Sensory Processing Dysfunction (SPD) is common yet understudied, affecting up to one in six children with 40% experiencing co-occurring challenges with attention. The neural architecture of SPD with Attention Deficit and Hyperactivity Disorder (ADHD) (SPD+ADHD) versus SPD without ADHD (SPD-ADHD) has yet to be explored in diffusion tensor imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) has yet to be examined.The present study computed DTI and NODDI biophysical model parameter maps of one hundred children with SPD. Global, regional and voxel-level white matter tract measures were analyzed and compared between SPD+ADHD and SPD-ADHD groups.SPD+ADHD children had global WM Fractional Anisotropy (FA) and Neurite Density Index (NDI) that trended lower than SPD-ADHD children, primarily in boys only. Data-driven voxelwise and WM tract-based analysis revealed statistically significant decreases of NDI in boys with SPD+ADHD compared to those with SPD-ADHD, primarily in projection tracts of the internal capsule and commissural fibers of the splenium of the corpus callosum.We conclude that WM microstructure is more delayed/disrupted in boys with SPD+ADHD compared to SPD-ADHD, with NODDI showing a larger effect than DTI. This may represent the combined WM pathology of SPD and ADHD, or it may result from a greater degree of SPD WM pathology causing the development of ADHD. Sensory Processing Dysfunction (SPD) refers to a clinical deficit in the ability to modulate, discriminate, or create an organized response to sensory information, affecting up to 16% of children . Due to Of children with SPD, approximately 40% will also meet research criteria for attention-deficit/hyperactivity disorder (ADHD) . ADHD isa priori due to its known importance for impulse control (Quantitative neuroimaging studies found no differences in gray or white matter (WM) volumes between children with SPD and the typically developing childhood cohort, indicating that the pathology should be sought in microstructural changes . Diffusi control .2, whereas the investigation of restricted and strongly hindered diffusion, such as within the intracellular space, requires higher diffusion-weighting factors. Therefore, common DTI measures, such as fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) are not specific to the underlying microstructural features of axons and dendrites  and often lack the specificity to differentiate between intracellular and extracellular disruption   representing only a single spherical shell in q-space. The assumption of Gaussian diffusion that underpins the DTI model breaks down at b values in excess of 1,000 s/mmsruption . In contsruption  extracelsruption  cerebrosn (FISO) . NDI is n (FISO) .Our study is the first to examine the neural architecture of SPD+ADHD versus SPD-ADHD using either DTI or NODDI. Prior studies have shown that FA and NDI are the most sensitive DTI and NODDI metrics in brain development and WM diseases, with rising FA and NDI values during childhood WM maturation and decreased FA and NDI in most forms of WM pathology ,b. PreviWe prospectively enrolled and evaluated children between 8–12 years of age at a community neurodevelopmental clinic. The research protocol of the present study was approved by the institutional review board at our medical center with written informed consent obtained from the parents or legal guardians and assent obtained from the study participants. Exclusion from the study is based on the following criteria:- Nonverbal Index ≤70 on the Wechsler Intelligence Scale for Children, Fifth Edition- < 1 ‘Yes’ or < 2 ‘Maybe / A Little’ responses on the ESSENCE-Q-REV parent questionnaire for neurodevelopmental concerns- Caregiver(s) unable to complete intake formsIn utero toxin exposure- - Gestational age < 32 weeks or intrauterine growth restriction - Hearing or visual impairment- Additional medical/neurologic condition, including active epilepsy, malignancy, or known brain injury/malformationAll participants were assessed for SPD using the Short Sensory Profile caregiver questionnaire . A score2  and 2,500 s/mm2   using single-shot spin echo echoplanar imaging with additional paired forward and reverse phase encoding b = 0 s/mm2 volumes. Simultaneous multiband (MB) excitation was used (MB factor = 3). The acquisition time for the b = 1,000 s/mm2 shell was 3 min and 23 s, and for the b = 2,500 s/mm2 shell was 4 min and 53 s.All subjects were imaged on a single Siemens 3 Tesla (3 T) Prisma MRI scanner  using a 64-channel head coil. Structural MRI of the brain was acquired with an axial 3D magnetization prepared rapid acquisition gradient-echo (MPRAGE) T1-weighted sequence. Whole brain diffusion MRI was performed at diffusion-weighting strengths (shells) of b = 1,000 s/mm2 and b = 2,500 s/mm2 scans were then concatenated. A brain mask was created from the first volume of the multi-shell data using Freesurfer’s SynthStrip  Toolbox  statistical packages. A data-driven voxelwise analysis was performed on diffusion metrics to further explore group comparisons that resulted in significant differences in white matter ROIs. This was done with a general linear model with permutation testing implemented with FSL’s randomise  scores given in 2 volumes from the participants was 49.4 ± 7.4, more than twice the threshold of 20 traditionally recommended for DTI. DTI assessing the global white matter revealed FA in the SPD+ADHD group trended lower than in the SPD-ADHD group (p = 0.083) with a small effect size (Cohen’s D = −0.36), directionally consistent with our hypothesis, that did not differ between boys and girls , congruent with our hypothesis. This effect was larger in males reaching medium effect size , than in females . Post-hoc exploratory analyses of other NODDI metrics showed global WM FISO trended lower in boys with SPD+ADHD versus boys with SPD-ADHD .The mean SNR across single b = 0 s/mmnd girls . The NODnd girls  also revp < 0.05  shows expanded foci of low NDI in the SCC, bilateral RLIC, PCR-R, PLIC-R and CP-R  for the SPD+ADHD group compared to the SPD-ADHD group at and CP-R .Post-hoc exploratory analysis of the JHU Atlas based white matter tracts , cerebellum, and corpus callosum . White mThe benefits of NODDI over DTI were robust in our study, where NODDI uncovered microstructural differences in more white matter tracts compared to DTI in SPD+ADHD relative to SPD-ADHD. Non-gaussian white matter microstructure imaging in ADHD is sparse. One study has used Diffusion Kurtosis Imaging (DKI) and found that patients with isolated ADHD had significantly greater WM microstructural complexity than typically developing controls in the bilateral frontal and parietal lobes, insula, corpus callosum, and right external and internal capsules . HoweverOur voxelwise and tract-level statistical analyses with multiple comparisons correction found that boys with SPD+ADHD have decreased NDI in many projection tracts, including the posterior corona radiata, which subserves higher-order sensory functions including multisensory integration, the retrolenticular limb of the internal capsule, which contains the somatosensory and auditory radiations, as well as the posterior limb of the internal capsule and the cerebral peduncles, which contains corticobulbar and corticospinal projection fibers. In addition, commissural fibers of the splenium of the corpus callosum also exhibit low NDI in SPD+ADHD in boys, therefore involving interhemispheric sensory connectivity. Given that WM NDI increases with age during childhood ,b, this Furthermore, the bilateral anterior limbs of the internal capsule also show reduced NDI in SPD+ADHD males, implicating prefrontal projection fibers including fronto-striatal connectivity that has been previously implicated in ADHD by a meta-analysis of DTI studies using TBSS . The matIn addition to these white matter microstructural differences between SPD+ADHD and SPD-ADHD, we found a sexual dimorphism that suggests at least partially different underpinnings in males versus females. There were much stronger NODDI group differences in boys than in girls. Hypotheses about the mechanism of ADHD in girls with SPD require further study in a larger cohort, given the relatively low rates of both ADHD and SPD in girls compared to boys.The main limitation of this initial study of ADHD in the SPD population is the modest sample size. Our cohort has a larger number of males compared to females, which mirrors the known sex distributions of both SPD and ADHD. Hence the female subgroup was underpowered to detect small or medium effect sizes . Second,Lower FA and especially lower NDI in males with SPD+ADHD compared to SPD-ADHD suggest more delayed and/or disrupted white matter microstructure of the former group. Multi-shell diffusion imaging with NODDI was more sensitive than traditional DTI for detecting these group differences. The posterior distribution of most of the observed white matter differences suggests that a greater degree of sensory tract microstructural disruption is associated with co-morbid ADHD.https://nda.nih.gov) Accession Number:4095004.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: NIH Data Archive  Scholar Award to IM and a National Institutes of Health (NIH) R01 MH116950 grant to PM and EM.ML, MR, and EM were employed by Cortica Healthcare during the conduct of this work.The remaining 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Secale cereale) have been recently recovered in Northwest Iberia. However, the chronological and cultural contexts of these remains have not been yet exhaustively analysed. To address this gap of research, previous and unpublished assemblages have been reviewed and analysed through an analytical set of methods: biometry, radiocarbon dates and integrating the remains of rye in the broad archaeobotanical record of the region. Results show the earliest macroremains of rye in the Iberian Peninsula date to a period between the 3rd century and the first half of the 1st century BCE. Rye was usually found in assemblages dominated by spelt and other cereals, in whose fields it was likely acting as a weed. There is no record of rye for about the two following centuries, after which it is probably reintroduced, now as a crop. It is found in several sites from the 3rd-4th centuries CE onwards, suggesting it is a staple crop as in other regions in Europe. Significant differences in grain size are only recorded in a 10th-11th century settlement, suggesting few changes in grain morphometry before Medieval times.Some of the earliest Western European macroremains of rye ( Secale cereale) did not travel as part of the agricultural crop package that spread from Southwest Asia to the Atlantic during the Neolithic )14C dates (Pits 18.1 and 18.2) showed that rye was present in two or more moments at CRT, perhaps in a recurrent way. It is possible that the frequent seeding of rye, deliberate or not, together with other cereals, led to an increase in grain size.On the other hand, at CRT spelt was largely dominant. Rye, comprising around 1% of the assemblage, may have been one of its weeds. Such kind of interpretations were proposed for analogous assemblages found in Iron Age sites from central Europe e.g. ,105). Ho. Ho105])st–2nd centuries CE that have been studied is still low )14C and modelling results suggest its introduction occurred between the 3rd century and the first half of the 1st century, probably between the 3rd century and the 2nd century BCE. Rye must have prevailed in the agricultural fields of the region until the turn of the era, likely associated with spelt. Although rye is dominant in one site and biometric data do not suggest grains increased in size from the Iron Age to the Late Antiquity, it is more frequently a secondary, sometimes rare cereal in the earlier phase. The development of morphometric analyses may clarify this matter in the future.This research addressed the introduction and dissemination of rye through archaeobotanical, biometric, and radiocarbon analyses. As a result, it is suggested that rye first appeared in Northwest Iberia, during the Iron Age, probably as a weed. The Secale taxa in the pollen curves is conditioned by several factors, not allowing secure considerations. Thus, more archaeobotanical studies are needed, both in Northwest Iberia and in other Iberian regions, to better understand the context of rye introduction and expansion. The same could be mentioned for other European areas. Isolated findings and small concentrations of rye likely need a reassessment and a wider integration to understand its introduction, dissemination, and transformation from weed to crop within the continent.So far, the chronology of rye´s arrival is coincident with changes in the local settlement and the first Roman incursions, but the short geographic area of the earlier findings, the absence of rye in the assemblages with spelt outside this small area, and doubts regarding how the introduction of rye is related to those dynamics make the interpretation rather difficult. Besides, we are missing macrobotanical data from the rest of the Iberian Peninsula. The nearest clear pre-Roman macroremains of rye were found in the French Pyrenees and in small amounts. The earlier record of After a gap of about two centuries, rye was introduced as a crop at a later time during the Roman Empire in Northwest Iberia and in other Iberian regions. Throughout Late Antiquity, rye was increasingly recurrent and abundant in the archaeobotanical record of Iberia, as well as of other European areas ,134,138.S1 Fig(PDF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 TableAnalysis per period, including the identification of the predominant cereal and other cereals as well.(XLSX)Click here for additional data file.S3 Table14C date from SB was not included. All modelled ages were rounded to the nearest five years, following Bayliss and Marshall [The Medieval Marshall .(XLSX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.S2 Text(DOCX)Click here for additional data file.


The as-synthesized optimal CCN/BOI-3 sample exhibited the highest efficiency of 80% for the photo-degradation of tetracycline  after 120 min visible light irradiation, which was significantly higher than that of pure CCN and BOI. The significant improvement in photocatalytic performance is mainly attributed to two aspects: (i) the 2D/2D van der Waals heterojunction can accelerate interface carriers’ separation and transfer and afford sufficient active sites; (ii) the S-scheme heterojunction elevated the redox capacity of CCN/BOI, thus providing a driving force for the degradation reaction. The degradation pathways of TC for the CCN/BOI composite were investigated in detail by liquid chromatography-mass spectrometry (LC-MS) analysis. This work provides a design idea for the development of efficient photocatalysts based on the 2D/2D S-scheme van der Waals heterojunctions.Utilization of semiconductor photocatalyst materials to degrade pollutants for addressing environmental pollution problems has become a research focus in recent years. In this work, a 2D/2D S-scheme crystalline carbon nitride (CCN)/BiOIO Over the past few decades, antibiotics have been used in a wide variety of fields and have become an essential part of people’s lives. However, overuse and mishandling of antibiotics makes it easy for them to accumulate in the environment and pose a health risk to humans and other organisms . There i−e and +h spatial separations are located on the conduction band (CB) and valence band (VB), respectively. Accordingly, −e tends to remain at a more negative potential for reduction, while +h tends to remain at a more positive potential for oxidation, resulting in a stronger redox ability while effectively inhibiting charge recombination [Recently, semiconductor photocatalysis has attracted a great deal of attention due to its ability to harness solar energy efficiently and its economic applicability. Among the various photocatalysts, carbon nitride (CN) stands out due to its non-toxicity, stability, excellent optical properties, and suitable electronic structure ,10. Nevebination ,36,37,383), a new member of the bismuth-based semiconductor family, exhibits excellent photocatalytic activity due to its favorable physicochemical properties and unique asymmetric sheet structure [3+ and I5+) of BiOIO3 and the structure exhibiting an Aurivillius-type (Bi2O2)2+ layer with an intercalated (IO3)− anion can play a role in promoting photo-induced carrier migration and separation [3 with a wide band gap (3.1 eV) is one of the most suitable candidates to meet the energy band alignment to construct heterojunctions with CN [3 and CCN could create an even more excellent activity.Bismuth-based semiconductors have recently become a hot topic in the field of photocatalysts . Bismuthtructure ,40. Furtparation . It is w with CN . ConsequIn this work, an S-scheme 2D/2D CCN/BOI VDW heterojunction photocatalyst was successfully fabricated via a simple hydrothermal method, which exhibited excellent photocatalytic activity in degrading tetracycline antibiotics. Moreover, the as-synthesized materials achieved the best photocatalytic performance by adjusting the ratio of CCN to BOI, which is remarkably higher than that of pure CCN and BOI. Furthermore, the enhanced photocatalytic performance of CCN/BOI composites and the reaction mechanism of S-scheme 2D/2D VDW heterojunctions were investigated and discussed through a series of characterization analyses and theoretical calculations. + thermodynamic driving force were successfully coupled to the BOI nanosheets by the VDW driving force to form a 2D/2D CCN/BOI heterojunction. Furthermore, the morphological features and crystal structures of the as-synthesized samples were clearly characterized by transmission electron microscopy (TEM) and high-resolution TEM (HRTEM). As displayed in The diagram of the synthesis mechanism of 2D/2D CCN/BOI heterojunction is displayed in 3 (JPCDS No. 26-2019), respectively [−1 corresponds to the characteristic breathing pattern of the s-triazine unit, while the peak in the region around 3000 cm−1 is attributed to the stretching vibration of the N-H bond [−1 are ascribed to stretching vibrations of the I-O bond, and the peak at 515 cm−1 is associated with stretching vibrations of the Bi-O bond [−1 is assigned to a bending vibration of the O-H group, indicating the presence of hydroxyl groups on the surface of BOI [2 hybridization, the sp2-hybrid C (N-C=N) coordination in the triazine ring, and π-excitation, respectively [2 nitrogen atoms (C-N=C), N-(C)3 groups, and N-H bonds, respectively [7/2 and Bi 4f5/2, indicating that Bi exists in the state of Bi3+ [5/2 and I 3d3/2, indicating that element I is present in the +5 valence state [The composition, phases, and crystal structures of pure CCN, BOI, and CCN/BOI composites were determined by X-ray diffraction (XRD), and the results are displayed in ectively . MeanwhiN-H bond . For puri-O bond ,50. Furtectively . In Figuectively ,54. The  of Bi3+ . In Figuce state . Notablyαhv = A(hv − Eg)n/2, where α, hv, A, Eg, and n are the absorption coefficient, photon energy, constant, band gap energy, and constant determined by the type of optical transition of the semiconductor material, respectively [−2 = 0 at 800, 1000, and 1200 Hz, which are −0.51 and −0.40 V, respectively (vs. Ag/AgCl). Furthermore, the conduction band (CB) potential of n-type semiconductors is approximately equivalent to the flat-band potential [CBE = VB − EgE), respectively. The corresponding band structures of CCN and BOI are exhibited in The optical absorption properties of the as-synthesized samples were analyzed by UV-vis diffuse-reflectance measurement, and the results are exhibited in ectively . Based oectively ,59. Furtotential . ConsequThe photocatalytic performance of the as-synthesized photocatalysts was evaluated by the degradation of tetracycline (TC) under visible light conditions. As displayed in k values (0.0105 min−1), which are higher than those of pure BOI (0.00333 min−1) and CCN (0.00508 min−1), respectively  and the Fermi level (Ef), which were calculated to be 5.02 eV and 2.96 eV for CCN and BOI, respectively. When the CCN is in contact with the BOI, electrons are transferred from the BOI to the CCN until the Ef of both compounds reaches the same level. In addition, the charge density difference (CDD) of the CCN/BOI composite was tested to further analyze the charge transfer mechanism . From echanism c. It is f. As a result, the CCN interface becomes negatively charged by accepting electrons, while the layered BOI interface becomes positively charged by consuming electrons [Before elucidating the degradation mechanism of the TC contaminants, the redox capacity and charge transfer pathways of the as-prepared CCN/BOI photocatalyst should be investigated. The energy band structures of CCN and BOI are given in lectrons . Furtherlectrons . MoreoveTo investigate the charge separation capability of the as-synthesized photocatalysts, photocurrent response curves and electrochemical impedance spectroscopy (EIS) tests were performed . As givem/z = 445, which is assigned to the deprotonated TC molecule [m/z = 465, 481, 455, 433, 409, 342, and 242. Based on the detected intermediates, the possible degradation pathways of TC were analyzed and are exhibited in m/z = 465). T1 is further oxidized by the hydroxyl groups to T2 (m/z = 481). By loss of the N-methyl group, product T2 is further converted to compound T3 (m/z = 455), with subsequent loss of amino leading to the formation of compounds T4 (m/z = 433). T5 (m/z = 409) is formed by T4 removing the c functional group [m/z = 345), and after continuous redox reaction, opens the six-element ring structure to form T7 (m/z = 242). Finally, with the extension of the irradiation time, all intermediates are further degraded to H2O, NH4+, and CO2, etc. [In order to investigate the degradation pathway of TC, the degradation intermediates of TC were detected by liquid chromatography-mass spectrometry (LC-MS) analysis, and the results are displayed in molecule . As the O2, etc. .The biotoxicity of the TC solution after photocatalysis has attracted much attention due to its negative effects on the daily environment. Mung bean sprouts were cultured in different solution systems to explore the changes of TC biotoxicity before and after photocatalytic degradation. First, mung bean sprout seeds were planted in petri dishes containing deionized water, TC solution, and photocatalyst-treated TC solution, respectively, and the pictures after seven days of planting are presented in − in water and further oxidize it to hydroxy radicals (OH) [2 to superoxide radical (O2−) [2− can be detected during the photocatalytic reaction via electron spin resonance (ESR) measurements, confirming the presence of ·OH and ·O2− active species  . Meanwhial (O2−) . Moreove species . Ultimat3N3(NH2)3), bismuth nitrate pentahydrate (Bi(NO3)3⋅5H2O), nitric acid (HNO3), and potassium iodate (KIO3) were all analytical-grade reagents and purchased from Sinopharm Reagent Co., Ltd . The tetracycline used for the experiment was purchased from Aladdin Reagent Co., Ltd .Melamine  with a covered crucible. After cooling down, the collected yellow sample was ground to powder and denoted as BCN.Crystalline carbon nitride (CCN) was prepared based on a previously reported one-step rapid polymerization strategy . A certa3 was prepared by a hydrothermal procedure. A quantity of Bi(NO3)3⋅5H2O (1.0 g) and KIO3 (0.4 g) were dissolved in 60 mL of pure water under continuous stirring for 30 min, with the addition of 2 mL HNO3 solution. Subsequently, the mixed suspension was transferred to a 100-mL Teflon-lined autoclave and heated at 150 °C for 15 h. The obtained BiOIO3 product was then washed three times with pure water and ethanol, before drying in an oven at 60 °C for 8 h and being denoted as BOI.The flake BiOIO3)3⋅5H2O and 2 mL HNO3 were added to 60 mL of pure water then stirred for 15 min. Subsequently, a quantity of CCN and 0.4 g KIO3 were added to the above mixture under continuous magnetic stirring for 30 min. The suspension was then transferred to a 100-mL Teflon-lined autoclave and heated at 150 °C for 15 h. After cooling to room temperature, the product was centrifuged and washed several times with water and ethanol, respectively. Finally, the processed product was dried in an oven at 60 °C for 8 h. For comparison, the CCN/BOI preparation was supplemented with 1, 3, and 5 wt.% of CCN content. For convenience, the resulting complexes are recorded as CCN-BOI-1, CCN-BOI-3, and CCN-BOI-5, respectively. For the synthesis of the CCN/BOI composites, 1.0 g Bi(NOIn summary, the 2D/2D S-scheme CCN/BOI van der Waals heterojunction was successfully fabricated via a simple hydrothermal method. The 2D/2D structured CCN/BOI allows the synthesized photocatalysts to possess a large interface area, providing a channel for charge transfer, while the van der Waals force between the components accelerates carrier separation and transfer. Furthermore, the S-scheme heterojunctions enhance the redox ability of 2D/2D CCN/BOI composites, contributing a significant driving force for subsequent photocatalytic degradation of TC. As expected, the as-synthesized optimal CCN/BOI-3 photocatalyst displayed an excellent degradation performance and an outstanding TC degradation rate within 120 min, which is 2 times and 2.7 times higher than that of pure CCN and BOI, respectively. This work provides guidance for the design of efficient photocatalysts with 2D/2D S-scheme van der Waals heterojunctions.


Low birth weight (LBW) has been linked to infant mortality. Predicting LBW is a valuable preventative tool and predictor of newborn health risks. The current study employed a machine learning model to predict LBW.This study implemented predictive LBW models based on the data obtained from the “Iranian Maternal and Neonatal Network (IMaN Net)” from January 2020 to January 2022. Women with singleton pregnancies above the gestational age of 24 weeks were included. Exclusion criteria included multiple pregnancies and fetal anomalies. A predictive model was built using eight statistical learning models . Expert opinion and prior observational cohorts were used to select candidate LBW predictors for all models. The area under the receiver operating characteristic curve (AUROC), accuracy, precision, recall, and F1 score were measured to evaluate their diagnostic performance.We found 1280 women with a recorded LBW out of 8853 deliveries, for a frequency of 14.5%. Deep learning (AUROC: 0.86), random forest classification (AUROC: 0.79), and extreme gradient boost classification (AUROC: 0.79) all have higher AUROC and perform better than others. When the other performance parameters of the models mentioned above with higher AUROC were compared, the extreme gradient boost model was the best model to predict LBW with an accuracy of 0.79, precision of 0.87, recall of 0.69, and F1 score of 0.77. According to the feature importance rank, gestational age and prior history of LBW were the top critical predictors.Although this study found that the extreme gradient boost model performed well in predicting LBW, more research is needed to make a better conclusion on the performance of ML models in predicting LBW. Birth weights less than 2500 g are called low birth weight (LBW). LBW has been linked to infant mortality and its consequences . PredictThe findings of this retrospective cohort study are based on birth records obtained from the “Iranian Maternal and Neonatal Network (IMaN Net),” a legitimate national system, from January 2020 to January 2022. IMaN Net is a comprehensive system for registering maternal and newborn information on the outcomes of each delivery, which is completed daily by midwives in all birth centers and hospitals throughout Iran in an integrated manner. All patients’ personal information was deidentified and not disclosed.Women with singleton pregnancies above the gestational age of 24 weeks who gave birth during a study period were included. The target population in this study was divided into LBW (≤ 2499 g) and not LBW (≥ 2500 g), which is the national standard definition . ExclusiA predictive model was built using eight statistical learning models, including logistic regression, decision tree classification, random forest classification, deep learning feedforward, extreme gradient boost classification (XGBoost), light gradient boost (LGB), support vector machine (SVM), and permutation feature classification with k-nearest neighbors (KNN). Expert opinion and prior observational cohorts were used to select candidate LBW predictors for all models , 10. PreInternal validation was carried out with the help of k-fold cross-validation. The cases were randomly assigned to either the “training set” (70%) or the “test set” (30%) using a random number generator. The original dataset kept the rate of LBW and non-LBW groups in the training and test sets constant. Using the training set, we arranged the parameters of the prediction models and evaluated their performance using the “test set”. The average performance was calculated by repeating these ten times.Metrics, including area under the receiver operating characteristic curve (AUROC), accuracy, precision, recall, and F1 score, were used to assess the predictive power of the models. The accuracy metric calculates how often a model is correctly predicted across the entire dataset. Precision measures how many of the model’s “positive” predictions were correct. The model’s recall estimates how many positive class samples in the dataset were correctly identified. The F1 score combines precision and recall by using their harmonic mean, and maximizing the F1 score implies maximizing both precision and recall simultaneously. As a result, researchers have chosen the F1 score to evaluate their models in conjunction with accuracy. We used AUROC as the primary performance metric because it is a widely used index to describe the ML model’s ability to predict outcomes. The metrics were scaled from 0 to 1, with higher values indicating a better model .Of 8850 eligible cases, we found 1280 women with a recorded LBW, for a frequency of 14.5%. The demographic and clinical characteristics of study population is given in Table In this study, we attempt to evaluate parameters and feature selection based on performance parameters using various ML algorithms. A plot ROC chart, as shown in Fig. Other performance parameters for each algorithm are shown in Table The confusion matrix of the XGBoost classification model is shown in Fig. Figure With the exponential growth in the quantity and dimension of healthcare data in recent years, ML approaches for dealing with complex and high-dimensional data have been introduced –15. In tRecent studies with larger sample sizes also demonstrated good performance. For example, in a survey by Eliyati et al., with a sample size of 12,500 study participants, SVM showed high diagnostic performance in predicting LBW with an accuracy of 0.93 . Ren et Although our study did not have the largest sample size of any study in this field, we believe that using hospital records made our feature selection rich enough to make a reasonable conclusion on identifying LBW risk factors. In our study, we surveyed maternal age, educational level, place of residence, inadequate prenatal care , drug addiction, maternal anemia, cardiovascular disease, chronic hypertension, pyelonephritis, hepatitis, COVID-19, overt diabetes, gestational diabetes and thyroid dysfunction, parity, preeclampsia, and history of LBW. Among all the potential predisposing factors of LBW, gestational age and previous history of LBW were the top critical predictors. In line with previous findings , 21, gesAlthough we used a large dataset with a lot of maternal and neonatal information, a significant variable, like body mass index, was missing in most of the birth records, so we couldn’t use this factor in our selection features, which is a significant limitation of the study.Using ML approaches to predict LBW yielded promising results. As a result, this study might add to the current perinatal care literature. Although this study found that the XGBoost model performed well in predicting LBW, more research is needed to make a better conclusion on the performance of ML models in predicting LBW.


Maternal infections during pregnancy are common events that have been suggested to be risk factors for Attention‐deficit hyperactivity disorder (ADHD) in offspring. Only a few studies have been conducted to date and results are conflicting. The current study investigates the associations between specific groups of prenatal maternal infections and offspring ADHD, considering timing of exposure and the role of fever.We used data from the prospective Norwegian Mother, Father and Child Cohort Study (MoBa), including more than 112,000 pregnancies, linked with data from the Medical Birth Registry of Norway and the Norwegian Patient Registry to estimate odds ratios for the likelihood that children develop ADHD after being exposed to maternal infections during gestation.Children exposed to any maternal infection during pregnancy showed increased risk of receiving an ADHD diagnosis . Specifically, increased ADHD risk was observed after exposure to genitourinary infections in second  or third trimester , and to respiratory infections in second trimester , provided these infections were accompanied by episodes of fever. Increased ADHD risk was also observed after exposure to diarrhea without fever in the third trimester .Overall, our results suggest that prenatal exposure to maternal infections, particularly with co‐occurring episodes of fever, are risk factors for ADHD. Fever (or severity of the infection) appears to be more important in mid‐pregnancy associations. Our results indicate that type of infection and timing of exposure might influence the associations, but small effect sizes require careful interpretations. The association between infection and ADHD should be estimated using discordant siblings or other negative control designs that give better adjustment for unmeasured familial confounding. The current study investigates the associations between specific groups of prenatal maternal infections and offspring ADHD, taking into account timing of exposure and the role of fever. Results suggest that prenatal exposure to maternal infections, particularly with co‐occurring episodes of fever, are risk factors for ADHD but that type of infection and timing of exposure are important factors. Fever (or severity of the infection) appears to be more important in mid‐pregnancy associations. In late pregnancy diarrhea without co‐occurring fever was associated with increased risk of ADHD, suggesting there may be other aspects of such infections that contribute to pathogenesis nearer to term. Prenatal exposure to maternal infections, particularly with co‐occurring episodes of fever, are risk factors for ADHD.Type of infection and timing of exposure may be important factors.In mid‐pregnancy associations fever (or severity of the infection) appears to be important.In late pregnancy there may be other aspects of infections that contribute to pathogenesis.Attention‐deficit hyperactivity disorder (ADHD), characterized by attention problems, hyperactivity, and impulsive behavior , and prospective data collection mitigating against the potential for subjective bias. However, the study also had some limitations. For example, only 13% of the sample provided information on gestational Weeks 33–36. Moreover, as genetic transmission is central in the etiology of ADHD , and offspring risk of ADHD.Explore sensitive periods during gestation.Investigate to what extent associations between maternal infections and ADHD risk differ according to the presence or absence of maternal fever.In this study, we aim to replicate and extend the findings of Werenberg Dreier et al. , using aMoBa is a prospective pregnancy cohort study conducted by the Norwegian Institute of Public Health  is a national health registry containing information about all births in Norway. The MBRN provided information about year of birth, parity, as well as maternal age.n = 3.550) were excluded from the sample . A flow‐chart of participating mothers and children is presented in Figure Twins are more likely to have low birth weight, which is an important determinant of neonatal outcome .Information about ADHD diagnoses was provided by data from the Norwegian Patient Registry (NPR). All government‐funded clinics in Norway report diagnoses according to the 10th revision of the International Classification of Diseases (ICD‐10) to the NPR, and since 2008 this information has been linkable to other data sources . Children registered at least once between the years 2008 and 2017 with Hyperkinetic disorder (F90) were classified as having ADHD. As the diagnostic uncertainty is high in the youngest age group, children with an ADHD diagnoses received before the age of 3 were excluded  reported within 4‐week time windows. In the first trimester, fever reaching a temperature of at least 38.5° was reported. In the second questionnaire, fever was registered with the highest temperature measured, and we used a cut‐off of 38.5° or more to define fever. For the third trimester, fever was reported with no specific information regarding temperature.We created a separate set of exposure variables combining infections and fever on a nominal scale: (a) Infection only; (b) Infection and fever; (c) Neither fever nor infection. Due to sample size limitations, this combined exposure was not used when investigating the 4‐week intervals.Covariates were chosen based on results from previous studies investigating prenatal risk factors for ADHD  correction at Statistical analyses were performed using IBM Statistical Package for Social Science Version 25 software .In our sample, 75,511 children had been prenatally exposed to any infection. By separating the four different infection groups, 35,271 children were prenatally exposed to genitourinary infections, 57,251 to respiratory infections, 20,759 to diarrhea, and 7,635 to persistent viral infections. Table S3 in Supporting Information The results of the unadjusted and adjusted logistic regression models estimating overall associations between prenatal infections and ADHD are displayed in Table Associations between infections during specific time windows and ADHD risk are shown in Table S5 in Supporting Information For the specific groups of infections, adjusted analyses showed increased odds for ADHD diagnoses in offspring after exposure to maternal genitourinary infections in gestational Weeks 5–8 , respiratory infections in gestational Weeks 13–16  and Weeks 21–24 , and diarrhea from gestational Week 29‐birth , with only the last one significant after FDR corrections.The results of the analyses including the fever‐infection combined exposure variable are presented in Table with fever at any time during pregnancy and offspring ADHD . Similarly, ADHD odds were increased after genitourinary infections with fever during the second  and third trimester , though these were not significant after FDR‐correction. There was no association between exposure to maternal genitourinary infections without fever and offspring ADHD.A robust association was observed between genitourinary infections Children's odds for receiving an ADHD diagnosis were increased after prenatal exposure (at any time) to respiratory infections in combination with fever . This association appears to be driven by exposures during the second trimester .Interestingly, while diarrhea at any time in pregnancy revealed no significant associations (neither with nor without fever), a closer look at the specific trimesters revealed a robust association for exposure to diarrhea alone during the third trimester . Exposure to diarrhea with fever in the same trimester revealed no significant association.No significant associations were observed between persistent viral infections and ADHD risk.In this study, prenatal exposure to maternal infections during pregnancy was associated with increased risk of ADHD. Overall, patterns were similar both with regards to estimates for different time points and types of infections. Effect sizes were in general small in the present study, but comparable to findings in other prospective cohorts . Fever could also be an indicator of elevated levels of pro‐inflammatory cytokines and other molecules  are usually healthier, better educated, etc., than the underlying source population  could be a key factor in associations observed between genitourinary infections and respiratory infections in mid‐pregnancy and risk of ADHD, although such associations could also be driven by infection severity. In the late‐pregnancy associations between diarrhea/genitourinary infections and risk of ADHD it appears that febrile episodes may not be equally relevant, and that other aspects of the infections themselves may be key to the associations. Our results require replication in future population‐based prospective studies.The authors have declared that they have no competing or potential conflicts of interest.The current study was approved by The Regional Committees for Medical and Health Research Ethics (2014/2266).Kjersti M. Walle: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Writing ‐ original draft; Writing ‐ review and editing. Ragna B. Askeland: Conceptualization; Funding acquisition; Investigation; Methodology; Project administration; Resources; Writing ‐ original draft; Writing ‐ review and editing. Kristin Gustavson: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Writing ‐ original draft; Writing ‐ review and editing. Eivind Ystrom: Conceptualization; Investigation; Methodology; Writing ‐ original draft; Writing ‐ review and editing. Michaeline Bresnahan: Conceptualization; Funding acquisition; Investigation; Methodology; Writing ‐ original draft; Writing ‐ review and editing. Mady Hornig: Conceptualization; Funding acquisition; Investigation; Methodology; Writing ‐ original draft; Writing ‐ review and editing. Ezra S. Susser: Conceptualization; Funding acquisition; Investigation; Methodology; Writing ‐ original draft; Writing ‐ review and editing. Camilla Stoltenberg: Conceptualization; Data curation; Funding acquisition; Investigation; Methodology; Project administration; Writing ‐ original draft; Writing ‐ review and editing. Ted reichborn‐kjennerud: Conceptualization; Data curation; Funding acquisition; Investigation; Methodology; Project administration; Supervision; Writing ‐ original draft; Writing ‐ review and editing. Helga Ask: Conceptualization; Formal analysis; Investigation; Methodology; Supervision; Validation; Writing ‐ original draft; Writing ‐ review and editing.Supporting Information S1Click here for additional data file.


Herein we report a novel animal model in which male Sprague-Dawley rats exposed to repeated hypoxic brain injury during the equivalent of extreme prematurity were ADHD-like hyperactive/impulsive in response to delayed reward and attentive at 3 months of age. Thus, a unique animal model of one of the presentations/subtypes of ADHD was discovered. An additional finding is that the repeated hypoxia rats were not hyperactive in the widely used open field test, which is not ADHD specific. Hence, it is recommended that ADHD-like hyperactivity and ADHD-like impulsivity, specifically in response to delayed reward, be a primary component in the design of future experiments that characterize potential animal models of ADHD, replacing open field testing of hyperactivity. Unknown is whether death and/or activity of midbrain dopaminergic neurons contributed to the ADHD-like hyperactivity/impulsivity detected after delayed reward. Hence, we stereologically measured the absolute number of dopaminergic neurons in four midbrain subregions and the average somal/nuclear volume of those neurons. Repeated hypoxia rats had a significant specific loss of dopaminergic neurons in the right ventral tegmental area (VTA) at 2 weeks of age and 18 months of age, providing new evidence of a site of pathology. No dopaminergic neuronal loss occurred in three other midbrain regions. Fewer VTA dopaminergic neurons correlated with increased ADHD-like hyperactivity and impulsivity. Novel early intervention therapies to rescue VTA dopaminergic neurons and potentially prevent ADHD-like hyperactivity/impulsivity can now be investigated.In attention deficit hyperactivity disorder (ADHD), hyperactivity and impulsivity occur in response to  The objectives of this research were, first, to further characterize behaviour in a rat model of ADHD-like hyperactivity in response to delayed reward. Specifically, we measured ADHD-like impulsivity in response to delayed reward and re-checked in a new cohort whether the animals were hyperactive and impulsive to delayed reward and attentive. Our aim was to establish whether we had discovered a new animal model of the ADHD-like hyperactive/impulsive presentation in response to delayed reward. A second objective was to characterize locomotor behaviour in an open field apparatus since this is an extensively used test, but it does not measure the hyperactivity in response to delayed reward that is characteristic of ADHD (see further details below). ADHD is linked to deficits in the midbrain dopaminergic system. Thus, our third objective was to establish whether there was a loss and/or decreased somal/nuclear volume of midbrain dopaminergic neurons in the same animal model. Some of our behavioural and anatomical  analyses were completed in the same 16–18-month-old animals. Hence, we also examined whether any correlations existed between behaviour and anatomy as our fourth objective.The context for this research is as follows: ADHD is the most prominent psychiatric condition in children, affecting ~5.3%, and persists into adulthood for ~2.5% of the population . ADHD isto delayed reward, a hallmark of ADHD, and inattention  for the NV of dopaminergic neurons in the RRF of the repeated hypoxic group at PN545, V data, 1.2–13.4% for the N data, 2/CV2 ratio is acceptable when the biological variance of a parameter is low )In the short and long term, midbrain dopaminergic neurons in repeated hypoxia rats did not have a significant decrease in somal/nuclear volume compared to repeated normoxia rats. This suggests that there was no change in the metabolic activity of these neurons for the two groups of animals.A major advantage of this novel rat model is its evidence of construct validity and face validity for ADHD. Increasing evidence indicates that extremely premature birth (22–28 weeks of gestation) is strongly associated with the development of ADHD . Hence, In repeated hypoxia rats aged 4 to 18 months, hyperactivity was not detected in an open field test. This is consistent with clinical findings in children with ADHD. Specifically, the locomotor activity of children using grid-line crossings in a clinical playroom did not correlate significantly with ratings of hyperactivity by parents  or cliniSome mouse animal models of the ADHD-HI presentation have been reported ,15,16,17Correlation of ADHD-like hyperactivity and ADHD-like impulsivity with a decreased absolute number of dopaminergic neurons in the right VTA supports extensive previous findings implicating the mesolimbic and mesocortical systems in ADHD. For example, hypoactivity of the dopaminergic mesolimbic pathway between the VTA and ventral striatum is considered to play a role in motivational deficits in ADHD patients . For theAn effect of perinatal anoxia on VTA dopaminergic neurons has been indirectly implicated . In thatThe new animal model provides a unique opportunity to investigate potential treatments to rescue dopaminergic neurons of the VTA and to prevent ADHD-like hyperactivity and impulsivity in response to delayed reward. Antioxidants are one potential treatment strategy to investigate because dopaminergic neurons are vulnerable to oxidants , and oxiMales born extremely prematurely have a long-term deficit in body weight at adolescence and 20 years of age . We obseThe strategy used for the repeated hypoxic exposures was ethically approved  20,21].,21.20,21The open field tests were performed in the same arena  for all tests, but behaviour in a novel environment was an aim. This methodological strategy has been used since the start of open field testing by Hall in 1934  and otheWith respect to other technical issues, one of the 16-month-old rats did not meet the criterion for the FI-EXT task  and hencAnatomical and behavioural correlations in the same rats were completed at 16–18 months of age but not at 3 months of age. No anatomy  was performed at 3 months, where behavioural changes were shown, because the cerebrum of these rats was used for neurochemical experiments not reported here. The neurochemical experiments required non-perfused tissue. The overall aim of the neurochemical experiments was to correlate the findings with the 3-month-old behavioural results. Since there was dopaminergic neuronal loss in the VTA at PN14 and 18 months of age, it seems likely that this is a lifelong deficit. It is acknowledged that anatomical data at 3 months of age are needed to confirm or refute this.It Is acknowledged that although the novel animal model may be a useful model of ADHD resulting from extreme prematurity, it may not necessarily reflect ADHD that occurs in the absence of extremely premature birth. It is also acknowledged that extreme prematurity is associated with all three presentations of ADHD and is not just limited to ADHD-HI ,72). Joh. Joh72])Future work using this animal model should investigate its predictive validity . This could include the response to methylphenidate and D-amphetamine during testing on the FI task for ADHD-like hyperactivity and ADHD-like impulsivity. Future research could also investigate other relevant behavioural paradigms . In addition, future work could investigate the genes most likely to be affected in ADHD , the bioAll animal procedures were approved by the Committee on Ethics in the Care and Use of Laboratory Animals at the University of Otago . Fifty-two male Sprague-Dawley rats  from eigPostnatal day (PN) 1–3 male rats were exposed to repeated hypoxia or repeated normoxia (the control condition) as previously described ,21. TheyFI-EXT schedules of reinforcement have been used to test for hyperactivity, impulsivity, and inattention in ADHD children  and in tPrior to the repeated hypoxia or repeated normoxia exposure, male offspring were weight-matched on the day of birth  and then allocated into either a repeated hypoxia or repeated normoxia group. The randomization into a group within a pair was as follows: For the first pair the heavier pup was the repeated hypoxia pup. For the next pair, the heavier pup was the repeated normoxia pup, and so on for each pair in a litter. This alternating sequence was continued for the other 2–3 litters exposed at the same time. The repeated hypoxia animals were exposed to humidified 1.5% oxygen, 5% carbon dioxide, and 93.5% nitrogen at 37 °C every 2 h for 12.25 h per day from PN1 to 3 ,21. ThisAll rats were handled the same for all behavioural analyses. It was not possible to blind the animals during behavioural analyses because the repeated hypoxia animals had decreased body weight see . TraininAll rats were food restricted to 85% of their free-feeding weight immediately prior to the start of training. To maintain their body weight at 85%, each animal was given a measured quantity of food daily after testing. Med Associates operant chambers (ENV-008-D1) were used to test rats from PN60. The food reward consisted of sweetened condensed milk delivered into the hopper via a liquid dispenser. All inputs and outputs and data collection were controlled by a computer. Details of the Campden Instruments operant chambers and testing procedure for animals tested at 16 months of age have been described previously . AlthougAnimals were habituated to the operant chambers and trained to access the food hopper and to press the left lever to receive a food reward, as previously described . SpecifiThe next stage was to train the animals to press the left lever to receive a food reward. To do this, another computer programme was used that delivered food into the hopper automatically every 30 s as well as when the animal pressed the left lever. A feedback light above the left lever was illuminated whenever the left lever was pressed. During these sessions the right lever was retracted. When each animal had learned to press the left lever to receive food and had reached a criterion of ≥ 150 presses during a 30 min session, they received four further training sessions before moving onto the testing schedule. The animals received one session of training daily.The FI-EXT testing schedule is a multiple component lights on/lights off schedule . We folFor FI-EXT testing, only data from the last 10 sessions  were used for analysis. This is because it takes a number of sessions for stability in the pattern of responding to develop and because ADHD-like behaviour is not normally present in novel situations but develops over time ,43,79,80To determine whether the repeated hypoxic rats were impulsive during the FI task, IRTs were distributed into bins of 0.33 s duration across all FI bins from day 23 to day 32  for the p is the average lever-pressing response rate (per second) across FI, t1 is the lower time limit for that bin , and t2 is the upper time limit for that bin . The difference between the expected and actual frequencies was calculated and the final burst index was the sum of these differences for each of the three IRT bins containing IRTs less than 1.00 s. After calculating this individually for each rat, the group average of the burst index for repeated hypoxia and repeated normoxia animals was obtained.The burst index is the difference between the expected frequency, assuming random pressing, and the actual frequency of responses over days 23–32 . A high Repeated hypoxia rats were hyperactive in response to delayed reward on the FI-EXT task at 16 months of age . It is uOn either PN14 or PN545, rats were anaesthetised and intracardially perfused with 4% paraformaldehyde  in 0.1 M phosphate buffer (PB). Brains were dissected out, separated into the hemispheres and the hindbrain, and cryoprotected in a 30% sucrose solution in 0.1 M PB. Each brain region was frozen on dry ice and stored at −80 °C. The right hemisphere from each rat was serially sectioned in the sagittal plane into adjacent pairs of 5 µm frozen sections using a cryostat. Four adjacent pairs were systematically collected, after a random start, throughout the right hemisphere onto 3-aminopropylthriethoxy-silane-coated slides. The systematic sampling interval was every 20th section at PN14. At PN545 it was every 20th section for the SNCd and SNCv, and every 40th section for the VTA, CLi, and RRF. Immunohistochemical staining was carried out on one pair of sections  throughout the right hemisphere. The remaining pairs of sections were stored in a polyethylene glycol antifreeze solution at −20 °C. Some of these pairs were used for a histochemical experiment (detailed below).For immunohistochemical processing, all steps were completed at room temperature unless otherwise indicated. The sections were washed in 0.1 M phosphate buffered saline  and incubated in 5% heat-inactivated goat serum  in PBS for 1 h to block non-specific binding sites. The sections were then incubated in a polyclonal rabbit anti-TH antibody  in antibody-diluting buffer  with 0.1% Tween-20 in 0.1 M PBS) overnight at 4 °C. Immunohistochemical processing using this TH antibody has previously been found to accurately stain for TH-positive dopaminergic neurons within the rat SNCd . TH is av of dopaminergic neurons in pairs of adjacent 5 µm sections. The physical disector method is used when other stereological methods, such as the optical disector method, are unable to be performed due to minimal penetration of antibodies through thicker 50 µm sections of the PN14 or PN545 brain. Some of the stereological methods used were not computerized, yet they are still valid practical approaches [All sections were coded prior to stereological analyses. The absolute  number of TH-positive dopaminergic neurons in the right VTA, CLi (at PN545), SNCd, SNCv, and RRF was measured using Cavalieri’s method to estimate the absolute reference volume (Vref) and the  disector method ,56,83 toproaches . It is aproaches ).One efficient way to perform both the Vref and physical disector methods was to take high-power photographs of the midbrain nuclei in each 5 µm section that was stained. This allowed for easy and accurate matching of neurons between disector pairs. Photographs of each section were taken using the ×10 objective of an Olympus AX70 light microscope . Using this objective, two to three images were usually required to capture the entire structure in each section. The final magnification of the images was ×220. Once the images of each structure were taken for each section, the images were printed, aligned, and sellotaped together to make one large montage of each section. This made it easier to identify common features between pairs of sections.To apply Cavalieri’s method to measure the Vref, one section  from each pair was used. Using previously defined criteria ,85,86; Fa. When tThe VTA began laterally as a widening and shortening of the SNCd c, as desThe RRF usually began in the last one to two sections containing the SNCd or the first section containing the VTA b,c. It wt) in this case was 0.005 mm and the section interval sampled (s) was 20 at PN14 and 20 or 40 at PN545. The area of each point, a(p), was calculated by dividing the length between each grid point by the magnification of the image and squaring it.Once the borders were drawn around each midbrain region, a specific grid on an acetate sheet was used with points spaced apart at the following distances, PN14, VTA: 25 × 25 mm, RRF, SNCv: 15 × 15 mm, SNCd: 10 × 10 mm; 18 months old, all: 30 × 30 mm. This grid was overlaid randomly on the printed images of each respective structure. Then the number of points landing on each dopaminergic region for each of the sections was counted and summed for the entire right hemisphere (∑P). The following formula  was usedv). A transparent plastic acetate sheet with square sampling frames measuring 30 × 30 mm for the SNCd at PN14, 20 × 20 mm for the SNCd at PN545, and 50 × 50 mm for the other nuclei was overlaid on the image of each of the nuclei on one of the sections from each pair. This section was referred to as the reference section. At PN14, a sampling interval of every square for the SNCd and every second square for the other structures was used. AT PN545, a sampling interval of every second square for the VTA and every square for the other structures was used. According to this sampling interval, the square frames that landed with at least half of their area over the structure of interest were drawn on the image. Once all the sampling frames had been drawn on each section, a transparent plastic acetate sheet was overlaid on top of each structure. The outline of the nucleus and the square grids to be sampled were then traced onto the acetate sheet. Any identifying features of the image, such as blood vessels or obvious nuclei, were also traced onto the acetate sheet. Once this was completed, the traced image from the first section of the pair on the acetate sheet was lined up and overlaid on top of the image of the second section from that pair. As each section was only 5 µm apart, it was usually easy to use the identifying features and the shape of the midbrain region to match up the first section to the identical position in the second section from the pair. The same sampling frames were then drawn on the second section. The second section was referred to as the look-up section. Each grid to be sampled was numbered for identification.The physical disector method was used to calculate the average number of TH-positive neurons in a known subvolume of each midbrain region . The entire procedure was repeated on each pair of sections throughout the right hemisphere for each midbrain dopaminergic structure.All of the individual TH-positive nuclei in each sampling frame of the reference section were then drawn onto the acetate sheets or drawn using Adobe Photoshop version 11  on a computer-captured image of the section and were marked with a tick if the TH-positive neuron had a nucleus and a cross if the TH-positive neuron did not have a nucleus . Once ea−) for each midbrain structure, the counts from each pair of sections were summed. The absolute number of TH-positive neurons within each midbrain dopaminergic nucleus was calculated by first using the following formula to calculate the total sampled volume (TSV) or total disector volume:2, and t = section thickness. The Vref and TSV were then used to calculate the absolute number of TH-positive neurons in each right midbrain structure for each rat using the following formula:− = total number of disector neurons counted. The data were then uncoded and the average number of TH-positive neurons in each midbrain structure was calculated for each group and age. Due to atypically pale immunostaining, the data from two repeated normoxia animals were excluded, yielding data from 7 of 9 repeated normoxia animals in cohort 1 . These sections were stained with 0.1% filtered thionin-acetate , dehydrated through a series of alcohol rinses, mounted with DPX , and coded. Images were taken at a magnification of ×220, printed, and montaged together. The identifying features from the TH sections were matched to the corresponding features on the thionin section to enable the borders to be drawn around the midbrain region of interest. Stereological analyses were then undertaken using Cavalieri’s method and the physical disector technique as described above. This yielded the absolute number of all neurons within the VTA, SNCd, SNCv, and RRF of PN14 repeated normoxia versus repeated hypoxia rats. At PN545, the absolute number of all neurons within the VTA, VTA + Cli, and SNCd of repeated normoxia versus repeated hypoxia rats was obtained.The point-sampled linear intercepts method ,88 was uThe somal or nuclear volume for each rat was then averaged for the repeated normoxia versus repeated hypoxia group and statistically compared.V or number per subvolume) estimate of the dopaminergic neurons within the midbrain structures analysed was calculated as 1/(∑Q−)1/2 [v)) = CV/(∑Q−)1/2, where v is the individual neuronal somal estimates for each rat and CV is the coefficient of variation of these estimates within each rat [The CE was calculated based on Gundersen et al.  for the (∑Q−)1/2 . For theeach rat .t-test was performed. If the criteria were not met, a Mann–Whitney U test was performed. Possible associations between the behavioural and anatomical data of the 16–18-month-old rats were analysed using Pearson’s correlation (corrected for multiple comparisons). p ≤ 0.05 was considered statistically significant. All statistical analyses were completed using Prism v9.3.1.Averages were expressed as mean ± SEM. An ANOVA for repeated measures was used to statistically compare FI and EXT responding, IRT distributions, body weight data, and between-session analyses on the open field task. Bonferroni’s post-hoc analyses were completed for the open field test, with correction for multiple comparisons. No correction for multiple comparisons was needed for the other analyses since post-hoc comparisons were not undertaken. For the stereological results and the burst index, the data for each measured parameter were first checked for the normality of the distribution. If the criteria for normality were met, a Student’s Since 1775, we have learned much about ADHD, and yet we are only beginning to understand how changes in the brain contribute to the disorder . The finThe theoretical implications of the research are that ADHD-like hyperactivity and ADHD-like impulsivity, specifically in response to delayed reward, should be a primary component of the design of future experiments that characterize potential animal models of ADHD. Based on the results, it is recommended that the testing of hyperactivity in an open field apparatus should not be the primary and only measure of hyperactivity. Another theoretical implication of the research is that the new animal model will enable future investigations of the biology of the hyperactive/impulsive presentation of ADHD, including analysis of the circuitry of the prefrontal cortex and of cognitive flexibility.The significance statement for this research is as follows: Prevention of ADHD and improvements in medication are significantly hindered by a lack of accurate animal models, particularly of the hyperactive/impulsive presentation. We investigated a novel rat model. Males exposed to repeated hypoxia during the equivalent of extreme prematurity exhibited ADHD-like hyperactivity and ADHD-like impulsivity in response to delayed reward, with no attention deficit. In the short and long term, repeated hypoxia rats had a specific significant loss of dopaminergic neurons in the right VTA. Fewer VTA dopaminergic neurons correlated with increased ADHD-like hyperactivity and impulsivity. Intervention therapies at birth, novel to ADHD, can now be investigated to rescue VTA dopaminergic neurons and potentially prevent ADHD-like hyperactivity/impulsivity. A permanent cure could ensue.


Pooled estimates showed that ADHD was significantly associated with an increased risk of CVDs in analyses based on adjusted effect size (odds ratio (OR) = 1.96; 95% confidence interval (CI) = 1.19–2.23, Q = 140.74, PQ < 0.001, I2 = 97.2%). When restricted among adults, the heterogeneity declined to null , suggesting age might be the main source of heterogeneity. In subgroup analyses, we found increased risk of CVDs associated with ADHD across age groups, type of CVDs, and data sources. This systematic review and meta‐analyses indicate that ADHD is associated with increased risk for CVDs, but further studies with various study designs are warranted to advance the understanding of the underlying mechanisms for the observed association between ADHD and CVDs. Additional research is also needed to resolve the role of ADHD medications which remains unclear due to the limited number of primary studies exploring this issue.Attention‐deficit/hyperactivity disorder (ADHD) often co‐occurs with other psychiatric and physical diseases. However, available evidence on associations between ADHD and cardiovascular diseases (CVDs) is mixed. To systematically review, quantitatively synthesize, and appraise available evidence on the link between ADHD with CVDs, we searched relevant articles in PubMed, Embase, PsycINFO, and Web of Science from inception to May 1, 2022. Study quality was assessed by using the Newcastle‐Ottawa Scale, and random‐effects model meta‐analyses were performed. A total of 18,391,169 (ADHD:  Individuals with ADHD were nearly twice as likely to develop at least one CVD, compare with non‐ADHD. The observed strength of associations were largely comparable to estimates of associations between sever mental illness and CVDs. Evidence on the associations between ADHD and CVDs is mixed.Individuals with ADHD were nearly twice as likely to develop at least one CVD, compare with non‐ADHD.The observed strength of associations was largely comparable to estimates of associations between severe mental illness and CVDs.More studies are needed to explore the role of ADHD medications.Cardiovascular diseases (CVDs) are the leading cause of morbidity, mortality, and rising health care costs worldwide  is one of the most prevalent psychiatric disorders, affecting around 5% of children and 2.5% of adults  on the observed associations, in order to provide insights into underlying mechanisms.The study was conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines  studies providing data on the strength of the association between ADHD and CVDs in children, adolescents, or adults. Eligible definitions of ADHD were as follows: (a) a categorical diagnosis of ADHD according to the DSM‐III, DSM‐III‐R, DSM‐IV, DSM‐IV‐TR, DSM‐5, ICD‐9, or ICD‐10; (b) ADHD‐medication prescriptions as a proxy for ADHD diagnosis; (c) ADHD symptoms based on value above cut‐off on a validated self/parents/teacher‐reported ADHD questionnaire; (d) ADHD diagnosed via a structured psychiatric interview or positive answer by self/parents/teachers to the question ‘Did your doctor ever tell you that you/the child have ADHD?’ Titles, abstracts, and full text of included studies were screened independently by two authors. Discrepancies were resolved through discussion with a senior investigator.The main outcome was the maximally adjusted odds ratio (OR), risk ratio, and hazard ratio, with their corresponding 95% confidence interval (CI) ratio expressing the association between ADHD and CVDs. The secondary outcome was the unadjusted estimate of the associations. When sufficient data  was available, crude ORs were manually calculated or obtained by contacting the original authors, if not reported in the original paper. The choice of primary and secondary outcomes was made because adjusted estimates are more informative and potentially less prone to biased derived from the selection of the participants  and information on confounding adjustment. We extracted both adjusted and unadjusted ratios if available, and we used the maximally adjusted ratios in the analyses. Unadjusted effect sizes were calculated based on the information provided in the paper when necessary. Two authors conducted the data extraction process separately, and any disagreements were resolved by discussing with a third investigator.The quality assessment of eligible studies was performed using the Newcastle‐Ottawa Scale (NOS) by two independent authors, and the discrepancies were solved by consensus. This 9‐star scale consists of three parts: selection of participants and the measurement of exposure (4 stars), comparability (2 stars), and assessment of outcomes and adequate follow‐up (3 stars) . If significant heterogeneity was detected by the Q test, we considered I2 values greater than 75% as high heterogeneity    , suggesting an overall moderate quality of the included studies. As shown in Table Q = 140.74, PQ < 0.001, I2 = 97.2%) and the between‐study standard variance was not high  but with wide CI. The effect size was robust in the leave‐one‐out sensitivity analysis   but this was not statistically significant , while the only study in children reported a stronger association between ADHD and CVD (hypertension as main outcome) than adults . As age was a main factor affecting the heterogeneity of the results, we restricted the following sensitivity analyses on type of CVDs and data sources among adults. Second, among four studies with adjusted data on specific types of CVDs, we found that ADHD was associated with a higher risk of hypertension  and other CVDs , even though the association between ADHD and Hypertension was not statistically significant.Table The meta‐analysis provided evidence that ADHD was significantly associated with an increased risk of CVDs, after adjusting for potential confounders. However, due to the limited number of available studies and lack of information in the original studies, it is currently unclear whether these associations can be explained by other confounders. Therefore, there is a critical need for future studies on this understudied topic to advance the understanding of the underlying mechanism for the observed association between ADHD and CVDs, especially the role of ADHD medications and other mediating factors, such as mental comorbid conditions (i.e. substance use disorders or depression). A better understanding of major mediating factors may inform clinical guidelines about how to intervene on CVDs in ADHD.Compared with evidence from meta‐analysis for well‐established risk factors for CVDs  among adults, the observed magnitude of association between ADHD and CVDs was slightly smaller than the magnitude of association for sedentary behavior  of the unadjusted ORs were from manually calculated effect sizes based on available information in the original studies, as these studies did not generate unadjusted effect size of the association between ADHD and CVDs. Second, we attempted to reduce publication bias by including both published and unpublished studies, but bias cannot be ruled out completely. Third, most of the included studies were conducted in Europe and the U.S., which limits the generalizability of the findings to other populations across the world. Therefore, more studies are needed to examine the associations between ADHD and CVDs using samples from different settings and regions. Fourth, the definition and measurements of ADHD and CVDs from original studies varied substantially. Due to the limited number of included studies, it is not possible to assess the associations among different definitions, which need to be evaluated in future systematic reviews and meta‐analyses on this topic.Compared with other psychiatric disorders , the risk of CVDs in individuals with ADHD is largely understudied. A number of important research questions, therefore, need to be addressed in future research. First, except for studies with a specific focus on hypertension, the most commonly used measure of CVDs was a broad category, encompassing a wide range of circulatory system diseases. Future studies are needed to explore the associations between ADHD and specific types of CVDs, which is critical to enabling risk reductions via targeted intervention and preventative efforts. Second, future research should also consider careful adjustments for a wide range of possible confounders of the observed associations between ADHD and CVDs, including but not limited to early life risk factors  for taking part in psychiatric meetings from Janssen‐Cilag, Rubió, Shire, Takeda, Shionogi, Bial and Medice. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 3 years: Janssen‐ Cilag, Shire, Oryzon, Roche, Psious, and Rubió. No other disclosures were reported. Z Chang serves on the Editorial Advisory Board for JCPP Advances.https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=274367).This article has earned a Preregistered Research Designs badge for having a preregistered research design, available at (Not applicable to this research review.Supplementary MaterialClick here for additional data file.


Although there is ample literature available on toxicity in games, as there is regarding trolling on social media, there are few to no cross-platform studies on toxicity and trolling. In other words, the extant literature focuses on one platform at a time instead of comparing and contrasting them. The present work aims to rectify this gap by analyzing interviews from a larger study of 22 self-proclaimed victims of in-game trolling to not only determine whether social media or gaming communities are considered more toxic but also to explore how definitions of the word ‘trolling’ change depending on the platform in question. We found that while definitions of in-game trolling behavior focused on behavioral styles of trolling , social media trolling is defined by more sinister actions such as misinformation spreading and ‘canceling’ other users. We also found that gaming is perceived as generally more toxic than social media, often due to company policies or lack thereof. Practical and theoretical implications for the study of toxicity in all online communities – gaming or social-media based – are discussed. Since its inception, the internet has been used for social interactions both benign and malicious e.g., . At the Trolling – a form of negatively perceived communication that exploits fellow netizens using website, game, or chat mechanics online  – can taThe present study’s aim is, therefore, to look at trolling on both gaming and social media platforms. More specifically, we spoke to people who have self-identified as victims of trolling in games and asked them (1) how their understanding of trolling differs between gaming and social media, (2) which behaviors constitute trolling on which platforms, and (3) how the perceived prevalence of trolling differs between social media and gaming platforms. From a theoretical point of view, this will add nuance to our understanding of what trolling is and how the platform shapes our understanding of the phenomenon. Practically, it will also enlighten policy-makers and platform owners and developers as to which kinds of behaviors they need to target and where best to protect their users.A recurring theme in trolling literature is the struggle to establish a single definition of trolling itself . While oIt is important here to note that, within the realm of games research specifically, there is also considerable discussion about the overlap of the term “trolling” with other similar terms, such as grief play and toxicity. Each of these terms comes with its own distinct literature, and so, before we move on to trolling on social media, we will briefly cover each of these terms and how they relate to one another. Toxicity is specifically the behaviors that are intentionally malicious and hurt other players e.g., . This isGrief play is extremely similar to trolling, with However, just as RQ1: How, if at all, does game players’ understanding of trolling differ depending on the platform on which the trolling behavior occurs?Another potential difference between trolling on gaming and social media platforms could be the trolls’ chosen methodology. In games, research has shown that although trolls will engage in their fair share of verbal trolling see , anotherThat said, this could reflect a bias in research more than an actual difference between the platforms. For instance, RQ2: Which behaviors constitute trolling on social media platforms and gaming platforms, respectively?RQ3: What is the perceived prevalence of trolling on social media and gaming platforms?M = 23.64, SD = 4.33). All but one (who selected Google Meets) participated via Discord. Please see SD = 1.99) hours of daily gaming, most of which took place in multiplayer games. The most popular genre was multiplayer battle arenas , followed by first-person shooters , then massively multiplayer online roleplaying games ; other genres mentioned included, in order of popularity, strategy games (5), mobile games (2), and console games (1). The participants used various social media platforms from 1.5 to 12 h a day . In order of popularity, these platforms were Twitter (16), Instagram (15), Facebook (14), Discord (12), Reddit (7), TikTok (4), LinkedIn (3), WhatsApp (2), Twitch.tv (2), and Snapchat (2). These game players do not represent any specific strata of society and are as diverse a convenience sample as we were able to recruit via social media advertisements in English, the language of the interviewer. It is important to note that although several cultures are represented within the sample, we are not performing a culture-by-culture analysis due to the limited size of the sample.The present study was part of a larger interview project with trolling victims involving 22 participants  between 18 and 36 years of age (https://craig.chat/home/); the one participant using Google Meets was recorded with a Google Chrome extension (see https://fireflies.ai/).After receiving their institutional review board’s ethical approval, the authors recruited people who (1) had been trolled at least once before in a gaming context, (2) were at least 18 years of age, and (3) were able to both receive payment and participate in an interview online. This recruitment took place via Twitter and Facebook posts, both of which were shareable by other users. It was a convenient sample. In order to avoid biases toward specific types of trolling, no definition was given to participants at any point in the recruitment or study phases. This also avoided the difficulty of selecting only one of the multiple definitions of trolling . Particia priori by the authors based partially on extant work interviewing trolls . After a verbal debriefing and answering any questions participants had post-interview, they were paid the local equivalent of 15 euros via PayPal (with one exception who received it in cash).As this was part of a larger study, the complete interview protocol will not be addressed here in full see . Questiog trolls , to alloTemi.com and reviewed by the second author for quality control. The first author then highlighted all instances in each interview where social media and gaming-based trolling were compared and developed a codebook using a grounded theory approach  intentional antagonism, (2) cancelation , (3) misrepresentation , (4) breaching privacy , (5) not trying to win (gaming only), and (6) playful “messing with”. These are not, however, mutually exclusive; some participants’ definitions included elements of two categories, while five participants failed to define trolling in social media, considering it a game-exclusive phenomenon.Our first observation was that participants had a much firmer, more coherent understanding of trolling in the gaming context; there was a lot more variety in terms of understandings of what it meant to troll on social media or if it was even possible (see above). In the gaming context, only three of the six possibilities emerged: intentional antagonism, not trying to win, and playful ‘messing with’. Of these, intentional antagonism was the most popular, with 17 of the 22 participants defining in-game trolling in this way for games and 11 defining social media trolling in this way. P6 defined trolling as follows: “I will classify trolling as annoying people … and harming other people … harming their experience … either verbally or using mechanics in the game to annoy other people for fun.” This summarizes the category well; trolling, to these people, is the act of ruining someone’s experience of a game or platform. This was the third most popular definitional category for social media as well. For gaming, however, the next most popular definitional category was “not trying to win the game” (12 out of 22 participants). In this category, the participants stressed actions such as “feeding” the other team by intentionally getting one’s character killed , thereby assisting the other team to the detriment of one’s own team. Finally, three participants  included elements of playfulness in their trolling definitions for both games and social media. For them, trolling is not purely evil as those in the intentional antagonist camp seem to believe but rather “playful, like joking, like messing with others in game” (P19). P20 describes trolling as:behavior that kind of edges, the cusp of being downright toxic, uh, but is not necessarily toxic per se. It's, it's, it's that gray area that I would liken unto the kid in junior high that kind of wants to be your friend but doesn't want to be uncool. So, they pretend to be your friend and then laugh at you for thinking that you were friends with them.In short, game players seem to believe that trolling in games is heavily tied to intentionality; whether that intention is malicious or playful, trolling is an action with a specific goal in mind, usually to capture a reaction from the target.in the case where the person was not perceived as deserving of such a punishment. This changed it from the canceling of a public figure to character assassination via online insults: an aggressive form of trolling. For instance, P2 describes social media trolling as “accusing people of stuff and maybe calling people for their preferences for no reason. Like, if I have an opinion, then you go out and say, ah, your opinion is bad.” However, for others, trolling on social media is more about misrepresentation (5 out of 22 participants), either by spreading misinformation  or by pretending to support a controversial cause in order to get a rise out of their target . P17 describes this as “saying one thing and doing the other,” a sort of bait-and-switch technique similar to Rickrolling in the early days of YouTube  for whom trolling is synonymous with cancel culture, which is the public removal of support from a person, usually due to an apparent moral failing see . It shouTube see . FinallyHowever, what is perhaps the most interesting aspect is that our participants seemed to find trolling on social media to be more playful than in gaming, with 9 of our 22 participants including an element of playfulness in their definition and 4 of those  defining social media trolling as a purely playful behavior. P8 describes it as “making bad jokes,” while P20 explains that on social media, “it’s a bit more nuanced … because the rules of society are much more intricate and complicated than, than the rules of a video game,” but concludes that trolling is “infuriating … [but] it [is] hilarious to the troll … and it [is] moderately amusing to some of us that [witness] it unfold.” Essentially, it would appear that social media trolling is more varied in its intent than in-game trolling, or at the very least, this is how victims seem to perceive it.The summary of our results is presented in What seems to separate social media trolling from gaming trolling, at least according to trolling victims, is its core motivation. If we look at the most popular types of in-game trolling, they are things that previous literature has rooted in frustration e.g., . We can Well, I mean, there's a lot of times where trolling is just about, you know, someone, like, slightly annoyed you while you were playing a game, um, they took your kill or something like that. These used to be super common, um, like a few years back, especially in, in, uh, maybe lower levels of play and league. But, like, for example, if, uh, your support takes a kill, then you just start trolling, um, just out spite really. There's no, like, rhyme or reason to it.Essentially, when things stop going one’s way – when one’s goals are frustrated by another player – this catalyzes a trolling response in games. Social media trolling, by contrast, does not seem to be borne primarily of frustration but rather out of boredom. P4, for instance, gives the example of “[joining] a flat Earth society as a joke and then [perpetuating] that idea ironically … that would be a troll.” When considering personal insults, however, these motivations seem to overlap, with many participants mentioning racism and sexism in particular being prevalent on both gaming and social media platforms  and participants from some regions stressing religious targeting (P5). We therefore have to be careful not to keep these two motivations as mutually exclusive and unique to each platform while recognizing that one motivation would seem to predominate over the other depending on the environment.To answer our final research question, we wanted to compare social media platforms and games to see which was perceived as more filled with trolls. Since so few of our participants defined trolling in a playful way , it would seem as though trolling is still largely seen as a toxic behavior to some degree, irrespective of platform , features of the platform , and features of society (Racism/Sexism: 3). One participant was unable to give any reasons for their opinion regarding the toxicity of social media and gaming platforms (P9). Many participants brought up the company policies regarding punishment of trolls as a major source of grief; P18 had this to say about how companies deal with trolling in games:A lot of the times it's 1% of the people who contribute 50% of the trolling or whatever. I don't think that there is, like, it is to the point where if you were to remove all the trolls from the game or anyone who, who has trolled more than once you'd have no players. I think it's more so take these instances where it is blatantly obvious, where it's actively ruining more than just one game's worth of pain. And, like, you can sort of sniff out the, the real culprits of everything and maybe actually taking, making disciplinary action on them is something that can be take, taken into account.Still, others focused on content moderation styles of certain platforms, with P20 praising Reddit’s moderators for “[taking] care of [trolls] when they are too prevalent” and P12 asking that Riot Games “bring back a form of the tribunal,” which was a player-based moderation system that existed in the past in League of Legends but has since been largely replaced with automatic tools such as chat filters. In essence, people often blame the companies that run the platforms and their poor decision-making when it comes to policies to punish trolls for toxicity levels today.However, almost equally important were features of the platforms themselves and, especially, the community norms that develop on these platforms, particularly in light of anonymity. P1 explains that “a lack of physical presence … means that people disconnect the human being they are talking to from the interaction, which makes things very comfortable and … normalizes behavior that would not necessarily be normalized in a real-world setting.” This is almost an exact definition of moral disengagement in the style of Like, if somebody's been being toxic and chat, you can report them. And, usually, they will do something about, like, they actually are pretty good at doing something about it. If you report them for toxicity, uh, and, uh, stuff, kind of simple, like, if they, if they have a report system and actually look at reports, that's a good enough system for me.In sum, platforms that are lower in anonymity, whose report functions are kept up to date and regularly addressed, and whose companies punish trolls for their actions are the platforms people want to use. Transparency here is key for both social media and gaming platforms alike. Platforms that fail to keep these things in mind not only turn away existing users but can develop a reputation that will ward off new clients.In the present study, our first aim was to compare how victims defined trolling on social media and how they defined it in the context of online gaming. Although there were elements that were the same across platforms, we did find differences in their understandings. The definitional categories provided for online gaming trolling – intentional antagonism, not trying to win, and playful ‘messing with’ – largely correspond to what has already been found in the extant literature on game-based trolling see , which iOur second goal was to capture more fine-grained detail regarding which behaviors were considered to be trolling on social media and which were considered trolling in games. The complete findings are presented in Firstly, it could represent a shift in trolling trends. It has been several years now since Finally, we wanted to see which platforms were perceived as being more toxic  and why. On the whole, most participants found online games to be more toxic than social media, but this finding must be contextualized in terms of the participant pool; most of our participants were relatively heavy game players, especially compared to their social media usage, so there could be an effect of time and usage creating this result in part. That said, most participants were able to give clear reasons for their opinions. A major factor in the participants’ opinions regarding toxicity levels was content moderation practices. They were appreciative of automatic tools such as chat filters and automatic detection of profanity on voice chat but stressed that these are not a replacement for human content moderators. There was no clear winner in terms of whether paid or volunteer moderators were considered superior, but there was a definite cry for human moderation of some form. Gaming companies such as Riot Games and Valve were especially criticized for having too little human intervention. Social media companies were also generally perceived as being better at doling out punishments to toxic offenders, unlike most games, whose reporting functions were derided as useless by many of our participants. In other words, game players seem to have the impression that social media is a more controlled environment, while online games are more of a cyberspace Wild West.However, our results have also highlighted the strong moral undercurrent that seems to apply to all forms of trolling. This concept of intentionality that is so critical to defining something as trolling, at least according to trolls see  and victIt is also worth connecting the present work to the broader world of media studies. For instance, the concept of stickiness in platform economies could play a role in how platforms differ from one another trolling-wise. User stickiness refers to how often users return to a platform for use ; it is aResearchers have also documented how trolling has been used as a political tool to sway opinions and/or discredit ideologies or political figures . This alThe first and most obvious theoretical implication of this work is the importance of the platform. As noted earlier, trolling is an inherently interdisciplinary topic with myriad available definitions for researchers to choose from see . To compAnother important distinction to make when reflecting upon differences between platforms is the communities that use said platforms. As previously mentioned, we specifically looked at game players in the present work, but even this is a broad categorization. One could imagine that players of World of Warcraft, a fantasy MMORPG, may differ significantly in their usage of their platform than players of the Call of Duty franchise, an intensely competitive first-person shooter. Naturally, these platforms differ in terms of affordances – they are different genres of game – but they are also likely to differ in terms of the social norms of their communities (for a complete discussion of gaming communities, see A second important note is that this is not the first time that boredom and frustration have shown up as major motivators for trolling behavior ; it has instead of human moderation teams as opposed to a support for human moderation teams. As previously mentioned, trolling is only truly limited by programming and human creativity, and it seems as though behavioral trolling is ingenuity’s current bypass of automatic content moderation techniques. User-based moderation works for websites such as Finally, the present work has highlighted just how much behavioral trolling, or non-verbal trolling, is perceived as a problem in the current gaming landscape. A vast majority of our participants experienced some form of behavioral trolling or at the very least mentioned it as a type of trolling that they see frequently in-game. Participants also indirectly highlighted the perceived reason for behavioral trolling’s prominence in games: an over-reliance on automated content moderation on gaming platforms. Chat filters and the like are, according to our participants, being used Though the present study highlights important differences between perceived trolling on social media and in online games, it is not without its limitations. As previously noted, because this is part of a larger study on game players, almost the entire population uses games more heavily than social media platforms; the study should therefore be replicated on more casual game players to see which trends hold and which are an artefact of our sample. This sampling also meant that our participants were mostly men, while this is not true of internet users taken as a whole. Future work should aim for a more even gender distribution to better capture a wider experience. In addition, several of our participants mentioned important cultural dimensions of trolling but not in enough detail or across enough participants to examine in more depth. Though there have been cross-cultural studies of trolling see , these hThere is still ample room for further work in this area. For instance, the present work did not focus on the emotional experience of victims, something that could be of particular interest to those designing interventions or counselling programs for trolling victims. This could be addressed in future qualitative work. With the categories of behaviors and definitions identified here, researchers could also ask a larger group of representative game players and social media users about their understanding of trolling in a larger-scale survey to determine which results hold true and which are artifacts of the small sample size. The question of generational influence on trolling also remains (see The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the National Chengchi University Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.CC designed the study, performed all data collection, analyzed all data, and wrote and revised the article. ST reviewed all interview transcripts for accuracy, analyzed all data, and reviewed the article. J-HL provided funding for the project and provided critical revisions prior to submission. All authors contributed to the article and approved the submitted version.This study was supported by grants #111-2811-H-004-006 and #109-2423-H-004 -004 -SS4 from the National Science and Technology Council.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.