Mild traumatic brain injury is a complex neurological disorder of significant concern among athletes who play contact sports. Athletes who sustain sport-related concussion typically undergo physical examination and neurocognitive evaluation to determine injury severity and return-to-play status. However, traumatic disruption to neurometabolic processes can occur with minimal detectable anatomic pathology or neurocognitive alteration, increasing the risk that athletes may be cleared for return-to-play during a vulnerable period and receive a repetitive injury. This underscores the need for sensitive functional neuroimaging methods to detect altered cerebral physiology in concussed athletes. The present study compared the efficacy of Immediate Post-concussion Assessment and Cognitive Testing composite scores and whole-brain measures of blood oxygen level–dependent signal variability for classifying concussion status and predicting concussion symptomatology in healthy, concussed and repetitively concussed athletes, assessing blood oxygen level–dependent signal variability as a potential diagnostic tool for characterizing functional alterations to cerebral physiology and assisting in the detection of sport-related concussion. We observed significant differences in regional blood oxygen level–dependent signal variability measures for concussed athletes but did not observe significant differences in Immediate Post-concussion Assessment and Cognitive Testing scores of concussed athletes. We further demonstrate that incorporating measures of functional brain alteration alongside Immediate Post-concussion Assessment and Cognitive Testing scores enhances the sensitivity and specificity of supervised random forest machine learning methods when classifying and predicting concussion status and post-concussion symptoms, suggesting that alterations to cerebrovascular status characterize unique variance that may aid in the detection of sport-related concussion and repetitive mild traumatic brain injury. These results indicate that altered blood oxygen level–dependent variability holds promise as a novel neurobiological marker for detecting alterations in cerebral perfusion and neuronal functioning in sport-related concussion, motivating future research to establish and validate clinical assessment protocols that can incorporate advanced neuroimaging methods to characterize altered cerebral physiology following mild traumatic brain injury. et al. report that blood oxygen level–dependent signal assessed by functional MRI outperforms a standard post-concussion neurocognitive test for classifying concussed athletes and predicting post-concussion symptoms. Blood oxygen level–dependent signal variability may hold promise as a neurobiological marker for alterations in cerebral perfusion and functioning following concussion.Anderson   Athletes with minimal physiological and neurocognitive symptoms may therefore be cleared to return-to-play prematurely, which can exacerbate symptoms, increase risk for severe secondary injuries and complicate or prolong recovery.8 Thus, current research aims to discover neurobiological markers that can be used to objectively assess the presence and severity of SRC and to determine when the brain has recovered sufficiently to permit safe return-to-play.Clinicians rely on a variety of assessments to diagnose SRC, including brief neurological examinations, symptom checklists, neurocognitive tests 9 Acute biomechanical injury—sudden stretching of neuronal and axonal membranes—triggers a cascade of neurometabolic changes including the abrupt release of neurotransmitters, ionic fluxes and unregulated extracellular glutamate release, ultimately leading to hyperglycolysis and axonal injury or cell damage.8 This intricate ‘neurometabolic cascade’8 can manifest sequelae including dizziness, nausea, headache, insomnia, amnesia, attentional issues and other physiological and neurocognitive symptoms.11Concussion symptoms reflect a complex series of neurometabolic events that occur during and after the initial impact. Physiological damage from SRC typically occurs in stages, starting with the initial impact or change in velocity  and subsequent structural deformation.13 Repetitive TBI in these areas is a particularly serious concern in SRC, as secondary blows that occur during this vulnerable metabolic window can produce catastrophic secondary impairments,14 highlighting the need for accurate diagnostics for safely clearing individuals to return to normal activity following a concussion.Several brain regions, including anterior frontal and temporal areas, medial temporal structures, corpus callosum and subcortical white matter pathways, are particularly vulnerable to bruising and injuries caused by inertial forces.15 researchers have increasingly utilized more advanced functional neuroimaging techniques to elucidate underlying changes in neuropathology post-injury.16 Functional MRI (fMRI) has shown promise for characterizing alterations in neural function post-mTBI across multiple domains. Task-based fMRI studies have demonstrated changes in activation in the parietal cortex, dorsolateral prefrontal cortex and the hippocampus in concussed athletes relative to healthy controls.17 Further, functional connectivity assessed from resting-state fMRI revealed altered connectivity within the default mode, fronto-parietal and motor-striatal networks relative to controls in individuals with mTBI.19 fMRI methods may provide objective biomarkers of neurophysiological injury, affording greater sensitivity and specificity for SRC diagnoses. Recent research suggests that while structural imaging and neurocognitive tests did not accurately discriminate mTBI patients from controls, resting-state functional connectivity measures correctly classified SRC status and predicted long-term cognitive sequealae.20 Functional neuroimaging methods may facilitate SRC evaluation through identification of altered haemodynamics and neurometabolism, detecting impaired neurovascular coupling, cerebral blood flow (CBF) and oxygen metabolism associated with abnormal brain function.21As neurobiological correlates of cognitive and mental health dysfunction from SRC are difficult to detect with standard axial neuroimaging techniques ,23 and that patterns of variability as measured from blood oxygen level–dependent (BOLD) signal are closely linked to neural information processing, cognitive function and brain health.25 Recent studies have demonstrated that BOLD variability can detect vascular pathologies in cerebral small vessel disease,26 Alzheimer’s disease,27 post-traumatic stress disorder28 and stroke29 by capturing underlying differences in cerebrovascular compliance26 that alter haemodynamic function and neurovascular coupling, motivating the investigation of BOLD variability for detecting neurophysiological alterations in mTBI.Neuroscience evidence demonstrates that regional brain activity is inherently variable over time31 increased reactivity of smooth muscle in microvessel walls32 and reduction in the density and diameters of capillaries both proximal and distal to the site of injury.33 Furthermore, altered BOLD variability can indicate sites of neural proliferation and synaptogenesis, indexing post-mTBI neuroplasticity that drives changes in neural signalling and BOLD activation during recovery.15 BOLD variability may therefore serve as a biomarker of changes in individuals’ cerebral vascular status during and following traumatic neurophysiological insult, potentially assisting in the diagnosis of SRC.Mechanisms that may alter BOLD variability following mTBI may include changes in cerebral perfusion,The aim of the present study is to compare regional measures of BOLD variability and cognitive assessment scores for their complementary roles in the evaluation of SRC. Neuroimaging indices of BOLD variability may represent a novel lens for objectively evaluating SRC status by detecting functional disruption, providing information beyond conventional neuropsychological assessment batteries that may improve the detection and management of concussion pathology. While clinically informative, neurocognitive assessments remain limited in their ability to assess the extent of injury or identify neurophysiologically vulnerable individuals. To investigate the potential role of neurocognitive testing and functional neuroimaging in SRC diagnosis, we examined group differences in regional BOLD signal variability and neurocognitive performance on ImPACT in athletes diagnosed with SRC (compared against age-matched control athletes without SRC). We then applied a supervised machine learning algorithm (bagged ensemble random forests) to assess whether whole-brain BOLD variability measures, ImPACT module scores or BOLD and ImPACT composite scores together can discriminate healthy, concussed and repetitive concussion patients. We further applied bagged random forests to assess the extent to which regional BOLD variability measures and ImPACT scores in isolation or combination accurately predict clinical symptom load. Our study therefore assessed BOLD variability in both classification and regression machine learning frameworks for detecting SRC status or post-concussion symptoms from functional neuroimaging data .This study was carried out in accordance with the recommendations and approval of the University of Birmingham Research Ethics Committee. The protocol was also approved by the National Institute of Health Research Centre for Surgical, Reconstruction and Microbiological Research Centre (NIHR SRMRC—Ethics Ref. 11-0429AP28). All subjects gave written informed consent in accordance with the Declaration of Helsinki. Deidentified data from this cohort may be made available by the authors on request.34 Participants included 29 semi-professional rugby athletes diagnosed with SRC and 6 additional rugby athletes diagnosed with repetitive SRC over a 21-day window. Athletes were excluded if they required hospital admission after initial assessment for concussion; presented with intracranial blood, brain tissue injury or non-concussion–related pathologies on initial CT/MR scan; or had history of neurodegenerative pathology or chronic alcohol or drug abuse. In addition, 15 age-matched controls who have not received a concussion in the previous 3 months were enrolled. Other study design features are reported in Yakoub et al.34Study participants were recruited through the Surgical Reconstruction and Microbiology Research Centre (SRMRC), based at Queen Elizabeth Hospital of Birmingham (United Kingdom), as part of the repetitive concussion in sport (RECOS) study.1-weighted magnetization-prepared gradient echo structural image was acquired for each participant .All data were collected on a 3 Tesla Philips Achieva MRI scanner in Birmingham University Imaging Centre (BUIC). A high-resolution multi-echo T35 sensitive to BOLD contrast .The functional neuroimaging data were acquired using an accelerated single-shot gradient echo echoplanar imaging (EPI) sequenceDuring the resting-state fMRI scan, participants were asked to keep their eyes closed. Visual contact could be established at any time to the control room via a coil-mounted reverse mirror. All participants were instructed to lie still, keep their eyes closed and to try and think of nothing.fMRIPrep 20.2.037 and XCP Engine 1.0.39 Pre-processing entailed slice timing correction, motion correction, spatial smoothing [3 mm full width at half maximum (FWHM) kernel], nuisance signal regression, temporal bandpass filtering, linear registration of functional images to structural images and non-linear registration of structural images to a standard-space MNI152 brain template (2 mm isotropic voxel resolution).All MRI data processing was performed using containerized processing pipelines for reproducible analysis of neuroimaging data. Pre-processing steps were performed using 40 All nuisance variables were modelled via a single generalized linear model (GLM), to remove spurious correlations and noise introduced by head motion and variables of no interest. In addition to ICA-AROMA components classified as noise, these included head motion correction parameters, individual volume motion outliers estimated using DVARS41 with outliers flagged above 1.5 standardized DVAR, framewise displacement exceeding 0.5 mm and mean white matter and cerebrospinal fluid signals averaged across all voxels identified from the segmentation of the high-resolution magnetization-prepared rapid gradient echo (MPRAGE). The fully pre-processed resting-state fMRI data were taken as the residuals from this GLM model. The residual image was transformed into normalized MNI152 space and resampled to 4 mm isotropic voxels.Head motion parameters were accounted for using independent component analysis with automatic removal of motion artefacts (ICA-AROMA) analysis.43 BOLD signal variability was computed as the standard deviation of successive differences in the time-series signal extracted for each of the 200 grey matter regions defined by the Schaefer parcellation atlas.44 MSSD mean-centres the amplitude of difference in BOLD signal between frames, providing a more reliable metric of BOLD variability than standard deviation by avoiding inflated estimates of variability. The Schaefer 200 atlas provided sufficient spatial resolution and functional homogeneity within each parcel for examining regional MSSDBOLD signal across the entire cortex.Resting-state mean square successive difference (MSSD)45 The test was designed in the early 1990s specifically to assess concussed players of the National Football League46 and is now a Food and Drug Administration (FDA)–approved neuropsychological testing tool in SRC.47 Inclusion of this particular cognitive test has been demonstrated to increase the sensitivity of post-concussion assessment beyond symptomatic evaluation and physical examination.48Participants completed the 25 min computerized ImPACT assessment under identical administration conditions. ImPACT is a multi-domain online neuropsychological test that has been used as a standard technique documenting baseline cognitive function, characterizing the effects of concussive injury and monitoring the progress of recovery.49 and test–retest reliability.50ImPACT includes a demographic survey, a brief medical history questionnaire and a post-concussion symptom scale consisting of 22 commonly reported symptoms. All participants indicated whether they endorsed each symptom and rated the extent of symptom severity on a seven-point Likert scale (0 = ‘not experiencing the symptom’ to 6 = ‘severe’). Scores were summed with higher scores reflecting more post-concussive symptoms. The six neurocognitive ImPACT sub-tests consist of word memory, design memory, X’s and O’s, symbol match, colour match and three letters. Five neurocognitive domain scores are derived from the sub-tests: verbal memory, visual memory, visual–motor processing speed, reaction time and impulse control. Higher scores on the verbal memory, visual memory and visual–motor processing speed composites reflect stronger performance, whereas a higher score on the reaction time composite reflects slower or worse performance. The impulse control composite provides a measure of errors on testing and is used to determine test validity. Test scores were converted to percentile measures and adjusted for age, gender, learning disability and level of education. ImPACT has adequate psychometric properties, including good construct validity34 Measures collected include Digit Span,51 Digit Symbol Coding and Symbol Search,52 a nine-hole peg test of fine motor dexterity53 and balance assessments including a virtual reality system,54 gait analysis56 and the modified balance error scoring system (mBESS),57 facilitating precise concussion diagnosis. Additional assessments, inventories and neuroimaging components collected by the RECOS protocol are reported in Yakoub et al.34As part of the RECOS study protocol, study participants completed additional screening and assessment inventories to examine clinical presentation of SRC.BOLD measures and ImPACT module composite scores, statistical unpaired t-tests were performed and corrected for multiple comparisons using Benjamini–Hochberg control of the false discovery rate (FDR). These comparisons provide for interpretable identification of the specific ImPACT scores and modules most readily associated with SRC status, assessing for group-level effects of SRC and repetitive mTBI that emerge in variables used by our machine learning framework.To identify between-group differences in regional MSSD58 RF machine learning achieves high prediction accuracy when presented with a large number of input variables relative to the sample size,60 as is the case for our neuroimaging data, while still performing well with small numbers of input variables (as is the case for ImPACT scores). This importantly affords the ability to directly compare predictions of concussion status and post-concussion symptoms made by modelling BOLD variability and ImPACT composite scores using the same machine learning approach. Other motivations for selecting RF machine learning for this study include RF’s understood performance, ease of use and resistance to outliers, as well as its capability to consider all BOLD variability regions jointly, avoiding an initial feature selection or engineering step in support of the exploratory nature of this study. Critically, this approach avoids using the results from between-group feature comparisons of BOLD variability to subset regional BOLD variability features that build a smaller and better-performing RF model, as feature engineering BOLD variability metrics is not a goal of the present study.BOLD variability indices and ImPACT composite scores were further assessed for their ability to differentiate healthy, concussion and repetitive concussion subjects and predict clinical symptom load using a random forest (RF) machine learning approach. RF is an ensemble machine learning method that trains an ensemble (i.e. forest) of decision trees to perform either classification or regression.BOLD measures and ImPACT composite scores were used variously as input features (i.e. independent variables), with output features (i.e. dependent variables) being group membership (classification) or post-concussion symptoms (regression). Each RF ensemble was parameterized using leave-one-out crossfold validation, with the minimum leaf size being the only tuned parameter. For ImPACT score models, minimum leaf size was tuned to 5 (preventing overfitting); otherwise, minimum leaf size was tuned to 20. Trees were grown by splitting input variables to maximize reduction in the Gini impurity index,61 repeated iteratively until maximum depth is reached or when all samples belong to a single class. The number of decision trees was increased until mean squared error (MSE) of out-of-bag (OOB) classification or regression predictions stabilized . Forests were grown to 5000 trees total.In our approach, bagged RF regression and classification were performed using built-in functions in MATLAB R2021a. MSSDK from a model fold (i.e. bag) that has been trained with resampling from all other athletes in our data set N, affording a direct test of RF models’ ability to generalize their training data to unseen test set (i.e. OOB) subjects. The overall OOB prediction performance of RF machine learning evaluate three separate sets of input features: (i) ImPACT module composite scores, (ii) whole-brain MSSDBOLD measures and (iii) ImPACT score and MSSDBOLD measures jointly combined. This approach allows us to assess the utility of BOLD variability or ImPACT scores in isolation or combination when predicting SRC status and post-concussion symptoms. One versus all receiver operating characteristic (ROC) curves were calculated for the classification of each group across the three classes of RF models, indicating the true positive rate (i.e. correctly predicting group membership) versus the false positive rate (i.e. incorrectly predicting group membership in the next most likely classification).Individual RF machine learning predictions were generated from an ensemble of OOB decision trees, where the ensemble of decision trees that generate a prediction did not include the test subject’s data in any resampled training data set. Restated, the set of decision trees used to make a prediction for test predicts subject The ROC area under the curve (AUC) was computed for all combinations of group and model to diagnose the overall prediction performance of each class. This AUC is the integral of the ROC curve—i.e. the probability that the conditional probability of a random positive observation is greater than the conditional probability of a random negative observation. Thus, larger probabilities represent greater sensitivity and specificity for the positive label, suggesting greater utility for detecting SRC.For regression models, RF machine learning was instead trained to predict total reported post-concussion symptoms from the same combinations of input BOLD variability and ImPACT score variables (while ignoring group membership). Importantly, control subjects may incidentally report low levels of concussion symptoms in the absence of SRC—further motivating the investigation of functional neuroimaging metrics for detecting SRC status.P value = 0.11). Impulse control is a measure of test validity, used to discard tests with a value above 30. The highest observed impulse control score in our sample was 15 , suggesting all ImPACT scores represent valid administrations and should be included in our analysis.Statistically significant between-group differences were not observed for ImPACT’s composite measures of verbal memory, visual memory, visual–motor processing speed, reaction time and impulse control between healthy control, concussed individuals and repetitive concussion individuals. BOLD measures for concussion or repetitive concussion athletes compared with healthy controls. In contrast with ImPACT score findings, reliable regional differences in MSSDBOLD signal are found in occipital and inferior temporal lobes, premotor areas and the ventral anterior cingulate. We observe that regional MSSDBOLD values are significantly decreased in concussed subjects relative to healthy controls, displaying significantly less fluctuation in BOLD signal amplitude over time. In contrast, all significant regions in repetitive concussion patients show greater MSSDBOLD than in healthy controls, reflecting significantly more pronounced variability in regional BOLD signal relative. This dissociation between BOLD signal decreases in concussion and increases in repetitive concussion suggests that unique pathophysiological mechanisms that implicate functional alterations may underlie the more severe sequelae observed in repetitive SRC.BOLD metrics and ImPACT scores were used to train RF machine learning models. BOLD demonstrated the highest classification accuracy, with ImPACT scores alone producing models with the lowest classification accuracy.Despite evidence for group-level differences in regional BOLD signal variability, no feature selection was performed prior to training RF classifier models, and therefore, all regional MSSDBOLD data. Only the model trained on ImPACT scores alone under-performs this baseline value for classifying concussion subjects . Here, we observe the greatest difference in classification performance between ImPACT scores and MSSDBOLD measures, suggesting BOLD variability is both a more sensitive and specific index of signal associated with repetitive SRC than ImPACT scores.BOLD variability in combination). Ground truth positive labels are reflected along rows, with OOB classification labels in columns . Label confusion suggests this best-performing RF model (correctly classifying 31/50 athletes in our sample) is most sensitive for detecting concussion and repetitive concussion. However, the RF model also displays markedly lower specificity for concussion, misclassifying a majority (11/15) of healthy control subjects as concussed. This suggests that while BOLD variability indeed facilitates detection of SRC and repetitive mTBI, models trained to include BOLD variability measures may require more targeted feature engineering to better distinguish between health controls and subjects with lower SRC severity, as has been shown using functional connectivity data.20 This model’s performance for classifying control subjects (4/15) is also an improvement over the RF model trained using only ImPACT composite scores, which misclassifies all control subjects as concussion subjects (0/15). This performance likely reflects the large label size of concussion athletes and the lack of reliable between-group differences observed with ImPACT scores. These results suggest that MSSDBOLD measures indeed contribute to a classification model with improved prediction accuracy for distinguishing healthy and concussed individuals.BOLD holds promise as a sensitive biomarker for detecting symptomatic abnormalities in cerebrovascular status in athletes with SRC. We briefly review the findings with respect to regional MSSDBOLD and ImPACT modules by examining (i) between-group differences, (ii) their classification accuracy using the categorical RF model and (iii) their regression accuracy using the continuous RF model.The present study demonstrates that MSSD12 Our results identify several cortical areas in those regions that demonstrate significant differences in MSSDBOLD measures in the presence of SRC or repetitive mTBI. Specifically, MSSDBOLD measures in occipital and inferior temporal regions  and midline structures (premotor cortex and anterior cingulate) significantly differ between control and concussed athletes. These regions are particularly vulnerable to injury due to inertial forces, either front to back or rotational. We also observed a dissociation in the directionality of BOLD variability changes. Concussed athletes displayed universally decreased BOLD variability across affected brain regions. In addition to reflecting altered neurovascular coupling, patterns of low regional BOLD variability observed for concussion patients may also in part reflect functional hyperconnectivity commonly observed following mTBI,62 such that stronger functional coupling of distal regions entrains BOLD signal amplitude to a more limited band. In contrast, repetitive concussion subjects display uniformly elevated BOLD signal variability in affected regions. As the elapsed duration between most recent SRC and clinical assessment is comparable for concussion and repetitive concussed athletes . In these models, the majority of features ranked as highly important represented BOLD variability measures, not ImPACT scores. Classification based on the categorical RF models demonstrated a higher sensitivity or true positive rate for accurately identifying individuals with repetitive concussions when using BOLD variability (AUC = 0.66) than was observed using ImPACT scores (AUC = 0.25). Overall multi-label classification accuracy was also increased when BOLD variability data were included, with classification error decreasing from 46%  to 38% when ImPACT scores and BOLD variability were jointly modelled. This was partially due to increases in classification accuracy for identifying subjects with high overall symptom loads as belonging to concussion or repetitive concussion groups. Classification accuracy of control subjects, while still low, also increased when BOLD variability data were included in the RF models, suggesting that BOLD variability may have greater specificity than ImPACT for detecting SRC. The left middle frontal gyrus, left frontal pole and temporal occipital fusiform gyrus had the largest effects in the RF model classification, which is in line with research suggesting regions in the frontal and temporal lobes are commonly affected in mTBI.BOLD data in a single model produced the best prediction performance with a MSE of 26.9. Feature importance scores indicated that the main variables used to generate predictions for this model were BOLD variability measures, suggesting that variance associated with ImPACT scores is of lower importance than BOLD variability during forest growth and model training. Results from these continuous RF models indicate that MSSDBOLD is a more sensitive predictor of post-concussion symptom totals and that jointly considering functional and neurocognitive data together is a useful approach for machine learning models to improve the accuracy of predictions for total SRC symptom load.Prediction accuracy was highest for RF models trained to predict the total number of post-concussion symptoms using the combination of ImPACT composite scores and BOLD variability variables. The continuous prediction model trained only on ImPACT scores converges during training to a MSE of 30.5 when predicting post-concussion symptoms, showing the largest error and the worst performance. A continuous RF model that trained only on BOLD variability data demonstrated lower MSE (28.7), reflecting improvements to predictive performance. Jointly including ImPACT and MSSDBOLD can be generalized to other populations (i.e. children and adolescents with SRC and non-athletic populations with mTBI). Second, MSSDBOLD cannot currently be used to assess severity of an injury itself, only the extent of the symptom load that it produces, and additional screening methods involving structural neuroimaging techniques will be still required to reveal the extent of injury and changes in pathology during recovery. Third, the analysis approach using MSSDBOLD cannot reveal the actual damage to the vasculature and surrounding neural cells at the site of injury. Fourth, while our study observes high performance for predicting total clinical symptom load in healthy and SRC athletes, our SRC classification models will often mistake healthy controls for concussed subjects. This may be due to our sample’s imbalance between control (N = 15) and concussion (N = 29) subjects or may suggest that more a more precise feature selection step is required to identify MSSDBOLD regions more specific for SRC, possibly requiring higher-resolution cortical parcellation schemes. On the other hand, mismatches in performance may potentially be addressed by methods that do heavily subset BOLD variability as an initial feature selection step, potentially inducing parity in the number of BOLD and ImPACT input variables to afford comparison of prediction accuracy through alternative ML approaches . While random forests appear to be sufficient for our purposes in this manuscript, we do not intend to suggest they are necessary. Fifth, there may be other representations of variability besides MSSDBOLD that better capture the extent of underlying functional alterations in SRC, including representations that jointly consider resting static or dynamic functional correlation or large-scale intrinsic brain network organization. Future research should consider investigating these elements at a fine-grained level to further elucidate neurobiological pathologies in SRC. Sixth, and finally, functional MRI acquisition remains prohibitive in many outpatient clinical settings, though we believe our results at do least motivate further exploration of BOLD variability for monitoring athletes before and after SRC, particularly from a personalized or precision medicine perspective.In this study, we demonstrate that BOLD signal variability holds promise as a diagnostic biomarker for detecting functional neural alterations following SRC. While our approach motivates systematic exploration into BOLD variability’s utility for detecting injury in clinical neuroimaging of concussion, there are several limitations and challenges to this approach. First, given that the concussed group is a highly homogenous athletic population, future studies should examine whether the observed deviations in MSSD73 consistent with the present findings. Executive dysfunction can be a pernicious consequence of TBI,75 implicating alterations to network topology and dynamics in neurological sequela following mTBI.76 Future research may wish to examine brain network alterations for their impact on other cognitive domains or as a potential neurobiological marker of injury and recovery status.These findings emphasize the need for future research to examine how network topology and dynamics are altered by TBI. Recent research has highlighted the importance of global brain network topology for facilitating cognitive abilities,BOLD assessed from resting-state fMRI are sensitive to abnormalities in cerebrovascular status in athletes with SRC. Further, we show that regional MSSDBOLD measures can more sensitively and specifically identify concussed and repetitive concussed individuals within a RF machine learning framework compared with standardized neurocognitive tests. In contrast, ImPACT composite scores do not capture reliable between-group differences in concussion status and cannot be used in isolation to build an RF model that discriminates between concussion, repetitive concussion and healthy athletes. Combining BOLD variability and ImPACT scores leads to the highest prediction performance, supporting the claim that altered BOLD variability provides novel information about altered cerebral vascular status that can aid diagnosis and return-to-play decisions when collected alongside existing assessment protocols for the detection of SRC. Further, we provide evidence that MSSDBOLD contributes to prediction of total post-concussion symptoms, outperforming ImPACT scores across healthy and concussed patients. In conclusion, this paper provides initial evidence that BOLD variability holds promise as a potential clinical marker for SRC, motivating a more systematic exploration of BOLD variability as a candidate biomarker in future work. To investigate the sensitivity and efficacy of MSSDBOLD in diagnosing SRC, future neuroimaging research may wish to deploy MSSDBOLD measures alongside neuropsychological testing protocols and structural neuroimaging methods, providing a more complete assessment of athlete health that includes cerebrovascular alterations and associated cognitive deficits to better facilitate detection of injury in SRC and guide return-to-play decisions.Diagnosis of SRC can be difficult due to the low sensitivity of assessments designed to identify cognitive deficits in athletes with suspected injuries. In addition, clinical evaluation of SRC using structural imaging methods is limited to characterizing anatomic pathology and cannot detect haemodynamic or neurometabolic disruptions. In this work, we provide evidence that functional neuroimaging indices of MSSD


Sparsity finds applications in diverse areas such as statistics, machine learning, and signal processing. Computations over sparse structures are less complex compared to their dense counterparts and need less storage. This paper proposes a heuristic method for retrieving sparse approximate solutions of optimization problems via minimizing the [[EQUATION]] quasi-norm, where $0<p<1$. An iterative two-block algorithm for minimizing the [[EQUATION]] quasi-norm subject to convex constraints is proposed. The proposed algorithm requires solving for the roots of a scalar degree polynomial as opposed to applying a soft thresholding operator in the case of $\ell_{1}$ norm minimization. The algorithm's merit relies on its ability to solve the [[EQUATION]] quasi-norm minimization subject to any convex constraints set. For the specific case of constraints defined by differentiable functions with Lipschitz continuous gradient, a second, faster algorithm is proposed. Using a proximal gradient step, we mitigate the convex projection step and hence enhance the algorithm's speed while proving its convergence. We present various applications where the proposed algorithm excels, namely, sparse signal reconstruction, system identification, and matrix completion. The results demonstrate the significant gains obtained by the proposed algorithm compared to other [[EQUATION]] quasi-norm based methods presented in previous literature.


Medical use of chemically modified synthetic estrogens caused toxic complications; thromboembolic events and increased cancer risk in female organs as they proved to be endocrine disruptors deregulating estrogen receptors (ERs) rather than their activators. Synthetic estrogen treatment exhibits ambiguous correlations with cancer risk at different sites, which may be attributed to an inhibition of the unliganded activation of estrogen receptors (ERs) coupled with compensatory liganded activation. The principle of estrogen induced breast cancer led to the introduction of antiestrogen therapies against this tumor; inhibition of the liganded activation of estrogen receptors and aromatase enzyme activity. The initial enthusiasm turned into disappointment as the majority of breast cancers proved to be primarily resistant to antiestrogens. In addition, nearly all patients showing earlier good tumor responses to endocrine therapy, later experienced secondary resistance leading to metastatic disease and fatal outcome. Studying the molecular events in tumors responsive and unresponsive to antiestrogen therapy, it was illuminated that a complete inhibition of liganded ER activation stimulates the growth of cancers, while a successful compensatory upregulation of estrogen signal may achieve DNA restoration, tumor regression and patient’s survival. Recognition of the principal role of endogenous estrogens in gene expression, gene edition and DNA repair, estrogen treatment and stimulation of ER expression in patients may bring about a great turn in medical practice.This work presents the history of the recognition of principal regulatory capacities of estrogen hormones having been mistakenly regarded as breast cancer promoting agents for more than 120 years. Comprehensive analysis of the results of clinical, epidemiological, immunological and molecular studies justified that endogenous estrogens are the principal regulators of embryonic development, survival and reproduction  The role of estrogen hormones in the carcinogenesis of female breasts has long been debated based on the ambiguous results of menopausal hormone therapy (MHT), however, the exact mechanism of their tumor inducing effect is not entirely clarified till now .via estrogen withdrawal by oophorectomy  approved marketing of synthetic estrogens, non-steroidal diethylstilbestrol (DES) and steroidal ethinylestradiol (EE) as well as conjugated equine estrogens (CEEs) for medical purposes .In 1944, Haddow et al. proposed the concept of “the estrogen paradox” suggesting that in spite of the well known stimulating effect of estrogen hormones on breast cancer, high doses of DES is a promising therapy against this tumor . DespiteIn the meantime, the controversial results of great menopausal hormone therapy (MHT) studies strengthened the presumed role of estrogen treatment in the development and progression of breast cancer , 9. AmonSeparated evaluation of the effects of specific HRT types applying natural and synthetic hormones justified that horse urine derived CEE alone is an outstanding formula decreasing the risk for breast cancer, coronary heart disease and bone loss. Conversely, synthetic estrogens and their combination with synthetic progestins may have unforeseeable toxic and carcinogenic impacts .The presumed carcinogenic capacity of endogenous estrogens promoted the introduction of current antiestrogen therapies against breast cancer. In 1971, Cole et al. reported the use of tamoxifen, a selective inhibitor of liganded activation of estrogen receptor (ER) for the treatment of advanced breast cancer in postmenopausal women . The expde novo (primary) antiestrogen resistance (Antiestrogen therapy of advanced breast cancer yielded many difficulties and failures from the onset. Tamoxifen as a first line therapy induced moderate tumor regression rate (<40%–50%) even among the targeted ER-positive breast cancer cases, while the remaining patients could not exhibit tumor responses or experienced tumor growth. Therapeutic failures were designated as sistance . During sistance . In addisistance .De novo or acquired resistance to AI treatment also developed in the vast majority of patients with advanced breast cancer.Aromatase inhibitors (AIs) also were developed for the therapeutic reduction of estrogen synthesis in breast cancer cases . Among AFollowing the failures in high dose estrogen treatment the development of antiestrogen therapy could also not realize the enthusiastic expectations for breast cancer defeat. In breast cancer cases diagnosed and treated at the earliest stage, unforeseeable tumor recurrence and fatal outcome may occur even after decades . Tumor rThe comparison between the major anticancer capacity of endogenous estrogens and the ambiguous effects of the endocrine disruptor synthetic estrogens and antiestrogens shows some parallelism with the history of Rosetta stone. It is a stele composed of granodiorite inscribed with three versions of a decree issued in Memphis, Egypt, in 196. The texts are in ancient Egyptian hieroglyphic scripts, in Demotic scripts and in Ancient Greek. The comparison of the three versions made Rosetta stone a key to deciphering the ancient Egyptian scripts.In 2007, estrogen deficiency was exposed as a newly recognized risk factor for oral cancer in a Hungarian clinical-epidemiological study . Oral caOral cancer induced by decreased estrogen levels seemed to be highly controversial to the old principle of estrogen induced breast cancer as the regulation of genomic processes may not be quite different at various sites. Analyzing the literary data, defective estrogen signaling proved to be a strong cancer risk factor for several organs including female breasts . The corEstrogen deficiency emerged as a new cancer risk factor directly deteriorating the signaling functions of mammalian cells. Moreover, results of clinical and experimental studies justified that behind insulin resistance associated chronic diseases a defect of estrogen signal may always be revealed suggesting their strong partnership in cancer development .Studies on breast cancer epidemiology suggested that the better the reproductive capacity of women the lower is their breast cancer risk. In healthy premenopausal women having higher estrogen levels, the breast cancer risk is much lower as compared with postmenopausal cases showing extremely low serum estrogen concentrations . StudiesImmunohistochemical imaging of ERs, progesterone receptors (PRs) and human epidermal growth factor receptors (HER2s) in breast cancers provided further possibilities to clarify the risk factors and therapeutic possibilities of variously differentiated tumors .Experimental and clinical studies examined the correlation between ER expression and the development and progression of breast cancer. The differences between ER-positive and ER-negative tumors regarding their gene expressions and genomic mutations remained to be clarified . HoweverIn postmenopausal women with decreased estrogen levels, the majority of tumors proved to be highly differentiated with abundant ER expression  showing In animal experiments, high estrogen concentrations in pregnancy and short term exposure to pregnancy mimicking high estrogen levels prevented mammary carcinogenesis induced by either chemicals or tumor inoculation . GeneticIn conclusion, either estrogen deficiency or ER-resistance to estrogen activation may lead to genomic disorders increasing the risk of breast cancer . MoreoveThe genome of living organisms is inherited; however, it shows a great plasticity through appropriate self-mediated changes continuously updating the regulatory processes throughout the life. Bio-intelligence means that the genome of living creatures is capable of perception of its environment (outer and inner) . Genome Malignant tumor cells are mistakenly regarded as enemies to be killed similarly like exogenous microbes. Presumably, “hostile” tumor cells develop survival techniques so as to escape from the regulatory commands of patient’s body. In reality, tumor cells are dysregulated human cells having more or less remnants of the same regulatory network like patients’ healthy cells have. The tumor initiator is an inherited or acquired failure of the principal regulator of the genomic machinery. Variously differentiated tumor cells exhibit spontaneous efforts for the improvement of their genomic regulation; however, this work in itself may rarely lead to a successful tumor regression. Tumor cells need medical help for the self directed repair of genomic alterations instead of crude inhibition of their spontaneous gene repairing efforts .Over the past decades, we acquired a deeper appreciation on the roles of estrogen receptors in human physiology and pathology . EstrogeIn humans, ER-alpha and ER-beta isoforms are co-expressed in many cells and tissues, and they control key physiological functions in all organ systems in strong interplay. ER alpha primarily drives and controls the proliferation and DNA stability of cells, while ER beta regulates cell growth in particular . Both ERERα is the highly predominant isoform in mammary gland, uterus, ovary , bone, male reproductive organs (testes and epididymis), prostatic stroma, liver, and adipose tissue. By contrast, ERβ is highly expressed in the prostatic epithelium, bladder, ovary (granulosa cells), colon, adipose tissue, and immune system. Both subtypes are markedly expressed in the cardiovascular and central nervous systems . This lavia unliganded pathway (ERs have possibilities for liganded (estrogen bound) activation through their activation function 2 (AF2) domain and for unliganded activation by several transduction molecules through the ancient activation function 1 (AF1) domain . In the  pathway . Ligand- pathway . Balance pathway . Artificvia regulatory circuits  and insulin-like growth factor-1 receptors (IGF-1Rs) . Ligandelear ERs . In preglear ERs . The eme pathway .regulatory circuit of fuel supply, activated ERs drive and control all steps of cellular glucose uptake and the maintenance of glucose homeostasis (via facilitating the expression and translocation of intracellular glucose transporters (GLUTs)  . Disorde (GLUTs) . In insu (GLUTs) . In MCF- pathway . In tumo pathway .ERs expressed in the adipose tissue mass regulate the energy supply of the whole body of mammalians. Abdominally located fatty tissue is a hub of the signaling network providing energy and ER signal to the work of visceral organs. Fatty tissue in the pericardium regulates heart, while fat positioned along great vessels drives and controls the function of arteries and veins . IncreasConversely, estrogen deficiency or ER resistance deregulates the signaling functions of adipocytes. In women, menopause associated estrogen loss may increase the risk for both metabolic disorders and weight gain . AdipocyFrom the early 1940s, synthetic estrogens DES and EE in high doses were introduced as promising treatments for patients with advanced breast cancer . High doIn female transgenic mice with inactivated AF2 domain of ERs, DES treatment could not induce an estrogen-like uterotrophic response through the activation of AF1 domain . This exvia high dose synthetic estrogen treatment led to controversial tumor responses and serious toxic complications via alterations in the expression of estrogen regulated genes.In pregnant rats, exposure to excessive DES and EE induced mammary tumor development in both mothers and their offsprings. These synthetic estrogens equally provoked persistent alterations in the expression of estrogen regulated genes, in DNA methylation and histone modifications . These ovia an additive deregulation of ER activation  comprising steroidal EE were developed in the early 1960s and EE became a standard component of near all forms of contraceptive pills . OCs comtivation .via a strong compensatory upregulation of the AF2 domain of ERs.In contrast, OCs comprising low doses of EE may decrease endometrial cancer  and ovarIn conclusion, EE is an endocrine disruptor compound even in low doses as it is rather a partial antagonist of ER activation instead of being an agonist. Since EE has been regarded as a bioidentical estrogen, the experienced thromboembolic events and increased breast cancer risk in OC users were mistakenly regarded as complications of elevated estrogen levels .Xenoestrogens deriving from the environment have endocrine disrupting properties acting as false ligands of nuclear receptors including estrogen receptors. Deregulation of estrogen receptors lead to changes in DNA methylation and histone modification leading to genomic instability. Environmental endocrine disruptor compounds may be natural like phytoestrogens and resveratrol or synthetic substances like solvents, pesticides, cleaning products and cosmetics. Many observations are suggesting that exposure to environmental endocrine disruptors do contribute to cancer, diabetes, obesity, metabolic syndrome and infertility .During the development of menopausal hormone therapy (MHT) both synthetic estrogens  and conjugated equine estrogens (CEEs) with natural origin were applied . Before Increased endometrial cancer risk was reported in postmenopausal women using miscellaneous exogenous estrogens . From 19In 2002, the results of a great, prospective, placebo controlled Women’s Health Initiative (WHI) study strengthened that combined CEE plus medroxyprogesterone-acetate (MPA) treatment  increased the risk of breast and colon cancer, thromboembolism, cardiovascular diseases and hip fracture . FollowiEvaluating the controversial results of MHT studies; the FDA US established several times that various approved estrogen and progestin formulations may alleviate menopausal symptoms in postmenopausal women. However, their use is associated with ambiguous “risks and benefits” concerning coronary heart disease, thromboembolism as well as for endometrial and breast cancers .In 2004, the results of a further great, prospective placebo controlled WHI study showed strikingly decreased breast cancer risk after using oral CEE alone; and the risk for total cancer also was slightly reduced . ConsideCritical analysis of the results of MHT studies revealed that the use of estrogens with different origin and even their combinations with synthetic progestins may explain the chaos of quite controversial clinical experiences among hormone user women . PremariIn 2021, the results of a new WHI randomized, placebo-controlled trial were published. Conjugated equine estrogen treatment  significantly reduced ER-positive, PR-negative cancers and deaths from breast cancer also were reduced by 40% . This fiThe pharmaceutical industry developed the first drugs for the inhibition of estrogen induced activation of ERs and they were introduced into the practice of breast cancer care. Tamoxifen was regarded as a selective estrogen receptor modulator, while letrozole worked as aromatase inhibitor reducing estrogen synthesis in breast cancer patients .Considering the whole population of breast cancer patients, antiestrogen treatment could not surpass the “magic” 30% of tumor response rate, similarly to the weaknesses of other endocrine therapies; such as oophorectomy or high doses of synthetic estrogens . The majDespite the 50 years practice and advance of antiestrogen therapy, the inhibition of liganded ER activation could not become the key to the tumor free survival of breast cancer cases. Enormous efforts have been exerted worldwide to overcome the tumor “resistance” to antiestrogen therapy, which develops near in all ER-positive breast cancer patients following long term treatment.via higher expression of ERs and activation of estrogen synthesis. In the meantime, the blockade of liganded ER activation is a crisis even for tumors promoting the upregulation of estrogen signal and DNA stabilization leading to apoptosis. Tumor response may be regarded as a common success based on the repaired genomic regulation of both patients and their tumors .In patients, non-responsive to antiestrogens, various toxic side effects are experienced suggesting a genome wide blockade of the estrogen signal in the whole body. Tumor cells remain without regulatory help, similarly, like tumor cell lines Molecular events behind the response and resistance of antiestrogen treated breast cancer cells were thoroughly analyzed. Different mechanisms of endocrine resistance were suggested, such as compensatory increased expression of ER coactivators , and a ctumor cells responsive to endocrine therapy, the increased expression and activation of ERs were typical observations counteracting the endocrine disruptor treatment  template stimulating the expression of a foreign protein via translation (In 1989, Malone and coworkers published a landmark experiment on inducing protein production in cell cultures nslation . In 1990nslation . These snslation .via mRNA technology may have great possibilities in human practice beyond vaccination. Considering that ERs are the chief regulators of all genomic processes, Malone’s mRNA technology may be an excellent method for the stimulation of appropriate ER protein production in patients. Theoretically, ESR1 mRNA treatment in patients with low ER levels or ER resistance may prevent breast cancer development by stimulation of ER production and increase in estrogen regulated gene expression. In addition, in patients with advanced ER negative and TNBC type tumors, a preoperative ESR1 mRNA treatment may achieve marked tumor regression coupled with stimulating defensive reactions in the adjacent tissues. In the postoperative phase, local ESR1 mRNA treatment improves the genomic functions in the remaining breast tissue and inhibits the development of recurrent tumor. In breast cancer cases with multiple metastatic lesions, systemic ESR1 mRNA treatment may achieve regression of tumors at all sites besides improvement of the metabolic and immunological status of patients. The dream of perfectly selective tumor therapy and the concomitant safeguarding of healthy tissues seem to be realized.The production of a desired protein The developing new trends in anticancer fight are targeting mutated genes by gene therapy and attacking their altered protein products by immunotherapy. However, the accumulation of altered genes and their abundant protein products in tumors may not show a parallelism with the progression of the disease as they are rather spontaneous compensatory efforts for DNA repair instead of oncogenic activities. All developed new methods of gene therapies are targeting the compensatory genome improving processes, while tumor cells need rather medical help supporting their DNA restoration so as to achieve apoptotic death.via synthetic estrogen and antiestrogen treatment, helped to reveal the omnipotent curing capacity of endogenous estrogens via balanced liganded and unliganded activation of ERs.Recognition of the molecular mechanisms of estrogen receptor deregulation


This letter to the editor discusses “the use of video-EEG monitoring to guide antiseizure medication (ASM) withdrawal in patients with epilepsy” . The aut Dear Editor,I read with great interest the recent article by Dhaenens-Meyer et al.  on “The One of the primary challenges in epilepsy care revolves around the safe and appropriate withdrawal of ASM. While ASM can effectively control seizures, it may entail significant side effects and financial burden for patients . AdditioThe study by Dhaenens-Meyer et al.  suggestsNonetheless, as the authors astutely acknowledge, further research is warranted to fully comprehend the effectiveness of this approach and to refine patient selection criteria for ASM withdrawal. Future studies should explore the utility of video-EEG monitoring in diverse patient populations and settings. For instance, investigations could delve into the model’s applicability in pediatric epilepsy or drug-resistant epilepsy cases, providing deeper insights into its broader suitability.Comparative analyses between video-EEG monitoring and other ASM withdrawal methods could also shed light on the model’s unique advantages. In this regard, Lamberink et al.  presenteMoreover, the implications of the study’s findings stretch beyond clinical practice and extend to public health policies related to epilepsy management. Existing policies that prioritize ASM access might necessitate reevaluation in light of the possibility of ASM withdrawal. Policymakers should contemplate how to best support individuals with epilepsy who opt for ASM withdrawal, including the provision of resources to manage withdrawal symptoms and continuous monitoring of seizure activity during the withdrawal process .In conclusion, the study by Dhaenens-Meyer and colleagues highlights the potential benefits of incorporating video-EEG monitoring into epilepsy management. By offering a more objective and data-driven approach to ASM withdrawal, video-EEG monitoring could substantially mitigate the risk of seizure recurrence and improve overall patient outcomes. I am optimistic that ongoing research will further explore and enhance this approach, and I strongly encourage healthcare providers to consider implementing video-EEG monitoring when appropriate.Sincerely,Apochi Obed Okwoli.


The specialty pharmaceuticals market is expanding more rapidly than the traditional pharmaceuticals market. Specialty pharmacy operations have evolved to deliver selected medications and associated clinical services. The growing role of specialty drugs requires new approaches to managing the use of these drugs. The focus, expectations, and emphasis in specialty drug management in an integrated health care delivery system such as Kaiser Permanente (KP) can vary as compared with more conventional health care systems. The KP Specialty Pharmacy (KP-SP) serves KP members across the United States. This descriptive account addresses the impetus for specialty drug management within KP, the use of tools such as an electronic health record (EHR) system and process management software, the KP-SP approach for specialty pharmacy services, and the emphasis on quality measurement of services provided.  Kaiser Permanente’s integrated system enables KP-SP pharmacists to coordinate the provision of specialty drugs while monitoring laboratory values, physician visits, and most other relevant elements of the patient’s therapy. Process management software facilitates the counseling of patients, promotion of adherence, and interventions to resolve clinical, logistic, or pharmacy benefit issues. The integrated EHR affords KP-SP pharmacists advantages for care management that should become available to more health care systems with broadened adoption of EHRs. The KP-SP experience may help to establish models for clinical pharmacy services as health care systems and information systems become more integrated.


Bacteriophages, the viruses that infect and replicate within bacteria, have long been recognized as potential therapeutic agents against bacterial infections. The rise of antibiotic resistance and the limitations of traditional antibiotics have prompted researchers to explore innovative strategies in the field of drug discovery. Bacteriophage bioengineering represents a promising avenue that offers targeted and precise solutions to combat bacterial pathogens . EngineeBacteriophages possess a high degree of specificity in targeting bacterial hosts . This exIn terms of refining bacteriophages for therapeutic purposes, genetic engineering techniques have played a crucial role . The manAs bacteriophages have specific host selectivity, bioengineered bacteriophages can be used to rapidly identify pathogenic bacteria in food products via reporter or labeled nanoprobe-mediated fluorescence or luminescence-based sensing systems . The purThe concept of utilizing bacteriophages for both vaccine development and cancer therapy demonstrates the versatility of these biological entities . In the Although bacteriophage bioengineering holds immense promise, it is not without its challenges. One significant obstacle is the potential for the emergence of phage-resistant bacteria . As bactBacteriophage bioengineering represents an innovative approach to drug discovery, offering precise solutions for targeting harmful bacteria while preserving beneficial counterparts. Through precision engineering techniques, such as CRISPR-Cas systems, bacteriophages are equipped with specialized antimicrobial tools to enhance their efficacy and scope. This transformative field addresses challenges posed by bacterial resistance and regulatory complexities, presenting boundless potential. Furthermore, integrating treatment and real-time monitoring through theranostics reshapes infectious disease management. Bacteriophage bioengineering is at the forefront of drug discovery, influencing antibiotic resistance, diagnostics, and innovative theranostics, positioning it as a promising frontier despite obstacles. Ongoing research, requiring collaboration among researchers, pharmaceutical companies, and regulatory bodies with adaptive strategies, is crucial to address the obstacles and unlock the full potential of bioengineered bacteriophages. As highly adaptable biologics, they offer innovative disease management and precision therapeutics solutions, reshaping the healthcare landscape. The era of "Designer Phages" heralds a new chapter in addressing critical healthcare challenges .


Colorectal surgery has witnessed a transformative shift with the advent of minimally invasive techniques, offering patients reduced postoperative discomfort, shorter hospital stays, and accelerated recovery compared to conventional open surgery. This comprehensive review aims to assess the current state of minimally invasive approaches in colorectal surgery, encompassing various techniques such as single-incision laparoscopic surgery, robot-assisted surgery, and conventional laparoscopic surgery. The article meticulously explores the benefits and drawbacks of each technique, delves into the established criteria for their application, delineates cautious circumstances, and analyzes the outcomes of minimally invasive colorectal surgery. Additionally, the integration of virtual reality and augmented reality for surgical planning and training is discussed, shedding light on the future trajectory of this field. Surgeons and researchers striving to enhance patient care and surgical outcomes in colorectal surgery will find this review article an invaluable resource, presenting crucial components of minimally invasive colorectal surgery and paving the way for continued advancements in the field. Over the past three decades, surgical innovation has been focused on the desire to lessen surgical stress and improve endoscopic access. Since Semm performed the first laparoscopic appendectomy in 1981, minimally invasive colon surgery has seen remarkable progress. Laparoscopic and minimally invasive surgery have been greatly advanced by recent developments in video and robotic technology . QualityA lengthy process spanning three decades has led to the examination and implementation of minimally invasive surgery for colorectal cancer, particularly for rectal cancer. Due to its intricacy involving many quadrants and early worries about a greater frequency of port site recurrences, colon cancer surgery offered hurdles in contrast to procedures like gallbladder and appendectomy. Prior to the publication of adequately planned trials in the mid-2000s, laparoscopic procedures were thoroughly assessed for colon cancer through a number of non-randomized observational studies. Notably, individuals with rectal cancer were frequently omitted from these studies. Randomized controlled trials (RCTs) contrasting laparoscopic and open surgery for colon cancer, including the Barcelona, Clinical Outcomes of Surgical Therapy (COST), Colon Cancer Laparoscopic or Open Resection (COLOR), and Conventional vs. Laparoscopic-Assisted Surgery in Patients With Colorectal Cancer (CLASICC) trials, consistently showed at least equivalent oncologic outcomes, comparable complications, a modestly shorter hospital stay, and the restoration of bowel function following laparoscopic surgery . But desThe Medical Research Council's (MRC) CLASICC experiment, which included patients with both colon and rectal cancer, featured the first randomized controlled trial contrasting laparoscopic versus open surgery for rectal cancer . There wMethodologyThis comprehensive analysis used a methodical process to compile and examine pertinent research on minimally invasive colorectal surgery techniques. To achieve a thorough grasp of the issue, the study included both qualitative and quantitative research studies and academic articles. To find pertinent materials, a thorough search was carried out across many academic databases, including PubMed, Scopus, and Google Scholar. A database like PubMed was searched using relevant keywords and phrases like "laparoscopy," "robotic," "non-invasive," "colorectal," and "surgery." There were only English-related results shown. The most recent report from a similar study was utilized if there were multiple published reports. We only considered review publications that also included original data. Figure ObjectiveThis research paper aims to conduct a thorough examination of the current status of minimally invasive colorectal surgery, highlighting progress, results, and future outlooks.Assessing ProgressThe main goal of this review is to examine current developments in laparoscopic and robot-assisted minimally invasive colorectal surgical techniques . Our objEvaluating Medical ResultsA comprehensive evaluation of the clinical results associated with minimally invasive colorectal surgery is another key goal . We willIdentifying Patient Selection CriteriaFinding the best criteria for selecting individuals for minimally invasive colorectal surgery is the aim of the research we are conducting. We will analyze factors including age, pre-existing health issues, tumor location, and cancer stage to determine which patients would benefit most from less invasive treatments . We willExploring Future PerspectivesThis review's objectives go beyond just reviewing the state of minimally invasive colorectal surgery today. It also explores potential directions for progress and the prospects for the future . We willDiscussionRobot-Assisted Laparoscopic Surgery for Rectal Cancer: The Ideal Solution?Robot-assisted laparoscopic prostatectomy is becoming increasingly common. Straight laparoscopic tools have limits in small anatomical areas; however, with EndoWrist instruments and a modern three-dimensional vision system, these restrictions are addressed. Particularly in the extraperitoneal area of the pelvic cavity, surgeons are drawn to the idea of robot-assisted laparoscopic surgery for rectal cancer . HoweverTechniques: Total Robotic or Hybrid Approach?There is continuous discussion over the placement of ports, docking methods, and tactics for controlling splenic flexure during robot-assisted laparoscopic TME. One fully robotic surgery and one hybrid strategy, which differs depending on the tool used for the splenic flexure takedown, are the two main procedures that are primarily employed. Some surgeons use a hybrid technique, depending on a straight laparoscopy for mobilizing the splenic flexure while using a robotic surgical system for vascular control and pelvic dissection . The goaSingle-Incision Laparoscopic SurgeryThe benefits of conventional multiport laparoscopy (CML) over open surgery are well-known and include less discomfort, shorter hospital stays, fewer wound problems, and a better outward look. By performing the whole process through a single abdominal incision, single port laparoscopic surgery (SILS) can maximize the benefits of CML while minimizing surgical stress. Single port laparoscopic surgery is a development in the direction of scar-free, minimally invasive surgeries. This method deviates from the basic "triangulation" idea of laparoscopy and poses difficulties by containing all laparoscopic ports within a single incision. Compared to CML, SILS requires more advanced laparoscopic skills, is more complicated, has poorer ergonomics and early studies suggest longer operating times than with CML . Beyond Learning Curve for Laparoscopic Surgery for Rectal Cancer: Is There a Magic Number?Rectal resections are more difficult to do than colectomies, as previously indicated, because of the complicated pelvic architecture, the significance of maintaining autonomic nerve function, and the effects of neoadjuvant therapy. Achieving enough exposure is essential in traditional open surgery, especially in male patients with a big mesorectal tumor and a restricted pelvis, where the retractor plays a significant role. For the necessary total mesorectal excision, a precise and crisp dissection is required to produce the best oncologic outcomes. All of these elements work together to make laparoscopic rectal resection more challenging . A JapanThis brings up a crucial issue: How can operators get the essential abilities without putting patients in danger? The utility of simulation, animal training, and cadaver courses in appropriately preparing surgeons for resection surgeries on human patients is yet unknown . From ouFindings from multiple studies are listed in Table The physical restrictions imposed by the bony pelvis and the necessity to preserve autonomic nerves make minimally invasive surgery for rectal cancer challenging. Straight laparoscopic, hand-assisted, and robot-assisted laparoscopic surgery have all been proposed as solutions to these problems. Laparoscopic rectal cancer surgery offers similar short-term benefits to other minimally invasive procedures. According to the available data, survival and recurrence rates for long-term oncological outcomes are comparable. It is anticipated that ongoing prospective, randomized, controlled trials will support the idea that laparoscopic surgery is superior to open surgery. Additionally, it seems that both methods have similar short- and long-term oncological consequences. Robotic surgery seems to promote a faster recovery of sexual and urogenital function. Three less invasive methods of local excision are now available, and they are all as effective as traditional local excision. In conclusion, minimally invasive surgery for rectal cancer has developed into a recognized and well-studied procedure over the past 30 years. However, concerns about the superiority of one modality over another persist, and future technological improvements are anticipated to put the present established platforms under pressure.


Another systematic meta-analysis reported that combined exercise protocols such as aerobic and low-intensity resistance exercises dampen oxidative damage and suggested additional antioxidants are unnecessary during exercise . As mentioned above, resistance exercise may disperse the local oxidative damage, and aerobic exercise may help carry this effect to the entire system. Nevertheless, this should be established with the proper oxidative damage-related mechanism. Several studies have reported the use of antioxidants for preventing exercise-induced oxidative damage. In this Research Topic, Wang et al. used taurine as an external antioxidant for preventing inflammation during running and concluded that taurine affects reducing inflammatory markers. Another study reported that treadmill exercise maintains a balanced oxidative-reductive environment within the joint by regulating inflammation . Apart from these, two studies reported the effect of exercise on different biomechanical properties, which helps recommend exercise as one of the essential strategies for preventing injury.The current Research Topic covers seven articles dealing with exercise effects on various physio-pathological functions, primarily related to oxidative stress as a main platform for inducing exercise benefits. An article dealt with the role of strenuous exercise as a potential candidate for inducing myocardial damage. It is reported that an increased volume of cardiac load can increase oxidative stress causing myocardial damage, suggesting the careful need for exercise before recommending it. This may be due to the increased HMGB1 and sRAGE reverted after 72 h, indicating the transient ischemic alteration rather than direct necrosis in the cardiac system (ammation . AnotherIn summary, this Research Topic addressed several aspects of physical exercise-induced oxidative damage-related diseases. In particular, this Research Topic covered how physical activity can be recommended for maintaining a healthy lifestyle. Nevertheless, revealing a specific mechanism of exercise types with different intensities can control the ROS production within the limit or induce the adaptation with the specific ROS concentration will firmly support the exercise as an essential tool for improving health benefits. Finally, we thank all the authors, reviewers, and editors who contributed and spent their precious time making this Research Topic successful.


Scedosporium aurianticum infection developed in 2 recipients of kidney transplants in India, acquired from the same deceased near-drowning donor. Given the substantial risk for death associated with Scedosporium infection among solid-organ transplant recipients, safety protocols for organ transplantation from nearly drowned donors should be thoroughly revaluated and refined. Scedosporium spp. fungal infection, which causes pneumonia with a high mortality rate among nearly drowned children and young adults  from nearly drowned donors (NDD) have been linked to substantial allograft loss and increased risk for death among kidney transplant recipients  recently introduced a distinct category for fatal cerebral infections after near-drowning incidents linked to Scedosporium, which has been documented to precipitate potentially fatal disseminated infections in 70% of immunocompetent and 100% of immunocompromised hosts , limited sensitivity of culture based methods, and relatively slow growth of cultured isolates compared to other common saprophytic molds. Those factors collectively lead to delayed diagnoses, elevated therapeutic failures, and increased relapse rates  has been operational for more than a decade, specific risk factors for DDSI transmission from NDDs have not yet been defined. The passive reporting system used by the Disease Transmission Advisory Committee and frequent omissions of crucial NDD data in donor medical records impede comprehensive understanding of DDSI transmission risks (Although the Disease Transmission Advisory Committee of the Organ Procurement and Transplant Network/United Network for Organ Sharing (Routine PCR screening of organs from NDDs for fungi would ensure accurate identification, timely detection, prompt management, and well-informed decision-making. In addition, uniform international guidelines regarding use of organs from NDDs are needed to address critical technical and procedural issues essential for mitigating risk for DDSI transmission. Scedosporium infection in kidney transplant recipients from deceased near-drowning donorAdditional information about study of


Bioengineered allogeneic cellularized construct (BACC) has recently been proven to be effective for treatment of burn wounds and now has FDA approval. There is a paucity of data describing long term (≥1 year) scar characteristics following treatment with BACC, including its potential to modulate the formation of hypertrophic scar (HTS). HTS causes significant physical and psychosocial implications which can result in diminished quality of life. This study aims to characterize post-burn scars resulting from BACC-treated wounds compared to within subject matched autografted wounds using clinical and histologic metrics.Adult patients (n=5) were previously enrolled in a Phase III clinical trial for treatment of their deep partial thickness acute burn wounds. Subjects had clinical scar examinations including imaging, Scar Assessment Scales (POSAS), and non-invasive skin measurements to quantify skin elasticity, erythema, and melanin. Punch biopsies were collected and fixed in formalin from the autograft-treated site (A), the BACC-treated site (B), the donor-site (D), and an area of normal skin (NS). The formalin-fixed biopsies were then embedded in paraffin, sectioned, and stained with H&E, Picrosirius Red, and Herovici.The use of BACC produced no difference in POSAS score and achieved elasticity measurements comparable to NS (Table 1). The erythema measurement demonstrated differences between scar sites and each scar site was different from NS. The donorsite also had some variation from NS. The measured melanin levels were different between each scar site, and both were different from NS. The donorsite also had detectable differences in melanin from NS. Measurements of epidermal thickness demonstrated differences between scar sites with BACC being similar to NS. Rete ridge ratio were different between scar sites and between autograft vs. NS. Papillary dermis cellularity had minor differences between scar sites and both scar sites were different from NS. Reticular dermis cellularity was equivalent between autograft and BACC sites and both were different from NS. Papillary and reticular alignment were not different between scar sites. Reticular orientation was not different between autograft and BACC but was different in BACC vs. NS. Papillary dermal thickness was different between autograft and BACC.The HTSs resulting from wound closure achieved using BACC are similar to autografting in metrics related to clinical POSAS scores, extracellular matrix, and collagen structure. Scars following autografting or the use of BACC to achieve wound closure differ in metrics related to pigmentation, epidermal structure, and papillary dermal thickness and cellularity.These findings may suggest that the use of BACC is a more optimal treatment for certain burn depths in certain patients because some HTS outcomes are equivalent, and it eliminates the need for a donor site.


CardiCatheter ablation is a viable therapy for ventricular tachycardia –3. It isConsidering advancements in clinical therapy and methods for cardiopulmonary support, cardiogenic shock and electrical storm are primary causes of death and morbidity in heart failure individuals –8. In paIndividuals with cardiogenic shock are prone to ventricular arrhythmias, which, despite the administration of effective antiarrhythmic medications, may compromise or prevent successful weaning off cardiopulmonary support , 3. The 2.Despite cardiopulmonary support, many ventricular arrhythmias are poorly tolerated hemodynamically, which might be due to a decrease in right ventricle output or inadequate hemodynamic left ventricle support in relation to tachycardia cycle durations and the degree of left ventricular failure . HoweverThe treatment of cardiogenic shock continues to be arduous, with a substantial fatality rate . This isThe higher mortality and morbidity documented in cardiogenic shock individuals indicate their underlying severe condition . The assIn addition, a number of investigations have demonstrated that patients who originally displayed cardiogenic shock demanding cardiopulmonary support and afterward formed ventricular tachycardia possess a greater in-hospital fatality rate than patient populations who at first needed hemodynamic support for both cardiogenic shock and ventricular tachycardia , 3.In certain circumstances, the rationale for extremely early ablation could be to regulate hemodynamics with the intention of decreasing the impact of arrhythmia . During A few individuals who are released from the hospital could experience ventricular tachycardia reappearance under the monitoring threshold of their implanted cardioverter-defibrillator (ICD) .In these contexts, clinical management is challenging and must consider comorbidities and baseline cerebral and cognitive state.3.In individuals receiving catheter ablation of ventricular tachycardia with complex substrates, several comorbidities, and a current record of repeated ventricular tachycardia-related ICD shocks, the initiation of cardiopulmonary support is crucial . These iThe Milan cohort of 74 extracorporeal membrane oxygenation (ECMO)-supported ablation treatments revealed equivalent outcomes. In addition, faster ventricular tachycardias were found in the five patients in whom ECMO was used as an intra-procedure rescue method, lowering the effectiveness of ECMO in avoiding end-organ hypoperfusion .The University of Pennsylvania described a cohort of 21 individuals undergoing ablation of ventricular tachycardia who needed ECMO support due to severe cardiac damage . Even wiNonetheless, the outcomes of ablation with preemptive support (Impella or Tandem Heart) are encouraging. The direct contrast of rescue vs. preemptive ventricular assist device (VAD) vs. the lack of cardiopulmonary support throughout ablation of ventricular tachycardia in a population of 21 individuals revealed a higher 30-day fatality rate in the rescue cluster, with a longer procedure time, apart from comparable ablation outcomes . ConsequOn the basis of clinical factors at hospitalization, efficient risk classification of newly admitted individuals is possible . Six demThe PAINESD risk score was created by a team from the University of Pennsylvania . Age, isIn a cohort of 75 individuals receiving scar-related ventricular tachycardia ablation, preemptive VAD placement directed by the PAINESD scoring system was helpful, yielding greater benefits than a propensity-matched cohort of 75 individuals receiving ablation absent VAD placement . DespiteThese findings suggest that ventricular tachycardia individuals must be accurately risk-stratified prior to the procedure . Even whWhen a bailout catheter ablation technique is required to address recalcitrant rhythm disturbances, cardiopulmonary support is an efficient therapy for cardiogenic shock caused by recalcitrant ventricular arrhythmias –3. PreveMS: wrote the first draft of the report. DZ, ES, DI, and GS: helped to wrote the final version. All authors contributed to the article and approved the submitted version.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.


Twisted layered material junctions, and in particular twisted graphene interfaces, exhibit fascinating physical properties of diverse nature including unique structural, tribological, electronic, as well as heat and electron transport characteristics . These pIn the paper entitled ‘Deducing the internal interfaces of twisted multilayer graphene via moiré-regulated surface conductivity’ by the groups of Prof. Qunyang Li and Prof. Wengen Ouyang , the autThe measurement results are rationalized by fully atomistic anisotropic force-field simulations, demonstrating the propagation of the intra-layer atomic reconstruction from the embedded twisted interface towards the stack surface. Based on these results, the authors construct a phenomenological classical electronic conductivity model that utilizes the registry index approach  to explaThe innovative development of recent experimental microscopy techniques for characterizing twisted layered interfaces, suggests that intricate momentum space interference effects may dominate interlayer transport . InteresThe joint experimental and theoretical tools developed by Li and Ouyang, thus pave the way for the non-invasive high resolution spatial characterization of twisted interfaces embedded within layered material stacks.


Editorial on the Research TopicBiomarkers of neonatal brain injuryDiagnosing brain injury in newborns is crucial because early intervention can significantly impact long-term development and overall quality of life. The brain undergoes rapid development during the neonatal period, and any injury to the brain can disrupt this delicate process. Neurodevelopment is a major concern in several conditions including preterm birth, intrauterine growth restriction, periventricular leukomalacia, white matter injury, neonatal encephalopathy (NE), hypoxic-ischemic encephalopathy (HIE), and neonatal stroke. Premature infants are particularly susceptible to brain injury due to their underdeveloped organs and fragile systems. Although survival rates of infants born extremely preterm continue to increase , one-thiPavel et al. conducted a cohort study to assess heart rate variability (HRV) as a potential biomarker for predicting the severity of EEG grade in neonates with HIE within the first 12 h of birth. The study included 120 infants with HIE, and HRV features were analyzed alongside clinical parameters. The results demonstrated that early HRV, combined with clinical information, accurately predicted EEG grade, providing valuable objective information on HIE severity when EEG monitoring was not available in the early postnatal period. HRV was analyzed using custom software and manual artifact detection in a process that would need to be simplified or automated prior to bedside use.Kyng et al. investigated the potential of neurofilament light chain (NfL) as a biomarker for brain injury in a newborn piglet model of hypoxia-ischemia. The study analyzed serum NfL levels in 48 piglets subjected to hypoxic-ischemic insults, along with brain imaging and histologic assessments. The results revealed a significant increase in NfL levels after hypoxia-ischemia, with the highest values observed at 72 h post-insult. NfL levels at 72 h were predictive of a poor outcome on cortical histopathology and magnetic resonance spectroscopy basal ganglia Lac/NAA ratio, indicating its potential as a sensitive and specific biomarker for moderate–severe HIE.Balog et al. conducted a prospective, observational study to analyze cardiac function parameters using non-invasive hemodynamic monitoring in neonates with moderate–severe HIE undergoing therapeutic hypothermia (TH). The study included 26 neonates, and heart rate (HR), stroke volume (SV), and cardiac output (CO) data were collected throughout TH and rewarming. The findings demonstrated that patients with adverse outcomes had lower SV and higher HR during TH, indicating differences in cardiac function associated with neurodevelopmental outcomes. HR during hypothermia was found to be independently associated with neurodevelopmental outcomes, emphasizing its relevance in guiding cardiovascular supportive therapy.Efstathiou et al. explored the kinetics of circulating progenitor cells (CPCs) in preterm neonates with encephalopathy, aiming to understand the brain's endogenous regeneration processes after injury. The study enrolled 47 preterm neonates and analyzed peripheral blood samples using flow cytometry to assess CPCs, along with brain injury biomarkers and clinical factors. The results indicated an enhanced mobilization of CPCs following brain injury, suggesting the presence of an endogenous brain regeneration process. The findings contribute to understanding the related pathophysiology and highlight the potential of CPCs as biomarkers for evaluating brain injury and predicting outcomes.Exploring the utility of biomarkers across different neonatal brain injuries can provide valuable insights into shared mechanisms and pathways. Investigating biomarkers that have the potential for cross-disease validation may lead to the identification of common therapeutic targets and facilitate the development of targeted interventions for multiple conditions. The studies discussed above highlight the progress made in this field, focusing on diverse biomarkers including physiological, biochemical, hemodynamic, and functional biomarkers. Incorporating these biomarkers into clinical practice has the potential to enhance early detection, risk stratification, and individualized management of neonates at risk of brain injury. Challenges for the future include the development and validation of biomarkers that can predict acute injury, cross-disease validation of biomarkers, validation of previous findings in larger cohorts, and establishing correlations with long-term neurodevelopment to assist in personalized care. Most likely not a single biomarker will make the diagnostic breakthrough but the intelligent combination of many. Thus, further research and validation are warranted to establish the utility of these biomarkers and their integration into routine neonatal care, ultimately leading to improved neurodevelopmental outcomes for affected infants.


Botulinum neurotoxin A (BoNT) is the first line treatment for cervical dystonia (CD) and treatment outcome significantly depends on the correct identification of the muscles involved.In a case with insufficient response to BoNT treatment further work up with magnetic resonance imaging (MRI) of the neck revealed a hypertrophic spinalis cervicis muscle, that is not commonly involved in CD.This highlights the use of MRI for muscle selection in treatment refractory CD cases. A 45-year-old cervical dystonia (CD) patient with retrocollis, right sided torticollis and left sided laterocollis responded insufficiently to botulinum toxin treatment. By ultrasound, the right longissimus capitis muscle appeared hypertrophic, otherwise no abnormalities were noted. Repeated ultrasound-guided injections of the right sided splenius capitis, longissimus capitis and obliquus capitis inferior muscles partially improved the torticollis component, while the laterocollis component showed only marginal response to injections into the left trapezius, semispinalis and levator scapulae muscles. No effect on the retrocollis was reported. Magnetic resonance imaging (MRI) of the neck then revealed an untypical prominent variant of the spinalis cervicis muscle on the left side . The typ4


Fistulizing perianal disease is a debilitating complication present in nearly half of all patients diagnosed with Crohn’s disease. The majority of anal fistulas arising in these patients are complex. Treatment can be challenging with therapy often requiring both medical and surgical interventions with differing levels of symptomatic relief. Fecal diversion is an option after medical and surgical modalities have been exhausted but demonstrates limited efficacy. Complex perianal fistulizing Crohn’s disease is inherently morbid and can be difficult to manage. We present a case of a young male with Crohn’s, severe malnutrition and multiple perianal abscess with extensive fistula tracts up to his back; a planned fecal diversion was instituted to control sepsis and allow for wound healing and optimize medical therapy. Crohn’s disease (CD) is a chronic inflammatory bowel disease that can occur throughout the entire gastrointestinal tract. Anal fistulae are a complication of CD secondary to anal crypt gland infection leading to abscess formation and an epithelized tract that communicates between the anorectal lumen and the perineal or buttock skin. . The cumA 22-year-old male with a past medical history of hidradenitis suppurativa (HS), malnutrition and recently diagnosed CD presented to our tertiary academic center with extensive trans-sphincteric, supra-sphincteric and extra-sphincteric perianal fistulas. He had fistulizing disease with multiple external openings, atypical locations and perianal abscesses that required several incision and drainage procedures and seton placements prior to presentation at outside institutions. On examination, these openings extended to his mid-back in addition to the perineum. We initially treated him by obtaining source control (drainage of abscess), draining setons and subcutaneous fistulotomies . After hIn the 8 months following his index surgery, the patient was readmitted on several occasions due to his extensive fistulizing perianal CD. A reluctance to undergo fecal diversion, issues with treatment compliance, loss of follow up and insurance authorizations contributed to the challenges in managing these complex anal fistulas that would eventually require multiple courses of antibiotics. Multispecialty care was guided by infectious disease consultations, use of biologics , interventional radiology drainage, bowel regimen, pain management, surgical nutrition and physical and occupational therapy. The patient eventually agreed to a laparoscopic loop sigmoid colostomy after further incision and drainage of his perianal abscess, subcutaneous fistulotomy and seton placement.At the 3-month follow up, the patient was no longer on biologic therapy but endorsed only minor improvement in symptoms. Abdomino-perineal resection had been discussed as a potential future surgical option and the patient remains currently on Ustekinumab therapy.CD patients frequently require surgical intervention despite recent advancements in biologics . PatientThe combination of noncutting setons and medical management has demonstrated complete or partial healing in two-thirds of patients . As our A combination of surgical and medical treatment can yield complete fistula remission in 62% of patients as compared with 43% with monotherapy . Critica


Premenopausal period is characterized by cognitive and mood disorders in women . Resveratrol  is a phytoestrogen present in the skin of a range of foods including red grapes, blueberries and peanuts. Resveratrol can act through multiple mechanisms, including binding and activation of estrogen receptors (ER), to increase nitric oxide bioavailability and thereby facilitate the endothelium-dependent vasodilatation necessary for adequate cerebral perfusion . Some evidences indicate that resveratrol can improve cognitive processes and emotional state .The aim of the present study was to compare the efficacy the combined treatmnet of SSRIs  plus resveratrol (50 mg twice per day) for 6 months therapy on the affective profile of premenopausal woman with clinically confirmed Major Depressive Disorder (MDD)For the assessment of affective profile in premenopausal women (35-45 years) with clinically confirmed MDD, we used the different tests: Montgomery-Asberg Depression Rating Scale (MADRS) and Shihan Anxiety Scale .After 6 months of SSRIs plus resveratrol therapy, MADRS Scale showed more significant improvement of the depressive symptoms in premenopausal women with clinically confirmed MDD compared to the SSRIs treatment alone . Moreover, these patients demonstrated a significantl low anxiety state using ShARS Scale.Thus, our pilot clinical study clearly demonstrated that co-treatment with SSRIs plus resveratrol (50 mg twice per day) was able to enhance the therapeutic effects of SSRIs on the affective-related symptoms in premenopausal women. We need to create new approaches to treat the premenopausal women with MDD using a combination of SSRIs with resveratrol.None Declared


Significant Influencing Factors and Effective Interventions of Mobile Phone Addiction - Volume II”. This Research Topic encompasses both empirical research and meta-analysis studies. Empirical studies allow for the discovery of new insights, while meta-analysis enables the formulation of more robust conclusions based on a synthesis of multiple research findings. Meta-analyses in our Research Topic have extensively synthesized previous research findings regarding the impact of self-esteem, self-control, social support , and academic burnout  on and exercise  mobile phone addiction. Our Research Topic has made notable advancements in understanding the causes of mobile phone addiction, as well as the practical implications for addressing this issue through effective interventions.The issue of mobile phone addiction has garnered significant attention among researchers over the past two decades. Expanding on our previous work, we have successfully completed the Research Topic titled “Ding et al.), emotional factors such as anxiety and depression , loneliness , and academic burnout , cognitive factors such as automatic thoughts , as well as executive dysfunction , have all been confirmed to have significant predictive effects on mobile phone addiction. From an environmental perspective, the family is an important environmental micro-system that influences mobile phone addiction , family cohesion and adaptability , and parenting style of encouraging autonomy  have all been found to be closely associated with mobile phone addiction. Moreover, based on comprehensive research findings, environmental factors not only predict mobile phone addiction through the mediation of individual factors, but also the predictive effect of environmental factors on mobile phone addiction varies depending on certain individual factors. In other words, mobile phone addiction is a complex outcome resulting from the joint influence of external environmental factors and internal individual factors.Our Research Topic contributes to a comprehensive understanding of influencing factors from both individual and environmental perspectives. Regarding individual factors, according to the Interaction of Person-Affect-Cognition-Execution model . Another meta-analysis systematically summarizes and compares the intervention effects of different types of exercise on Internet addiction . These studies not only inspire further research on internet addiction/mobile phone addiction but also offer empirical support and practical recommendations for future educational practices. Indeed, there are numerous other efficacious intervention approaches to address internet addiction and mobile phone addiction, including cognitive-behavioral therapy (Kim et al., Our Research Topic delves deeper into intervention methods and their effectiveness. One study examines the direct and indirect effects of physical exercise on Internet addiction (In summarizing our two Research Topics, it is evident that they hold significant theoretical and practical implications. However, they also present several areas that merit further investigation by future researchers. Firstly, our Research Topics did not comprehensively explore the complex interactions between multiple environmental systems and various individual factors. To achieve research results of greater ecological validity, it is crucial to consider the combined effects of these factors. Secondly, our Research Topics lacked studies simultaneously analyze and compare the effects of certain influencing factors on different types of internet addiction/mobile phone addiction. Different types of internet addiction/mobile phone addiction exhibit distinct behavioral characteristics (Liu et al., QL: Writing—original draft, Writing—review and editing. ZZ: Writing—review and editing. CE: Writing—review and editing.