It relies on accurate coordination of a variety of muscle and nerve groups aiming at efficient bolus preparation and safe and efficient bolus transfer from the oral cavity and pharynx to the esophagus . Damage Besides affecting overall health, HNC may also affect mental health, social functioning, and employment . This raA wide variety of instruments are developed to screen for affective (anxiety and depression) symptoms and swallowing dysfunction. Screening tools are used for early identification of individuals at potentially high risk for a specific disorder. A screening tool such as the hospital anxiety and depression scale (HADS) is useful to identify clinically relevant anxiety and depressive symptoms . For furThe aim of the present study is to systematically review and appraise the literature to obtain insight into the prevalence, strength, and causal direction of the relationship between OD and clinically relevant affective symptoms in HNC patients. A better understanding of this relationship will contribute to a better interdisciplinary approach to both problems (OD and affective symptoms) that can adversely affect each other during oncological treatment and rehabilitation.The search strategy was developed using the PICO  format as described in Table The methodology and reporting of this review were carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement . MedicalThe level of evidence of all included studies was assessed using the ABC-rating scale . In thisSubsequently, the reviewers independently appraised the included articles for methodological quality according to the QualSyst critical appraisal tool . The QuaBoth independent reviewers extracted relevant data into summary tables Tables  and 4. EThe systematic searches across all databases yielded a total of 139 abstracts after duplicate references were removed. Of these, 86 abstracts were removed based on the exclusion criteria. The full-text of the remaining 53 abstracts was reviewed. Two articles were identified after hand searching the reference lists of the included studies. Finally, 15 articles were included in this systematic review. The PRISMA flow diagram illustrates the search process  on the selection based on title and abstract screening. Articles that were selected by just one of the reviewers were subsequently screened using the full-text. At the full-text review stage, the two reviewers had 84% agreement (κ = 0.63) on their ratings. The two reviewers had 100% agreement on the ABC-rating scale and 93.3% on the QualSyst ratings. Disagreements were discussed and resolved in consensus.All studies met the criteria of level B according to the ABC-rating scale  . The metSwallowing function was investigated by a range of CRO tools such as OD screening tools (WST) and CRO tools such as VFSS and FEES , 34, 35.Affective symptoms were measured using CRO or PRO questionnaires. The majority of the questionnaires was specifically developed to measure depression or anxiety symptoms such as the hospital anxiety and depression scale (HADS), hospital Beck depression inventory fast screen (BDI-FS), depression anxiety stress score (DASS), Montgomery Asberg depression rating scale (MADRS), and the Zung self-rating depression scale (SDS) , 43–46. FHS was measured using the performance status scale for head-&-neck cancer patients (PSS-HN), functional assessment of cancer therapy-general, functional assessment of cancer therapy-head and neck questionnaires (FACT-G and FACT-H&N) –50. An oTable In the included studies, the prevalence of OD ranged from 16 to 100%. The reported prevalence for clinically relevant affective symptoms ranged from 12 to 54%. A positive relationship between OD and affective symptoms or emotional status was described in most of the studies –32, 51. The initial purpose of the present study was to systematically review and appraise the literature on the prevalence of affective symptoms and to identify the strength and direction of the relationship between OD and clinically relevant affective symptoms in HNC patients. A better understanding of this relationship will contribute to a better interdisciplinary approach to both problems (OD and affective symptoms) that can adversely affect each other during oncological treatment and rehabilitation. In general, OD and affective symptoms were related to each other as described below. However, the results of this systematic review have not been able to adequately answer the question on the strength and direction of this relationship.In total, 15 articles were included. The methodological quality of the included studies ranged from adequate (0.86) to strong (0.96). Due to the heterogeneity of study designs, terminology, outcomes, and outcome measures used, a meta-analysis could not be conducted.A positive relationship between OD and affective symptoms or emotional status was described in the majority of the studies –32, 51. Although a positive relationship between OD and affective symptoms has been described in the majority of the included studies, other studies found a non-significant or negative relationship between swallowing function versus anxiety, depression, or emotional status , 29, 33.A variety of tools measuring swallowing function and affective symptoms were used in the included studies. These different tools vary in use and purpose (screening versus diagnostic) and the interpretation and clinical relevance of the outcome measures should be taken into account. Multiple PRO HRQoL questionnaires were used to measure patients’ perception of the swallowing function based on the multi-dimensional concept of HRQoL including domains related to physical, mental, emotional, and social functioning. However, only one study included PRO FHS questionnaires to determine the impact of OD on the ability to perform daily activities . In a crIt is not uncommon to find a discrepancy between the results of PRO and CRO measures . AiroldiNon-validated measurement tools were used in eleven of the included studies. The use of high-quality measurement tools based on robust psychometric properties such as validity and reliability is strongly recommended and essential to accurately estimate the prevalence of affective symptoms and OD .Although no meta-analytic conclusions can be drawn from the included articles, OD and affective symptoms often appear to be coincidental in HNC patients. The included studies reported a prevalence of OD ranging from 16 to 100% and a prevalence of clinically relevant affective symptoms ranging from 12 to 54%. This wide variation in the prevalence of OD and clinically relevant affective symptoms in the different studies may be due to several reasons: different study designs with various HNC patient samples , the use of different and/or non-validated measuring instruments for OD and affective symptoms in HNC patients, different timing of measurement, etc.Seven studies reported the effects of tumor location, tumor stage, and/or oncological treatment modality on swallowing, and affective symptoms –32, 51. All included studies applied patient-reported questionnaires on OD and affective symptoms. However, only few studies screened or assessed the level of cognition of the included patients –23. WhenThis systematic review has some limitations. The systematic search generated a low number of articles on affective symptoms and OD in HNC patients. Reasons for this low number may be related to the inconsistent terminology used in this research topic. The lack of randomized controlled trials and pre- and post-treatment data studies may limit the strength of the findings. All studies had methodological limitations . The heterogeneity of the included studies is likely to have contributed to the overall variation in reported frequencies of OD and affective symptoms and precluded eligibility to pool data across studies.This study shows that screening for affective symptoms in dysphagic HNC patients should be considered as affective symptoms and OD seems to be prevalent and coincident in this population. The strength and direction of the relationship between affective symptoms and OD still remain unclear. Considering the impact of affective symptoms and OD on patients’ daily life, early detection and an integrated interdisciplinary approach are recommended. Future studies should use validated measurement tools, bigger sample sizes, and study designs that lead to high-quality evidence.


Spiking neural networks are biologically inspired machine learning algorithms attracting researchers’ attention for their applicability to alternative energy-efficient hardware other than traditional computers. In the current work, spiking neural networks have been tested in a quantitative structure–activity analysis targeting the toxicity of molecules. Multiple public-domain databases of compounds have been evaluated with spiking neural networks, achieving accuracies compatible with high-quality frameworks presented in the previous literature. The numerical experiments also included an analysis of hyperparameters and tested the spiking neural networks on molecular fingerprints of different lengths. Proposing alternatives to traditional software and hardware for time- and resource-consuming tasks, such as those found in chemoinformatics, may open the door to new research and improvements in the field. Machine learning  techniques provide data-driven tools to screen small molecules for quantitative structure–activity or property relationships , contributing to the preliminary selection of candidate compounds that will be validated experimentally by in vitro or in vivo assays . ML QSARIn ML QSAR, relating a molecule to a property requires encoding the molecule’s structural information into a learnable representation. After encoding, the molecular formula could be utilized in specialized software  or libraThe current study aims to employ SNN for toxicity prediction using datasets of compounds converted into MAACS fingerprints. The choice of fingerprints as input data for the SNN is derived from the observation according to which binary vectors are the natural input of SNNs. Indeed, SNNs receive incoming information encoded as bit sequences that simulate neuronal spike trains . The mecThe results include the single dataset assessment by the SNNs , SNN hypThe results of the numerical experiments applying SNNs on each dataset for medicinal chemistry were reported in the following tables. Only the top five outcomes were included, with accuracy values reported as mean and standard deviation  of the CV repetitions.The toxicity in clinical trials found by the U.S. Food and Drug Administration is the binary outcome (FDA-approved or not) of the Clintox benchmark. Classification outcomes of SNNs were collected in The Tox21 dataset contains several measurements regarding toxicity by in vitro high-throughput screening. The NR-AR measures the anti-androgenic toxicity estimated in nipple retention. The SNN performance on this task is portrayed in From Tox 21, the NR-ER-LBD variable determines the estrogen receptor nipple receptor binding site for transcriptional activity. It is an indicator of organ toxicity through the pathway for etonogestrel, a medication for birth control in women. The outcomes of the numerical experiments with SNN are delineated in In Tox21, the measurement SR-ATAD5 is not a toxicity target as a nuclear receptor but a quantity connected with the stress response pathway. It quantifies the genotoxicity captured by the ATAD5 signaling pathway as part of the stress response panel activated when a cell detects DNA damage. Classification outcomes from SNNs could be found in The dataset TOXCAST was created by in vitro high-throughput screening and included several effects on biochemical endpoints, cellular processes, and phenotypes in humans or animals. The SNN investigation focused on the thyroid function mediated by TR genes regulated by the GH3 cell line. The TR-interacting compounds disrupt thyroid homeostasis. The balanced accuracies of the top-performing SNNs were gathered in The blood–brain barrier plays an essential role in protecting the nervous system and maintaining the microenvironment of the brain. Drugs targeting the central nervous system should be able to penetrate the blood–brain barrier. The SNN results on the compounds of the BBBP benchmark in detecting permeability were included in The Side Effect Resource dataset describes marketed drugs and their adverse reaction to specific human body systems. Those affecting the immune system were analyzed in the ISD screened by SNNs. Outcomes are summarized in Commercial drugs that affect the nervous system as side effects are present in the NSD part of the SIDER dataset. The SNNs evaluated for this type of disorder reached accuracies shown in The SNN hyperparameters of the best SNN models were reported in To enhance the comparison with previous articles in This section is subdivided into two parts: an initial report of previous works running classification on MFs as inputs , and a lThe first comparison was conducted over the results presented by  using a In , the autThe following bar plots show AUC obtained by the SNNs’ best models for each dataset employed in the study, referencing previous results as reported in During this numerical experiment, MAACS MFs was compared to extended-connectivity fingerprints  calculated with a radius of 2 and 1024 bits in length. Balanced accuracy for BBBP and Clintox datasets was tested using ECFP as input and employing the best models of Final scores were noted on The numerical experiments demonstrated the application of SNNs for the virtual screening of molecule databases targeting toxicity. Using structural information derived from MF, the SNNs obtained remarkable results compared to the previous literature. The meta-analysis of One complication of SNNs mentioned in other sources is the difficulty in setting the right HPs . During Another remark regarding SNNs that may be of interest for future developments in drug discovery is that the existing architectures do not fully cover all mechanisms of learning, and ongoing research is needed both on the software and hardware side. For example, the authors of  recentlyFive public-domain toxicological datasets were investigated, each evaluated in separate numerical experiments through specific SNNs. All SNNs had in common the neuronal model, the leaky integrate-and-fire  , and theCompared to normal cells, biological neurons have peculiar features such as dendrites to capture incoming external signals, an axon to transmit pulses at a distance, and terminal parts called synapses to forward information to the dendrites of other neurons. Through the axon, information is transmitted temporarily varying the concentration gradient of transmembrane ions. This change affects the axon from the beginning to the end, creating a charged ionic flow similar to electric currents in a cable . When a R and are subject to a capacitance C: the resistance depicts the narrowness of the membrane’s ion channels that slow down the influx, and the capacitance is the lipidic membrane bilayer acting as an insulator  to be tuned: in the previous literature ,73,74, tt issues . Anothert issues .HP optimization was performed with a random search over a regularly spaced grid of values, except for the learning rate  with pre-selected intervals. The search range is reported in TOXCAST , containTox21 , predictBBBP  assessinSIDER , employeClintox , containThe compounds explored came from the following repositories, with a summary in All of the datasets’ molecules were in the SMILES format with annotated binary labels. The number of instances was unequal in all cases, processed balancing by oversampling the minority class. If class balancing was not performed, the risk was that the classifiers may be over-exposed to the majority class during training. The last column of After standardizing and normalizing the functional groups, the SMILES to fingerprint conversion was performed via the RDkit Python library . PreprocAnother preliminary aspect to verify was the similarity of the molecules inside each dataset. If the compound similarity is high, the classifier may learn representations of analogous molecular structures, affecting the model’s generalization. The heterogeneity of the molecules in each dataset was evaluated through the Jaccard–Tanimoto index and reported as mean values in In the datasets, the probability of co-occurrences between compounds ranged from 20.8% to 33.5%, or conversely, a mean dissimilarity ranging from 79.2% to 66.5%. The Tox21 family of data and TOXCAST exhibited the most significant heterogeneity between molecules, while BBBP, Clintox, and SIDER collected closer compound types.Current classification results on MAACS MFs applying SNNs were compared to the previous literature for each dataset. Journal articles were selected using the Google Scholar engine, integrated with Università del Piemonte Orientale library resources. The dataset name was inserted as keyword together with “molecular fingerprint”. Pre-prints were not considered because they were not yet peer-reviewed. The article list was sorted per publication data, with the most recent on the top, and results scanned in descending order; priority was assigned to works showing outcomes on MAACS MFs for direct comparison with the current investigation. Only articles employing area under the receiver operating characteristic curve  or accuracy as evaluation metrics on the test set were considered for compatibility with current outcomes. Another precaution as inclusion criteria involved the selection of studies dividing the samples of the original datasets in random splits (consistent with Molecule Net ); other This work witnessed the usage of spiking neural networks for the virtual screening of multiple databases of compounds targeting toxicity. The results were in line with top-notch predictors from the literature, opening the door to the possible usage of neuroscience-inspired artificial intelligence for quantitative structure–activity or property relationship analysis. Future works will further evaluate the applicability of spiking neural networks to other chemoinformatics domains, with the intent of employing an integrated software and hardware neuromorphic architecture.