Video super-resolution aims to generate high-resolution frames from low-resolution counterparts. It can be regarded as a specialized application of image super-resolution, serving various purposes, such as video display and surveillance. This paper proposes a novel method for real-time video super-resolution. It effectively exploits spatial information by utilizing the capabilities of an image super-resolution model and leverages the temporal information inherent in videos. Specifically, the method incorporates a pre-trained image super-resolution network as its foundational framework, allowing it to leverage existing expertise for super-resolution. A fast temporal information aggregation module is presented to further aggregate temporal cues across frames. By using deformable convolution to align features of neighboring frames, this module takes advantage of inter-frame dependency. In addition, it employs a hierarchical fast spatial offset feature extraction and a channel attention-based temporal fusion. A redundancy-aware inference algorithm is developed to reduce computational redundancy by reusing intermediate features, achieving real-time inferring speed. Extensive experiments on several benchmarks demonstrate that the proposed method can reconstruct satisfactory results with strong quantitative performance and visual qualities. The real-time inferring ability makes it suitable for real-world deployment. Video is a widely used multimedia format combining image frames with audio. However, the quality of video often is limited by factors such as capture, storage, and transmission . Video sRecently, deep learning-based methods have shown promising performance in video SR tasks  and imagFurther, numerous video SR models ,14,15,16In this work, a novel video SR method is proposed to address these limitations. To exploit spatial information, the proposed method incorporates the architecture and well-trained weights of an image SR model as the foundational framework. A fast temporal information aggregation module is introduced to effectively leverage inter-frame dependency. Since moving objects exist in different positions, deformable convolution  can effeThe main contributions of this paper are as follows: (1) A novel video SR model is proposed to fully incorporate a pre-trained image SR model and achieve a trade-off between accuracy and real-time efficiency. (1) A novel video SR model is proposed that can be inferred in real-time while providing high-quality SR video frames. (2) A fast temporal information aggregation module is introduced where deformable convolution is adopted to extract the information of a moving object. The channel attention is also employed for adaptively capturing important information. (3) A redundancy-aware inference is developed for video SR. By avoiding repetitive feature extraction, the computational cost is significantly reduced.The remainder of this paper is organized as follows: The image SR problem is a typical ill-posed problem. In 2014, Dong et al.  were theIn this study, the IMDN  is emploRecently, there has been a growing interest in the video (SR) problem, leading to the proposal of numerous deep learning-based models . Given tThe first category includes methods that utilize optical flow. These methods make use of optical flow to align neighboring frames or features. For instance, VESPCN  aligns nThe second category contains methods based on 3D convolutions. Three-dimensional convolution is capable of extracting spatial and temporal information simultaneously from multiple input frames. For example, Kim et al.  applied The third category consists of methods employing deformable convolutions, which have gained popularity recently. Deformable convolutions were proposed in . The leaIn addition, there are attention-based approaches. These methods extract spatio-temporal information via various attention mechanisms. For example, Yi et al.  and Li eFor better performance on video SR reconstruction, the proposed method incorporates both deformable convolution and channel attention. The proposed fast temporal information aggregation is achieved through two stages: spatial aggregation and subsequent temporal aggregation. In the spatial aggregation stage, the deformable convolution is employed to align neighboring features. In order to effectively aggregate information from neighboring video frames, channel attention is used. Further, both stages significantly contribute to reconstruction performance.t. The model consists of three key components, i.e., the spatial feature extraction module, the fast temporal information aggregation module, and the upsampler module. The spatial feature extraction module is based on a pre-trained image SR model called IMDN 7], and SIn addition to the Vid4 benchmark, comparisons on the SPMCs-30  benchmarThe qualitative comparison is shown in The temporal consistency of the proposed model is evaluated following the methodology in a prior study . The temThe efficiency is analyzed from four aspects: number of parameters, number of computational operations, inference latency, and quality of SR results. The float point operations (FLOPs) and latency of each model are evaluated by producing 100 SR frames with a resolution of In this section, ablation studies are presented to examine the impact of key components. IMDN establishes a baseline for comparison, which takes one LR frame as input. Subsequently, the spatial aggregation and temporal aggregation are evaluated. They are key stages in the fast temporal information aggregation module. For measuring the performance of the model with spatial aggregation only, the spatially aggregated features are fused using concatenation and a On the Vid4 benchmark, the baseline model without temporal information achieves a PSNR result of 25.3254 dB and an SSIM result of 72.49%. By incorporating spatial aggregation, there is a noticeable improvement of 0.6499 dB and 3.96% in terms of PSNR and SSIM. Notably, the temporal aggregation in this variation is a simple Furthermore, an additional analysis is conducted to evaluate the impact of well-trained parameters from the image SR model on the video SR task. As shown in Although the proposed method can infer 720P video frames in real-time, there are some limitations. First, the LR video frame is synthesized by bicubic degradation. This may deviate from the degradation of actual low-resolution video. Secondly, the performance of the proposed method can be further improved. In In this paper, a novel approach for real-time video super-resolution is presented. The method incorporates a pre-trained image super-resolution model as its foundational framework to effectively exploit spatial information. To further leverage inter-frame dependencies, a fast temporal information aggregation module is introduced with the utilization of deformable convolution. This temporal modeling extracts motion cues across frames to enrich the spatial details. Additionally, a redundancy-aware inference algorithm is developed to minimize redundant computations by reusing intermediate features. It reduces the inference latency, enabling real-time performance for 720p video super-resolution with a minimal impact on accuracy. Experiments on several benchmarks show that the proposed method produces high-quality SR results quantitatively and qualitatively. The real-time inference capability makes the proposed method suitable for practical applications requiring live video enhancement. In the future, the efficient video super-resolution approaches can be improved by but not limited to the following directions: advanced degradation model for real-world low-resolution video; attention mechanism for better spatial-temporal feature extraction; novel techniques for efficient inference.


Whilst BCG-Russia, BCG-Japan and BCG-Danish showed strong geographical isolate clustering, the late strains, including BCG-Pasteur, showed more variation. A wide range of SNPs were seen within geographically classified strains, and as much intra-strain variation as between-strain variation was seen. The date of distribution from the original Pasteur laboratory (early pre-1927 or late post-1927) gave the strongest association with genetic differences in regions of difference and virulence-related SNPs, which agrees with the previous literature.The bacillus Calmette–Guérin (BCG) vaccine has been in use for prevention of tuberculosis for over a century. It remains the only widely available tuberculosis vaccine and its protective efficacy has varied across geographical regions. Since it was developed, the BCG vaccine strain has been shared across different laboratories around the world, where use of differing culture methods has resulted in genetically distinct strains over time. Whilst differing BCG vaccine efficacy around the world is well documented, and the reasons for this may be multifactorial, it has been hypothesized that genetic differences in BCG vaccine strains contribute to this variation. Isolates from an historic archive of lyophilized BCG strains were regrown, DNA was extracted and then whole-genome sequenced using Oxford Nanopore Technologies. The resulting whole-genome data were plotted on a phylogenetic tree and analysed to identify the presence or absence of regions of difference (RDs) and single-nucleotide polymorphisms (SNPs) relating to virulence, growth and cell wall structure. Of 50 strains available, 36 were revived in culture and 39 were sequenced. Morphology differed between the strains distributed before and after 1934. There was phylogenetic association amongst certain geographically classified strains, most notably BCG-Russia, BCG-Japan and BCG-Danish. RD2, RD171 and RD713 deletions were associated with late strains (seeded after 1927). When mapped to BCG-Pasteur 1172, the SNPs in  All genome data for this study have been deposited in GenBank. Oxford Nanopore sequence reads were deposited under BioProject ID PRJEB61685. Accession numbers for previously published sequencing reads used to construct wider phylogenies are also in Table S3, available in the online version of this article. The authors confirm that all supporting data and protocols have been provided within the article or through supplementary data files.We describe a large collection of reference and experimental BCG vaccine strains both reference and experimental, many of which do not appear to have undergone whole-genome sequencing before. The availability of these novel sequence data for some strains will allow further analysis into potential vaccine targets in non-commercially available BCG strains. Genetic analysis provides a greater understanding of virulence factors and regions of difference and gives further insights into potential vaccine targets.Mycobacterium bovis bacillus Calmette–Guérin (BCG) vaccine has been in use for over 100 years and is currently the only widely available vaccine against tuberculosis (TB)  all occurred together on a single branch of the tree, but the geographical clustering was less apparent, apart from BCG-Connaught and BCG-Frappier, both from Canada, which were also distributed after 1934 but form their own cluster within this branch. From this study, BCG-Dutch, designated as such within the laboratory strain collection, but for which there seems to be no reference in the literature, is located within the post-1934 cluster.Of the 195 RDs examined, 84 were present in every strain sequenced in this study and 31 were absent across all strains sequenced. RDs that showed geographical strain-specific deletions are shown in Other notable RDs, but not related to early and late classification, include RDcap_spain5, which was present in BCG-Russia strains, but not in the other geographical strains, RDDenmark or Glaxo, which was present in all geographical strains except BCG-Danish, BCG-Connaught and BCG-Glaxo, and RD_Russia, which was present in all except BCG-Russia .Whilst there was no significant difference in the mean number of deleted RDs between geographical strains when one-way analysis of variance (ANOVA) was applied, there was a trend to a slight increase relating to the time lapse before the geographical strain was taken from the original Institut Pasteur strain see . The earn=1, BCG-Japan n=8, BCG-Danish n=7, BCG-Prague n=1, BCG-Glaxo n=2 and BCG-Pasteur n=5).The mean number of total high-quality SNPs (as compared to the BCG-Pasteur 1173 P2 reference genome) was compared between the geographical strains and no significant difference was found when one-way ANOVA was applied see . There wsigK (p.Ile1Met), pcaA (p.Thr154Pro), mmaA3 (p.Asp98Gly) and either one or two in eecC5 .BCG-Japan appeared to show the greatest number of SNPs, when compared to the BCG-Pasteur 1173 P2 reference genome, across genes related to virulence, growth or cell wall functionality, with at least one isolate having SNPs in multiple genes of interest see . The earThe variation in the efficacy of BCG vaccination protocols has been widely discussed and there is evidence that vaccine strain variation is a contributing factor. Here we examined the genetic variation between strains in a historical archive, shedding light on the degree of genetic variation and specific differences that may impact on the protective immune response that is elicited.et al. examined the culture of BCG strains  in different routine production techniques [The morphological variation between BCG strains that was observed is likely to be a product of both historical culture methods and variation in the expression of certain proteins. In 1983, Osborn chniques . In theiBoth the isolates sequenced within this study and the reference genomes also included in the phylogenetic tree show clustering that agrees with the chronological distribution from the original Pasteur laboratory and the early geographical strains (BCG-Russia and BCG-Japan) appear to show more defined clustering . Russia Whilst the late strains distributed after 1934 were all located together in the same section of the dendrogram, there appeared to be less defined clustering of the geographical strains. BCG-Phipps, BCG-Tice, BCG-Korea and BCG-China , and BCG-Dutch and BCG-Dakar (sequenced in this study) were located within the BCG-Pasteur strain cluster . This laM. tuberculosis genome, the multiple passages and different culturing methods resulted in accumulation of genetic variations and loss of important regions in BCG strains [M. tuberculosis, RD171 contains Rv1982A, which encodes the antitoxin VapB36, which may contribute to greater virulence and therefore immune response [In order to provide long-term protection, vaccines should mimic the natural infection immunologically without disease development. Even though BCG strains share >99 % of the  strains . These g strains . The pre strains . Howeverresponse .SNPs were more likely to be seen in early strains, as the reference to which they were all mapped was BCG-Pasteur 1173 P2 , a late pcaA, which encodes a mycolic acid cyclopropane synthase and plays a role in methyltransferase activity [3,mmaA with a change in cell wall structure in late BCG strains [sigK, a positive regulator of the antigenic proteins MPT70 and MPT83 [sigK in M. tuberculosis show variable production of these proteins and MPT70, an antigen unique to the Mycobacteria, is only produced in large quantities by BCG-Russia, BCG-Japan and BCG-Moreau, and produced in lower quantities in later strains and in M. tuberculosis [M. tuberculosis, MPT83, a surface lipoprotein, was shown to be one of the strongest Th1 cell antigens [sigK gene may therefore play a role in the greater immune response believed to be elicited by the early BCG strains.Early strains exhibited SNPs that appear to confer greater virulence, which agrees with the previous literature . This inactivity , and mma strains , both ofnd MPT83 . Mutatioantigens . Possess5eccC, a lesser described gene in BCG. eccC5 encodes a protein in the ESX-5 membrane complex secretion system [M. tuberculosis–host cell interactions, related to its important role in PPE protein secretion, cell wall stability and virulence [M. tuberculosis is being tested as a vaccine candidate [Two variations were identified in the early strains in n system . The ESXirulence . The ESXirulence . Deletioandidate .M. tuberculosis and BCG, and for this study it was especially advantageous in identifying the RD regions. Longer reads are also advantageous for de novo assembly. Additionally, the set-up cost of ONT platforms is much lower than, for instance, an Illumina MiSeq, which, combined with the portability of the devices, makes the MinION platform more accessible in resource-constrained settings.In this study we opted to use long-read ONT methodology and when these sequence data were compared to sequences simulated from reference genomes generated by Illumina sequencing within the phylogenetic tree, they interspersed as expected, suggesting that the data outputted from both platforms were comparable. However, the higher error rates in the ONT data may make the placement on the tree less reliable. Whilst short-read sequencing is well established and accounts for the vast majority of genomes uploaded to online databases, there are a number of advantages to long-read technologies when it comes to building detailed genomes of traditionally hard-to-sequence organisms. An especially important use of long-read sequencing is for building genomes with long runs of repeating sequences, such as in Whilst BCG-Russia, BCG-Japan and BCG-Danish showed strong geographical isolate clustering, the late strains distributed after 1934, including BCG-Pasteur, showed more widespread distribution. A wide range of SNPs were seen within geographically classified strains, and as much intra-strain variation as between-strain variation was seen. The greatest number of virulence-related SNPs and regions of difference were identified in those strains classed as early . This suggests, in agreement with the previous literature, that early strains may be more virulent and therefore likely to elicit a greater immune response in the host.Click here for additional data file.


Dance is an art form that integrates the body and mind through movement. Dancers develop exceptional physical and mental abilities that involve various neurocognitive processes linked to embodied cognition. We propose that dancers’ primary trait representation is movement-actuated and relies on the extended mirror neuron system (eMNS).A total of 29 dancers and 28 non-dancer controls were recruited. A hierarchical approach of intra-regional and inter-regional functional connectivity (FC) analysis was adopted to probe trait-like neurodynamics within and between regions in the eMNS during rest. Correlation analyses were employed to examine the associations between dance training, creativity, and the FC within and between different brain regions.Within the eMNS, dancers exhibited increased intra-regional FC in various brain regions compared to non-dancers. These regions include the left inferior frontal gyrus, left ventral premotor cortex, left anterior insula, left posterior cerebellum (crus II), and bilateral basal ganglia . Dancers also exhibited greater intrinsic inter-regional FC between the cerebellum and the core/limbic mirror areas within the eMNS. In dancers, there was a negative correlation observed between practice intensity and the intrinsic FC within the eMNS involving the cerebellum and basal ganglia. Additionally, FCs from the basal ganglia to the dorsolateral prefrontal cortex were found to be negatively correlated with originality in dancers.Our results highlight the proficient communication within the cortical-subcortical hierarchy of the eMNS in dancers, linked to the automaticity and cognitive-motor interactions acquired through training. Altered functional couplings in the eMNS can be regarded as a unique neural signature specific to virtuoso dancers, which might predispose them for skilled dancing performance, perception, and creation. Dance is a multi-faceted art form that expresses ideas, emotions, and transformative thought processes through spatially and temporally coordinated actions . These aIntensive dance practice over several years may promote neurocognitive functioning on multiple levels, inducing persistent alterations in the brain and mind, commonly referred to as trait effects, that endure over an extended period of time . This reWe reasoned that the neural mechanisms underlying embodied cognition of skilled dancers are primarily movement-actuated and involve regions with mirror properties, including the IFG, PMv, IPL, intraparietal sulcus (IPS), insula, anterior cingulate cortex (ACC), supplementary motor area (SMA), sensorimotor cortex, primary motor cortex (M1), superior temporal sulcus (STS), dorsal premotor cortex (PMd), middle temporal gyrus (MTG), superior parietal lobule (SPL), cerebellum, and basal ganglia . CollectGiven the extensive and dedicated practice involving various cognitive and psychological processes, it is reasonable to propose that prolonged dance training significantly impacts how the brain functions in perceiving and performing dance. We accordingly hypothesized that the neural representation of dance expertise would exhibit a complex and optimized pattern of connectivity. To explore this, we utilized resting-state functional magnetic resonance imaging (fMRI) and examined brain-behavior correlations to understand the organization of the dancer’s brain and its connection to their dance experience. Our goal was not to focus on specific cognitive or mental processes during a particular task, but rather to gain insight into the overall associations between the dancer’s brain and their dance expertise. In essence, we aimed to understand the overall impact of long-term dance training on brain connectivity patterns, rather than establishing a direct correspondence between specific cognitive processes and brain activation. Resting-state FC has been shown to be modulated by long-term experiences such as cognitive training, motor skill learning, and art learning . We sougWe recruited 29 dance students  from art universities and 28 non-dancer controls . This study was part of an integrated multimodal neuroimaging research program focusing on undergraduate and graduate students majoring in various forms of arts. Both groups were matched for age and general education. DANCE reported 14.52 ± 4.52 years of dance training with 28.76 ± 12.81 h of weekly practice. Among the dance students included in the study, seven of them had undergone music lessons, and one student had additional training in visual arts. CON had less than 3 years of institutional dance or music training and were not currently practicing. None of the participants were skilled athletes or reported a history of neuropsychiatric disorder, and all were right-handed, as assessed using the Edinburgh Handedness Inventory . The stut-test  with a significance level of p < 0.05.Our integrated multimodal neuroimaging research program collected psychological data to portray demographic and psychological characteristics of young Taiwanese artists (20–30 years). In this study, we used the Abbreviated Torrance Test for Adults (ATTA) to assess general creativity and verbal/non-verbal creative thinking . The empResting-state fMRI data were obtained using the 3T MAGNETOM Trio™ system located at the National Yang-Ming University. Participants were positioned supine in the scanner with foam cushions holding their heads fixed to reduce motion artifacts. T2*-weighted gradient echo planar image (EPI) sequences were used to obtain resting-state fMRI images for each participant, with the following parameters: repetition time (TR) = 2500 ms, echo time (TE) = 30 ms, flip angle = 90°, field of view (FOV) = 220 mm × 220 mm, slice thickness = 3.4 mm, slice number = 40, matrix size = 64 × 64, tilted angle = 30°, and voxel size = 3.4 mm × 3.4 mm × 3.4 mm. To mitigate potential initial fMRI signal instability, the scanner automatically discarded the first three volumes of the scan, which served as dummy scans. Each resting-state fMRI time series comprised 200 volumes, with a duration of 500 s per time series. Additionally, high-resolution T1-weighted structural images were acquired using the magnetization prepared rapid gradient echo (MPRAGE) sequence, with the following parameters: TR = 2530 ms, TE = 3.03 ms, flip angle = 70°, FOV = 224 mm × 256 mm, matrix size = 224 × 256, slice thickness = 1 mm. Participants were instructed to remain still and awake with their eyes open and not to think about anything in particular. Fourteen participants dropped out, and 12 were excluded, resulting in a final sample of 29 dancers and 28 non-dancer controls for analysis.The Data Processing Assistant for Resting-State fMRI (DPARSF) V4.5 Advanced Edition, which is based on the Data Processing and Analysis of Brain Imaging (DPABI) toolbox version 4.1 , with Stz-score maps, and the resulting standardized ReHo maps were smoothed using a Gaussian kernel with a full-width at half-maximum (FWHM) of 6 mm, as suggested by previous studies -corrected cluster level of p < 0.05.Individual ReHo maps were generated using Kendall’s coefficient of concordance (KCC) of the time series between each voxel and its 26 nearest neighbors, in a voxel-wise manner . Individ studies . Betweenr) between the seed and other regions of the brain. The seed regions of interest (ROIs) were derived from brain regions exhibiting significant ReHo differences between groups , as eight seed ROIs were analyzed in this study.The same preprocessing procedures as for ReHo analysis were followed for FC analysis, with the exception of spatial smoothing, which was performed using a 6-mm FWHM Gaussian kernel prior to the analysis. Individual FC maps were generated by computing Pearson’s correlation coefficients , considering that four measures  were analyzed.In order to examine the effects of dance training on the brain, we conducted a correlation analysis between measures of ReHo and FC seeded by ReHo, with variables related to dance training and creativity indicators. The variables of dance training considered were the duration of training and the average daily/weekly practice time. Additionally, creativity indicators that showed significant differences between groups were included in the analysis. Regions that exhibited significant between-group differences in ReHo and ReHo-seeded FC were identified, and the extracted p = 0.002), with no differences between groups in fluency, elaboration, flexibility, visual creativity, verbal creativity, or CI , left PMv, left cerebellum (crus II), and subregions of the bilateral basal ganglia  in DANCE compared to CON . These rTo investigate the role of the eMNS in dancers, we utilized seed-based FC analysis to examine FC patterns seeded from significant ReHo results. DANCE showed that the left AI and left PMv were both strongly connected to the left posterior cerebellum. Intrinsic FC between the posterior cerebellum and the core/limbic mirror areas within the eMNS was also consistently higher in DANCE compared to CON. However, no significant differences were observed in the FC seeded from the left IFG. These findings suggest a synergy between core/limbic mirror areas and the posterior cerebellum within the eMNS in DANCE. Details can be found in Our hypothesis that dancers possess neuroplasticity, involving enhanced engagement of subcortical structures within the eMNS, was supported by our findings. Specifically, our findings showed that DANCE exhibited an elevated extended cortico-subcortical MNS compared to CON. These findings are consistent with our previous graph-based study that highlighted intra-modular connections within the cortico-cerebellar loops among the cerebellum, dorsolateral prefrontal cortex (dlPFC), IPL, and caudate in dancers .In DANCE, enhanced FC was observed between the left posterior cerebellum (crus II) and the contralateral posterior cerebellum, bilateral dlPFC, and right IPL within the cortico-cerebellar loops . FurtherOur study aimed to examine the associations between ReHo and ReHo-seeded FC and demographic/psychological characteristics, including dance training variables and creativity indicators. The objective was to gain a better understanding of the overall connections between the dancers’ brains and their expertise in dance. Pearson’s correlation analysis revealed that DANCE showed significantly negative correlations between the average practice time per day/week and FC, but no clear correlation between the duration of dance training and FC. These findings suggest that the intensity of training is more strongly associated with spontaneous brain dynamics than the duration of training. Our results were supported by the negative correlations between the average practice time in DANCE and functional couplings between the posterior cerebellum and the right core MNS (IFG and IPL) , as wellIn DANCE, the originality scores were negatively correlated with functional couplings between sensorimotor and cognitive/associative regions in the cortico-cerebellar-basal ganglia system, such as the left GP–right dlPFC (BA 8), left putamen–right dlPFC (BA 9/46), and right GP–right posterior cerebellum (lobule VI) FCs . AdditioThere were no notable differences between groups concerning the association between demographic/psychological characteristics and ReHo.In our ReHo and ReHo-seeded FC analyses, we found virtuoso-specific neural signature that manifest embodied cognition as increased functional connections within the eMNS in DANCE. Our findings suggest that the movement-actuated synergy between distributed brain areas within the eMNS is critical for expert dancers.The current study observed a left-lateralized increase in ReHo within the eMNS  among dancers, suggesting neuroplasticity associated with learning. The dominance of the left hemisphere in the eMNS of dancers could be attributed to extensive dance practice, as the left hemisphere is known for its role in controlling well-established behavior in familiar situations . The intThe left IFG and adjacent left PMv in the core MNS of dancers appear to exhibit functional segregation, as suggested by between-group results of FCs seeded from those two areas. In the case of the IFG of dancers, enhanced ReHo with no ReHo-seeded FC was observed in this region, implying local functional integration with functional specialization . It is pOur findings reveal not only enhanced connectivity within the core MNS but also heightened connectivity within the limbic MNS, located between the left dorsal and left ventral AI. The dorsal and ventral AI regions are involved in higher-level cognitive functions like switching, inhibition, and error processing, as well as affective processes related to emotions . For danThe observed enhanced intra-regional FC patterns within core/limbic mirror areas can be interpreted as a result of experience-dependent neuroplasticity that arises from embodied learning in dancers. These patterns reflect not only a transient neural state but a persistent neural trait associated with the consolidation of experience. In traditional terms, “consolidation” refers to the stabilization of memory traces. Within the framework of system memory consolidation , the HebOur neuroimaging findings of enhanced intra-regional functional connectivity within core/limbic mirror areas in dancers are in line with previous research that underscores the significance of the MNS in artistic training, specifically dance . AdditioOur study has shown that the enhanced functional connection between the cerebellum and mirror areas in dancers can be attributed to the combination of embodied simulation-driven mirroring mechanisms and predictive internal forward models. This connection connotes the integration of observed actions with an individual’s motor repertoire in the core mirror areas, which send a command to the cerebellum, which in turn sends a forecast back to the premotor area for subsequent action planning . The heiOur study also found that the left posterior cerebellum works in tandem with the core/limbic mirror areas, including the right IFG, right IPL, bilateral AI, and right ACC , to procThe left posterior cerebellum (crus II) may play a role in learning action sequences linked to social traits from a social perspective . Given tOur study found that dancers have stronger functional integration in cortico-basal ganglia and cortico-cerebellar loops compared to non-dancers, as evidenced by increased ReHo-seeded FCs. The cerebellum and basal ganglia, essential neural substrates involved in subcortical loops responsible for processing motor, cognitive, and emotional information, are believed to contribute to the development of action understanding abilities . The posIt has been suggested that both the cortico-cerebellar and cortico-basal ganglia loops are involved in motor skill development . The GP Our results showed that dancers’ subcortical areas, including the cerebellum, basal ganglia, and thalamus, as well as cortical areas, including the dlPFC, IPL, and PMd, interconnect functionally to form the integrated network/system of the cortico-cerebellar-basal ganglia system , that isThe current study contributes to the growing body of evidence indicating that intensive dance practice leads to the integration of cortical-subcortical hierarchical organization, which is involved in cognitive-motor interactions. Compelling evidence has indicated that there are inverted U-shaped relationships between brain factors  and behavioral measures across different skill levels  , 2022. IOur study did not find a significant correlation between the number of years of dance training and the FC. The absence of association could be explained by the fact that longer training duration does not necessarily imply consistently greater length, quantity, or intensity of practice, nor does it guarantee a higher level of specialization  in dancers may be grounded in sensorimotor experiences. Dance training involves a significant amount of multi-modal and cross-modal learning and sensorimotor processing. Intensive dance training may thus translate into enhanced novelty-based creative thinking in both the motor and visual domains . The effA few points need consideration. Firstly, while the ReHo analysis is a useful tool for identifying important regions in the brain, its use alone may be limited for discussing long-range functional connectivity. To address this, besides our hierarchical approach, a network-based approach could be used in future research. Secondly, since the local and global functional integration of resting-state networks may be linked to specific cognitive abilities , multiplLong-term dance training sculpts the brain of a dancer in a domain-specific way, as revealed by our hierarchical combination of ReHo and seed-based FC analysis. This analysis uncovered a neural “fingerprint” specific to highly trained dancers, indicating trait effects of dance training on neurodynamics. The strengthened connections observed in the resting state of dancers’ eMNS may contribute to their preparation for skilled performance. This is supported by the well-functioning cortical-subcortical hierarchical organization of the eMNS.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Institutional Review Board of Taipei Veterans General Hospital. The patients/participants provided their written informed consent to participate in this study.C-JY: conceptualization, investigation, formal analysis, validation, visualization, methodology, writing—original draft, and writing—review and editing. H-YY: resources and funding acquisition. T-YH: investigation. C-HS: investigation. T-CY: methodology and funding acquisition. L-FC: conceptualization, methodology, and funding acquisition. J-CH: conceptualization, resources, funding acquisition, project administration, methodology, supervision, and writing—review and editing. All authors contributed to the article and approved the submitted version.


Although the multifactorial nature of falls in Parkinson’s disease (PD) is well described, optimal assessment for the identification of fallers remains unclear. Thus, we aimed to identify clinical and objective gait measures that best discriminate fallers from non-fallers in PD, with suggestions of optimal cutoff scores. METHODS: Individuals with mild-to-moderate PD were classified as fallers (n = 31) or non-fallers (n = 96) based on the previous 12 months’ falls. Clinical measures  were assessed with standard scales/tests, and gait parameters were derived from wearable inertial sensors (Mobility Lab v2); participants walked overground, at a self-selected speed, for 2 min under single and dual-task walking conditions (maximum forward digit span). Receiver operating characteristic curve analysis identified measures (separately and in combination) that best discriminate fallers from non-fallers; we calculated the area under the curve (AUC) and identified optimal cutoff scores  corner). RESULTS: Single gait and clinical measures that best classified fallers were foot strike angle  and the Falls Efficacy Scale International , respectively. Combinations of clinical + gait measures had higher AUCs than combinations of clinical-only or gait-only measures. The best performing combination included the FES-I score, New Freezing of Gait Questionnaire score, foot strike angle and trunk transverse range of motion (AUC = 0.85). CONCLUSION: Multiple clinical and gait aspects must be considered for the classification of fallers and non-fallers in PD. Falls are common in individuals with Parkinson’s disease (PD) and have devastating consequences . FallingFalls have a multifactorial etiology in PD and several risk factors have been identified ,8,9,10. The appropriate management of fall occurrence in PD requires the development of optimized assessment protocols for risk of falls. Standard clinical fall risk assessment in PD involves functional tests, balance scales, patient-reported symptoms and disease-specific clinical scales. Despite their easy applicability, these clinical tools have two major limitations: they are subjective and unable to measure subtle changes in gait. Therefore, fall risk assessment in PD may be enhanced by the inclusion of objective measures of gait. Recent studies demonstrate that the addition of objective measures of gait to clinical variables improved the classification of fallers and non-fallers in PD ,14. HoweThe primary aim of this study was to identify clinical  and objective gait measures that best discriminate fallers from non-fallers in PD, with suggestions of optimal cut-off scores. Additionally, we explored combinations of clinical and objective gait measures  that best identify fallers in PD. We hypothesized that combinations of clinical and objective gait measures would better classify fallers and non-fallers among people with PD when compared to clinical-only or gait-only measures.One hundred and twenty-seven individuals with mild-to-moderate PD ,16 partiThe study was approved by the London-Bloomsbury NHS Research Ethics Committee  and the Institutional Review Board of the Oregon Health & Science University (#9903). All participants provided their written informed consent prior to the experiment. Assessments were carried out at the Balance Disorders Lab  and the Clinical Gait Lab .Falls were defined as an unintentionally coming to the ground or some lower level not as a result of a major intrinsic event or an overwhelming hazard ,11. BaseParticipants underwent a clinical assessment, which included collection of socio-demographic information and medical history, clinical and cognitive tests. PD symptoms, severity and stage were assessed with the Movement Disorders Society (MDS-revised) Unified Parkinson Disease Rating Scale from Movement Disorders Society (MDS-UPDRS)—part III  and the For the walking assessment, participants were instructed to walk, at a self-selected comfortable pace, back and forth on a straight 10 m walkway (tape marked at either end) for 2 min. Two walking conditions were tested: single and dual-task (the cognitive task was the maximum forward digit span) walking. Eight wearable inertial sensors  that included triaxial accelerometers, gyroscopes and magnetometers were used to instrument the walking tests. They recorded at 128 Hz and were attached, with Velcro straps, at the lumbar spine (5th lumbar vertebrae), sternum, bilaterally on the wrists, shins and feet. A total of 39 objective gait measures within 4 domains  ,24 were Data normality was assessed using the Shapiro–Wilk test. For demographic variables, comparisons between fallers and non-fallers were performed using the Mann–Whitney test or Student t test, according to data distribution. Receiver operating characteristic (ROC) curve analysis tested the performance of each outcome measure in discriminating fallers from non-fallers. The area under the curve (AUC), sensitivity and specificity were calculated. An AUC can be interpreted as follows; ≥0.9: outstanding, 0.8–0.9: excellent, 0.7–0.8: acceptable . The optCombinations. Only outcome measures with significant performance in classifying fallers and non-fallers were considered eligible for the combinations of outcome measures in different scenarios: clinical-only, gait-only  and clinical + gait measures. To avoid multicollinearity within the combinations, correlations matrices were built, and highly correlated outcome measures (r/rho ≥ 0.6) were excluded (keeping the one with the highest AUC for the combinations). Then, combinations of up to five outcome measures (due to our sample size) were considered for each of the above-mentioned scenarios. The optimal cut-off points observed for the individual measures were used for the combinations. For each hit cut-off score, one point was added to the final score of each combination. For example, if a participant reached the cut-off score in two individual outcome measures within the combination of five measures, the final score would be equal to two (out of five). Finally, ROC curve analysis was used to assess the performance of the combinations and the optimal cut-off score of each combination was determined  corner in the ROC plane) [C plane) . StatistThirty-one participants (24.4%) were classified as fallers  and 96 (75.6%) as non-fallers. Demographics and clinical characteristics are shown in Several clinical measures significantly classified fallers and non-fallers. Clinical measures with highest AUCs included: FES-I , NFOGQ , FOG status , MDS-UPDRS III , HY  and TMT-B . The performance parameters and cut-off scores of all clinical measures tested in the current study are presented as The best three clinical-only combinations in classifying fallers and non-fallers had similar AUCs  and clinical + gait measures. Findings confirmed our hypothesis: the highest AUC in discriminating between fallers and non-fallers was achieved when combining clinical + gait measures. Our findings reinforce the well-described multifactorial nature of falls in PD ,8,32,33 No individual outcome measure had outstanding (AUC ≥ 0.9) or excellent (AUC = 0.8–0.9) discriminative ability in classifying fallers and non-fallers among people with PD. Top performing measures achieved only acceptable discriminative ability, namely FES-I (AUC = 0.743) and foot strike angle . Similar AUCs (<0.8) have been reported by both prospective   and retrThe combination of clinical and gait outcomes better classified fallers and non-fallers among people with PD than clinical-only or gait-only combinations. Current findings are consistent with recent studies which demonstrated that the incorporation of objective measures of gait  does not enhance the discriminative ability of combinations involving clinical and gait measures. Therefore, the forward digit span task while walking  may not be useful as part of fall risk assessment in PD as this would add time and complexity to the assessment. This is supported by previous research showing enhanced classification of falls in PD when a different dual-task condition  is considered ,40.Although the use of AUC as the primary measure is supported in the literature , the decThe key strengths of the current study include the comprehensive clinical assessment (including motor and cognitive symptoms), use of objective and validated gait measures obtained with wearable inertial sensors, and the assessment in the ON state of PD medication. This approach covers the multifactorial nature of falls in PD and represents enhanced ecological validity in comparison to our previous study . ParticuOur findings suggest that combinations of clinical and gait measures have higher discriminative ability in classifying fallers from non-fallers among people with PD than combinations of clinical-only and gait-only measures. In particular, several combinations of clinical + gait measures had excellent discriminative ability (AUC > 0.8); combinations with the highest AUC included FES-I, NFOGQ, foot strike angle and trunk transverse range of motion variability.


Anorexia nervosa (AN) is characterized by severe emaciation and drastic reductions of brain mass, but the underlying mechanisms remain unclear. The present study investigated the putative association between the serum-based protein markers of brain damage neurofilament light (NF-L), tau protein, and glial fibrillary acidic protein (GFAP) and cortical thinning in acute AN.n = 147).Blood samples and magnetic resonance imaging scans were obtained from 52 predominantly adolescent, female patients with AN before and after partial weight restoration (increase in body mass index >14%). The effect of marker levels before weight gain and change in marker levels on cortical thickness (CT) was modeled at each vertex of the cortical surface using linear mixed-effect models. To test whether the observed effects were specific to AN, follow-up analyses exploring a potential general association of marker levels with CT were conducted in a female healthy control (HC) sample (In AN, higher baseline levels of NF-L, an established marker of axonal damage, were associated with lower CT in several regions, with the most prominent clusters located in bilateral temporal lobes. Tau protein and GFAP were not associated with CT. In HC, no associations between damage marker levels and CT were detected.A speculative interpretation would be that cortical thinning in acute AN might be at least partially a result of axonal damage processes. Further studies should thus test the potential of serum NF-L to become a reliable, low-cost and minimally invasive marker of structural brain alterations in AN. Anorexia nervosa (AN) is characterized by a persistent restriction in energy intake leading to cachexia and serious medical complications . Several studies have shown widespread CT reductions in acutely underweight AN patients , an intermediate filament found in mature astrocytes  in acAN would be negatively associated with CT  and that changes in marker levels following partial weight restoration would contribute above and beyond increase in BMI to explain normalization of CT. To test whether the observed effects were specific to AN, we conducted a follow-up analysis examining potential associations between damage markers and CT in a large sample of healthy participants.Study data were obtained from 54 underweight female patients with acute AN diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders . HC had to be of normal weight, eumenorrhoeic, and without any history of psychiatric illness. Several additional exclusion criteria were applied to both AN and HC participants, including psychotropic medication in the four weeks preceding study participation .AN was diagnosed using a modified version of the German expert form of the Structured Interview for Anorexia and Bulimia Nervosa  using a rapid acquisition gradient echo (MP-RAGE) sequence with the same parameters as in our previous studies  from the mean of the respective diagnostic group and time point after logarithmization) were excluded from all analyses (online Supplementary Information 1.5.1). For the analysis of demographic variables, non-parametric tests (Wilcoxon rank sum tests or Wilcoxon signed rank tests) were used since not all variables were normally distributed. Group comparisons of log-transformed damage marker levels were conducted using Welch two sample t-tests  and matched sample t-tests (for one-sided acAN-TP1 v. acAN-TP2 comparisons). One-sided t-tests were chosen because based on existing literature, we expected to find higher marker levels in acAN-TP1 compared to HC and in acAN-TP1 compared to acAN-TP2 as a sign of brain damage . tAge is the age at time t and TP1marker is the log-transformed marker-level in acAN-TP1 (both mean-subtracted) of the subject. B, C, D, and E thus represent the rate of CT change in AN associated with change in BMI-SDS, change in marker levels, age (as a control variable) and marker levels in acAN-TP1, respectively. In this model, A was a random effect and all other terms were fixed across participants.Following Bernardoni et al. , CT in At-cTP1 was orthogonalized with respect to bt-bTP1. Further elaborations on the statistical model can be found in Bernardoni et al. , and B thus represents the effect of age on CT. Marker is the mean-subtracted log-transformed marker-level of the subject, and C thus represents the effect of marker-levels on CT. For the practical implementation we used FreeSurfer Matlab tools .Since our analyses revealed an association between NF-L levels in acAN-TP1 and CT, we investigated whether this association was specific to acAN by assessing the same relationship in an independent sample of HC participants. Therefore, in a follow-up analysis we used a general linear model (GLM) to model CT in HC asv. HC) on CT. This model is described in the online Supplementary Information (1.5.2).A supplementary model including both groups was built to locate areas with an effect of diagnostic group  levels and CT in acAN in several brain regions with the most predominant clusters in regions of the bilateral temporal lobe (which showed particularly reduced CT relative to HC). This association was absent in HC. While elevated brain damage marker levels and reduced CT have been reported independently in non-neurodegenerative psychiatric illnesses  disorders, only one known study has investigated associations between NF-L and global measures of brain volume: In alcohol dependence, elevated levels of NF-L were found to be associated with the degree of WM lesions and were negatively correlated with global WM volume (Li et al., Speculatively, the differential relationships found between the three investigated markers and CT might be due to their different origins: NF-L is abundant in large-caliber myelinated axons (Gaetani et al., Using a vertex-wise analysis approach, we were able to locate cortical regions, in which NF-L was associated with cortical thinning in AN. The largest clusters were located in the bilateral temporal lobe. Associations between NF-L and CT have previously been found in these regions in dementia (Alcolea et al., Taken together with our finding, these results suggest that the temporal lobe, especially the right fusiform gyrus, might be particularly affected by neuronal-injury-related structural brain alterations occurring in acute AN. However, the present results only allow speculations about the reason why NF-L is associated with CT in exactly these temporal areas. Both the inferior temporal cortex and the fusiform gyrus play a role in visual tasks such as object, face, and body perception Conway, . AlexithBesides the contribution of the present results to hypothetical explanations of the neurobiological mechanisms underlying brain structural alterations in acute AN, they could potentially also help future research in identifying targets for the development of new therapeutic interventions. Such potential interventions could include neuroprotective pharmacological agents mitigating the drastic consequences of undernutrition on brain structure Frank, . AnotherOur hypothesis of an association of the longitudinal decrease in NF-L levels with the increase in CT was not supported by the data. This might be because NF-L is released into the blood stream upon axonal injury (Gaetani et al., The findings of our study have to be considered in the light of some limitations. First of all, our sample included only female, mostly adolescent participants of mainly European ethnicity. The effects seen might thus not generalize to adult, male, or more chronic patient populations or to other ethnicities. For example, the adolescent brain might be particularly vulnerable due to ongoing developmental effects and also the brain damage marker levels could be influenced by maturational processes such as ongoing myelination, synaptic pruning, etc. (Casey, Jones, & Hare, In the present study, we found associations of serum concentrations of the neuro-axonal marker NF-L in acAN with CT in several regions of both brain hemispheres, predominantly in the bilateral temporal lobe. This finding, together with the recent results from virtual histology and connectivity analyses of CT changes (Bahnsen et al., Hellerhoff et al. supplementary material


Tai Chi (TC) controls pain through mind–body exercise and appears to alter inflammatory mediators. TC actions on lipid biomarkers associated with inflammation and brain neural networks in women with knee osteoarthritic pain were investigated.A single-center, pre- and post-TC group (baseline and 8 wk) exercise pilot study in postmenopausal women with knee osteoarthritic pain was performed. 12 eligible women participated in TC group exercise. The primary outcome was liquid chromatography tandem mass spectrometry determination of circulating endocannabinoids (eCB) and oxylipins (OxL). Secondary outcomes were correlations between eCB and OxL levels and clinical pain/limitation assessments, and brain resting-state function magnetic resonance imaging (rs-fMRI).1 and PGE2 and higher 12-HETE, LTB4, and 12-HEPE compared to baseline. Pain assessment and eCB and OxL levels suggest crucial relationships between TC exercise, inflammatory markers, and pain. Higher plasma levels of eCB AEA, and 1, 2-AG were found in subjects with increased pain. Several eCB and OxL levels were positively correlated with left and right brain amygdala-medial prefrontal cortex functional connectivity.Differences in circulating quantitative levels (nM) of pro-inflammatory OxL after TC were found in women. TC exercise resulted in lower OxL PGETC exercise lowers pro-inflammatory OxL in women with knee osteoarthritic pain. Correlations between subject pain, functional limitations, and brain connectivity with levels of OxL and eCB showed significance. Findings indicate potential mechanisms for OxL and eCB and their biosynthetic endogenous PUFA precursors that alter brain connectivity, neuroinflammation, and pain.ClinicalTrials.gov, identifier: NCT04046003. Knee osteoarthritis (OA), a progressive disease characterized by joint degeneration and inflammation , is maniWhile the etiology of knee OA pain and underlying causes are complex, compelling evidence suggests that oxylipins (OxL) and endocannabinoids (eCB) are involved in the progression of knee OA pain. The endocannabinoid system (ECS) has emerged as a possible therapeutic target for OA pain reduction , 3. The Many of the eCB and OxL are biosynthesized from PUFA of the essential omega-6 and omega-3 families , althougExpression of CB2R protein by both neurons and microglia in the spinal cord was significantly increased in an OA pain model, suggesting that targeting eCB may have potential in treating OA . In humaOxLs are recognized lipid-derived mediators of inflammation and immune cell function in patients with OA pain . For exaThe eCB system (ECS) is a strategic factor for synaptic plasticity and homeostatic processes of the nervous system  includinTai Chi (TC) exercise, a form of mind–body moderate-intensity exercise, affords both physical benefits for knee OA   and a coChronic pain is thought to alter brain reward circuitry , 24 to iThe present study was based on a single group pre-test and post-test design in 12 subjects to examine the effects of an 8 week TC exercise intervention on circulating eCB and OxL levels in postmenopausal women with knee OA. Sex is a strong risk factor for knee OA. After the age of 50, there is steep increase in incidence of knee OA in women compared with men, leading to a higher prevalence in women . Also, wClinicalTrials.gov Identifier: NCT04046003). In the correlation analyses of bioactive lipids and clinical outcomes 9 subjects were used. The criteria of knee OA exhibited symptoms was based on American College of Rheumatology clinical classification criteria for OA. Correlations between eCB and OxL levels and clinical outcomes  data and between eCB and OxL levels and rs-fMRI data were also evaluated. Subjects were requested to maintain their current diets, medication, and physical activity, and not take any new supplements or vitamins.Blood samples were collected at baseline and after 8 weeks of TC intervention. After centrifugation, plasma samples were obtained and stored at −80°C for later eCB and OxL analyses. This study was approved by the Institutional Review Board at the Texas Tech University Health Sciences Center  with knee pain were recruited from clinics and community centers in the Lubbock, Texas (United States) area by flyers and advertisements through newspaper . InclusiIn this study the participants were enrolled in an 8 week 24-form Yang style TC program . InstrucDetails of the patient recruitment and screening, TC intervention and compliance, self-reported clinical outcomes assessed by Western Ontario and McMaster Universities Osteoarthritis Index , Visual Analog Scale (VAS), Brief Pain Inventory (BPI), and rs-fMRI data have been published previously .Twenty four plasma samples (50 μL) (baseline and after TC) were subjected to protein precipitation in the presence of isotopically labeled analytical surrogates, filtered, and stored at −20°C until analysis as previously reported . After st-test value of ps.Descriptive statistics were calculated to inspect the distributional properties of eCB and OxL. Further, values for eCB and OxL are also presented as standardized differences calculated from the difference between values of treatment and control, divided by the pooled SEM , 29. AllValues for plasma levels of eCB AEA, 1,2-AG, and DHEA were lower based on standardized differences after TC exercise compared to baseline . Relativ1 and PGE2, were reduced after TC. The reduced level of pro-inflammatory PGE2 is a clear indication that TC reduced this potent pro-inflammatory OxL. The levels of 12-HEPE and 12,13-DiHODE  as well as 12-HETE, 20-HETE, and LTB4 (metabolites of arachidonic acid) in subjects were higher post TC. The increase in LTB4 could be due to higher inflammation or macrophage activation with TC (TC resulted in significant changes for many OxL compared to pre-TC (baseline) in women . OxL der with TC . The notIn general, many products of arachidonic acid can support pro-inflammatory actions compared to those derived from the substrate eicosapentaenoic acid. Interestingly TC resulted in lower LEA compared to baseline. The higher blood levels of 12-HETE and 12-HEPE likely indicate greater 12-LOX pathway flux supported by inflammation . The fulp ≤ 0.05) and negative relationship with TC exercise. The positive values associated with TC exercise appear in the right upper quadrant of 2, 8,9-DiHeTrE, and 8,15-DiHETE and eCB AEA, which are all derivatives of arachidonic acid, but led to higher 12-HEPE (EPA derivative), and LTB4 and 12-HETE (both arachidonate derivatives). Moreover, for the measured variables many of the eCB and OxL showed strong VIP values, negative or positive relationships. Several other eCB and OxL measurements revealed weaker VIP values. The weaker VIP values suggest a lower confidence in their apparent actions in TC exercise, but do not mean a lesser role of TC on subjects and relationships to pain and well-being. It is interesting that eCB DHEA derived from DHA showed a VIP score of greater than one and might suggest that DHA could help attenuate inflammation or serve in another capacity during TC. Based on VIP values, numerous OxL-derived from long-chain n-6 and n-3 PUFA were changed and thus may play a role in mediating the effects of TC exercise.p = 0.95). The variable coefficient plot shows metabolite strength in discrimination. Metabolites with variable importance in projections (VIP) >1 are considered to have discriminating power. Due to the low subject number, leave one out cross validation was used to build the model. Group discrimination was achieved with a minimum of 2 dimensions as shown  but was improved considering a third dimension . A complete list of metabolites, their concentration group means, VIP scores, and value of ps from 2-tailed t-tests are included in Analyses in 2,15-keto PGE2, LTB4 (BPI_3: pain level at its worst in the past 24 h) with the pain assessments. In contrast, higher plasma eCB levels, such as DHEA  were associated with less pain  as were higher plasma levels of eCB-like compound LEA .Another analysis revealed significant correlations (Spearman’s correlation coefficient) between pain assessment and circulating levels of OxL and eCB, suggesting important relationships between inflammatory/anti-inflammatory markers and pain assessment as shown in Several positive correlations were found between brain left and right amygdala-mPFC functional connectivity (LA_mPFC and RA_mPFC) and OxL and eCB . For exa2, 5-KETE) and decreasing subject variability for these compounds.Additional correlations for changes in OxL and eCB were done as individual pre- and post-TC scatter plots to illustrate the effects of TC as these parameters relate to pain and brain connectivity. Consistent with significant correlations for differences in values presented in The relationships of three HETE  show a positive correlation with brain connectivity after TC . MoreoveThis pilot study is the first to examine the effects of 8 week TC intervention on circulating eCB and OxL levels in postmenopausal women with knee OA pain. The self-reported pain reduction and its impact on physical functioning results of WOMAC and BPI in OA subjects is evidence that 8 weeks of TC intervention diminishes pain, stiffness, and functional limitations that are linked to some extent with pro-inflammatory OxL biomarkers. The changes in lipid-derived eCB and OxL after TC are associated with improved well-being , which iOxidative stress and systemic low-grade inflammation are upregulated in OA . Thus, sOur hypothesis examined an important knowledge gap on how TC improves pain associated with knee OA by measuring eCB and OxL as targets to alter inflammation in the peripheral and central nervous systems . We estaN-acylethanolamines (NAEs), and their precursors N-acylphosphatidylethanolamines (NAPEs) , and LTB4 and 12-HETE (both arachidonate derivatives) observed after TC are important since these OxL afford anti-inflammatory activity and modulate inflammatory response, respectively, via the PUFA substrate  . Moreove (NAPEs) . Thus, c (NAPEs) , 43, 44.ubstrate .The effect of TC appears to stabilize OxL levels to a new physiological threshold for homeostasis. Considering these findings, future clinical research must include dietary PUFA and TC interactions on the amounts and types of circulating OxL and eCB (and eCB-like compounds) and on pain and brain connectivity. In support of our findings with TC, the actions of stretching were described to reduce inflammatory mediators and oxidative stress to lower pain . The autA limitation of this study is the small subject group; however, each subject was included for baseline and post TC treatment for analysis of eCB and OxL levels. The duration of TC was 8 weeks from baseline as two time points for the measurements. Nevertheless, this study confirms differences in pre- and post-TC exercise changes of the same OA subjects for a comprehensive panel of eCB and OxL levels in blood. These novel findings afford a new approach to understand exercise benefits on clinical biomarkers for OA. The application is two aspects of improving pain and wellbeing utilizing patient pain assessment and brain connectivity. TC altered levels of OxL derived from n-3 and n-6 PUFA family substrate and decreased pro-inflammatory states. The changes in brain connectivity post-TC and correlations with plasma eCB and OxL levels are noteworthy and suggest an important relationship with neuroinflammation and brain neuroplasticity for these lipid biomarkers under mind–body exercise. Future studies should examine the effects of dietary n-3 PUFA and include dietary records to ascertain if n-3 PUFA substrates alter the types of eCB, and further change pro-inflammatory OxL.Our findings identified an anti-neuroinflammatory role of TC exercise which is linked to modified blood levels of specific OxL, a reduction in pain and stiffness, and improved physical function in subjects with knee osteoarthritis pain. TC appears to serve as a viable means for non-pharmaceutical treatment to modify systemic production of pro-inflammatory OxL compounds. Controlled clinical trials are warranted to confirm our findings and expand on the specific changes for both OxL and eCB following TC exercise. Moreover, TC altered levels of OxL derived from n-3 and n-6 PUFA family substrate and decreased pro-inflammatory states. The changes in brain connectivity post-TC and correlations with plasma eCB and OxL levels are noteworthy and suggest an important relationship with neuroinflammation and brain neuroplasticity for these lipid biomarkers under mind–body exercise. Future studies should examine the effects of dietary n-3 PUFA and include dietary records to ascertain if n-3 PUFA substrates alter the types of eCB during TC, and further change pro-inflammatory OxL during TC in a randomized placebo-controlled trial with a larger sample size for an adequate power. Dietary approaches or supplements that lower substrate for arachidonic acid with n-3 PUFA or fish oil may work synergistically to help reduce pain with TC exercise. In this scenario, emphasis must be placed on brain connectivity and plasticity. Hence, we do support the practice of TC to help control pain in women with knee osteoarthritis given the changes in eCB and OxL.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving humans were approved by Texas Tech University Health Sciences Center Lubbock IRB. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.C-LS, JN, M-CC, CK, VN, and BW: conceptualization and methodology. JN, ME, KB, and CK: data collection and analysis. C-LS, JN, ME, and BW: writing-original draft preparation. C-LS, JN, ME, M-CC, CK, KB, VN, and BW: writing-review and editing. C-LS, M-CC, and VN: supervision, project administration, and funding acquisition. All authors contributed to the article and approved the submitted version.This study was supported by NIH/NINDS R01 NS038261 (VN), Texas Tech University Neuroimaging Institute, Texas Tech University, Lubbock, TX (CLS) and the Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX (CLS and VN). Additional support was provided by USDA Intramural Projects 2032-51530-025-00D (JN). The USDA is an equal opportunity employer and provider. The funders had no influence on the conceptualization, data collection, analysis, or interpretation of data presented within the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


How to ensure precision-targeting of the tumor and the attainment of biological effectiveness while sparing normal tissues remains one of the most crucial technical and clinical questions in the domain of local cancer treatment modalities using ionizing radiation, within the continuously changing and improving oncological treatment landscape. In recent decades, besides dedicated stereotactic radiosurgery (SRS) methods and procedures , and stereotactic body radiotherpay SBRT), LINAC-based stereotactic radiosurgery and radiotherapy has emerged as a groundbreaking technology that is reshaping daily oncology practice. With its ability to deliver highly precise radiation doses to well-defined tumor regions within and outside the brain while sparing surrounding healthy tissues, and with the wide range of accessibility and availability of LINAC-based SRT, SBRT has garnered significant attention in local treatments in modern oncology.“LINAC-Based Stereotactic Radiosurgery in Daily Practice” in Frontiers in Oncology. These studies provide valuable data and insights into the technology’s clinical applications and outcomes. We present the imaging, clinical, technological, and innovative findings related to this Research Topic and acknowledge the researchers contributing to this work.This editorial delves into the feasibility and clinical impact of imaging and treatment delivery methods, technological advancements in these domains, and the future of LINAC-based stereotactic irradiation methods in modern complex oncology care. Significant technical development has been achieved in the last decade, providing access to a wide and variable range of LINAC-based radiosurgery and radiotherapy methods. Several prospective multicentric clinical trials have proven the advantage of stereotactic radiotherapy  of single and oligometastatic cancers in different locations, both intra- and extracranially. Recent research on novel imaging methods, such as new PET tracers , 4D CT, PET-CT, PET-MR, and advanced dedicated sequences of MRI, has provided superior accuracy in tumor definition and intra-fractional target motion management. Fractionated stereotactic radiotherapy and radiosurgery delivery enable the use of daily high-precision adaptive radiation approaches. Optimization efforts for the standard operating procedures in stereotactic radiotherapy will result in improvement of its effectivity and the therapeutic index. To gain deeper insight into LINAC-based stereotactic radiosurgery procedures, we highlight recent articles published in the Research Topic 1Huang et al.) and modern prostate-specific membrane antigen-PSMA PET-based imaging of tumor progression . Conventional MR imaging is the basic method in all intracranial SRS procedures. In the paper by Huang et al., the authors noted the high impact of improved MR resolution on target definition and also on reduced inter-observer variability. Varga et al. reported their results on the effect of PSMA PET information in improving prostate tumor staging and detection of low-volume prostate tumor progression.This Research Topic highlights imaging procedures focusing on MR-based target definition of SRS procedures  with flattening-filter-free (FFF) beams (the FFF-based VMAT technique) in SBRT. They concluded that the FFF beam technique for lung SBRT with VMAT results in a better dose fall-off, better dose-sparing of OAR, lower NTCP of the lung, and a shorter beam on-time compared with the FF beam technique.Feasibility and various dosimetric concepts must be studied and clarified in the design of LINAC-based stereotactic treatments. 3Caivano et al. of a retrospective mono-institutional study in a large cohort of patients with lymph node metastases treated by LINAC-based SBRT concluded that LINAC-based SBRT is a good therapeutic option in light of survival, patient safety, and tolerance. Beyond these promising results, the authors recommended multicentric prospective studies to clarify the importance of tumor volume, tumor burden, lesion size and site, and applied dose as predictive factors in SBRT.LINAC-based SRS and SRT are used in various intra- and extracranial clinical indications. In this Research Topic, a report by Nguyen et al. reported the promising results of stereotactic focal radiotherapy in treating low-risk prostate cancer patients. In this specific stereotactic indication, the focus of the procedures  is more on preserving patients’ quality of life (QOL), rather than on improving survival. The authors concluded that a new, innovative robotized approach to focal SBRT is a feasible, well-tolerated method that preserves the patient’s QOL and can challenge active surveillance.Another single-arm phase II study by 4Tallet et al. presented their results on the added value of using MRI-LINAC in treatment of liver tumors by SBRT. The authors concluded that using MRI as an IGRT tool for SBRT allows for the significant reduction in the volume of normal healthy liver parenchyma to be irradiated, without any decrease in the tumor control rate. In addition to reducing normal tissue toxicity, MRI-LANC-based SBRT provides the opportunity for total dose escalation and subsequent irradiation of a malignant liver tumor.Beyond conventional CT- or CBCT-controlled LINAC systems, MR-LINAC-based stereotactic methods are approaching. A novel LINAC unit using MRI as an image guidance method is opening up new dimensions in clinical practice. 5As we conclude this editorial, it is becoming evident that, at this point, LINAC-based stereotactic radiotherapy and radiosurgery are not merely treatment opportunities but are becoming a standard of care within the complex landscape of approaches to oncological treatment. Its high conformality and precision, advanced image guidance, and radiobiological effects are transformed into true clinical benefits . Many open questions exist, and much ongoing research worldwide underscores their significance. As we look ahead, collaboration, innovation, and patient-centered care will continue, and LINAC-based stereotactic radiotherapy and radiosurgery will take on a robust role in treatment of cancer patients worldwide.AK: Writing – original draft. FL: Writing – review & editing.


The COVID-19 pandemic caused delays in care-seeking due to fears of infection and decreased healthcare access globally. These delays have been linked in some countries to COVID-19 perceptions, decreased income, and food insecurity, but little is known about patient-level factors for decreased care-seeking specifically at the beginning of COVID-19 in West Africa. Understanding these factors is important to identify those at highest risk and address healthcare-related barriers.n = 1352), Ghana (n = 1621), and Sierra Leone (n = 1301) in May–June 2020. Questions assessed delays in care-seeking, sociodemographic variables, COVID-19 beliefs, and food insecurity. Bivariate analyses using chi-square and multivariate analyses using logistic regression were used to explore associations between factors and delays in care-seeking by country. Independent variables were chosen based on prior research suggesting that financial insecurity, older age, female sex, rural location, and COVID-related concerns are associated with delays.This study used self-reported data from telephone surveys in a population-based sample in Burkina Faso  and in bivariate analyses was associated with delays in care-seeking in Burkina Faso and Ghana. Concern about risk of household contraction of COVID-19 was common (18.1–36.0%) and in Ghana and Sierra Leone was associated with delays in care-seeking in both bivariate and multivariate analyses. In bivariate analyses, females showed more delays in Burkina Faso, while age above 30 and urban location were associated with delays in Ghana. In multivariate analyses, food insecurity was associated with increased delayed care-seeking in Burkina Faso.Multiple factors were associated with delays in care-seeking early in the COVID-19 pandemic, with food insecurity and concerns about infection showing significant associations in multiple countries. These findings highlight the need to invest in clinic accessibility, community education, and financial assistance to address barriers in healthcare. While many delays have subsided since the initial phase of the COVID-19 pandemic, understanding factors associated with early disruptions of care-seeking at the patient and household level will inform strategies for maintaining healthcare access during future pandemics in West Africa.The online version contains supplementary material available at 10.1186/s12913-023-09812-x. The COVID-19 pandemic resulted in delays in care-seeking behavior in countries globally . ParticuStudies thus far have yielded mixed results regarding differences in care-seeking across countries and settings during the COVID-19 pandemic. Several studies have suggested that low-income countries were disproportionally affected by delays of care-seeking due to COVID-19, particularly early in the pandemic , 16. ForStudies that have emerged during this pandemic have also shown mixed findings regarding what populations and risk factors have been linked to decreased care-seeking, particularly in communities that already experienced significant barriers to care-seeking prior to COVID-19. One study comparing pre- and post-COVID-19 care-seeking in slum communities in four countries saw major decreases in care-seeking related to healthcare cost increases, income decreases, limited transportation to healthcare, and high fears of COVID-19 infection . AnotherHowever, many patient-level factors that may influence care-seeking remain unknown, specifically in West Africa, where there were several known risk factors for the underutilization of healthcare prior to COVID-19. Previous research in this region suggested that access to healthcare is generally hindered by lack of transportation , long diEvidence regarding access and delivery of care during this pandemic is still emerging. Globally, many countries developed increased resources for routine, non-COVID-19 care in response to the first wave of the pandemic, but there have been mixed results on the relationship between pandemic stage, patient access to care , and likThe Research for Effective COVID-19 Responses (RECOVR) survey was developed by Innovations for Poverty Action (IPA), a nonprofit organization, and administered via telephone in ten countries between May and June 2020 . The purWe analyzed the survey results to understand the rates of self-reported delays in care-seeking and explore factors linked to delays in Burkina Faso, Ghana, and Sierra Leone during the first wave of the COVID-19 pandemic. We used these results to describe variability in factors associated with delays in care-seeking in these West African countries that, while geographically close, differ in economic and human development, with Ghana having a substantially higher human development index. Our aim was to use early data from the COVID-19 pandemic to explore community-reported themes related to the challenges in care-seeking that emerged during this pivotal time. Understanding the impact of COVID-19 on care-seeking behavior in West Africa, particularly at the beginning of this pandemic, is ultimately important to inform early interventions to address barriers to care at the individual, household, and health system levels during current and future pandemics.Table The target population of the surveys was adults who were over 18 years of age, owned a mobile phone, and lived in Burkina Faso, Ghana, or Sierra Leone. Participants were contacted via random digit dialing of all possible mobile phone numbers based on national communications authority number allocation plans and stratified by mobile network operator market share in each country. Individuals with working numbers were invited to participate in the survey.Details of the RECOVR survey can be found in Egger et al. . BrieflySurveys captured sociodemographic characteristics of the respondent and household, healthcare usage since the start of the pandemic, COVID-19 attitudes and prevention behavior, social safety net access measures, food insecurity, and financial health. Measures of COVID-19 attitudes and prevention strategies included questions asking how many days in the past week were spent at home, without leaving or receiving visitors; whether the respondent felt that they or any household members were at risk of contracting COVID-19; their perception of the government’s response to COVID-19; and their primary concern regarding the effects of COVID-19. Measures of food insecurity and financial health included changes in income since mid-March 2020 and days in the last week where they had to reduce number of meals, limit portion sizes, or avoid buying food due to lack of money.Participants’ self-reported delay in care-seeking was measured by one question: “Have you or any other person in your household delayed, skipped or been unable to complete needed health care visits since the middle of March ; lack of available services ; concerns about COVID-19 infection; and other reasons . This subgroup that reported delays in care-seeking underwent a separate analysis.All analyses were conducted in STATA 16.1. Participants with missing responses to the primary outcome of delay of care-seeking were excluded from analysis  or Greater Accra or Ashanti (Ghana) as well as living in the largest city/town in their region.There were three food insecurity questions, which asked whether someone in their household had limited food portions, reduced the number of meals eaten, and/or been unable to buy food in the past seven days. We created a composite food insecurity variable and dichotomized food insecurity as having reported that someone in their household had limited portions, reduced the number of meals eaten, and/or been unable to buy food for at least one day in the past week. Change in income was assessed as earning “more, the same, or less pay" in the last week as compared to a typical week before mid-March 2020. Change in income was later manually dichotomized as earning as more/same income versus less/no income as compared to pre-March 2020.p values < 0.20 in bivariate analyses were included in multivariate logistical regressions for each country.The survey data set was weighted by participant gender and geographic unit; weighting methods are further described in Egger et al. . WeighteThe initial RECOVR research was approved by IPA’s IRB Protocol 15608 (Burkina Faso), 15542 (Ghana), and 15592 (Sierra Leone). The Northwestern University IRB designated this study as non-human subjects research, as the publicly available dataset was deidentified. Those who participated in the survey gave informed consent and received phone credit worth approximately 90 U.S. cents for their participation.Overall, participants aged 18–30 years represented 52.5–60.4% of the total sample across the three countries, and men represented 42.4–45.9% of the sample. Participants living in urban areas made up 60.5% of the sample in Burkina Faso, 22.9% in Ghana, and 83.7% in Sierra Leone ; in Ghana, 12.0% of those unable to buy food delayed care-seeking compared to 7.0% of those who did not report food insecurity (p < 0.01). Respondents who felt that they or their household members were at risk of contracting COVID-19 had significantly higher rates of delayed care-seeking in both Ghana and Sierra Leone . In Ghana, respondents in urban locations reported more delays in care-seeking . Ghanaian respondents of older age also reported more delays . In Burkina Faso, being female was associated with increased delays , but this was not seen in Ghana or Sierra Leone. There were no significant associations between delays in care-seeking and level of education completed, days spent at home, perception of government reaction to COVID, or changes in income since mid-March 2020.Table  p < 0.05; OR = 2.02, 95% CI [1.30–3.14], p < 0.01). Additionally, participants who reported food insecurity had increased rates of delays in care-seeking only in Burkina Faso . In Ghana, being 31- to 40-years-old was associated with increased delays in care-seeking compared to under 30-years-old . In both Ghana and Sierra Leone, feeling at risk of contracting COVID was associated with delays in care-seeking .Factors associated with reported delays in care varied by country in the multivariate analyses Table . In Burkp < 0.05); and in Sierra Leone, 51.5% of those experiencing food insecurity delayed care-seeking due to cost, compared to 4.4% of those who did not experience food insecurity (p < 0.001).Self-reported reasons for delaying care-seeking also varied by country Table . In BurkWe found that there were significant population-level rates of self-reported delayed care-seeking during the first wave of the COVID-19 pandemic in these three countries in West Africa. In bivariate analyses, factors associated with increased reported delays in care-seeking in at least one country included being female, concern about someone in the household contracting COVID-19, and food insecurity. Multivariate analyses ultimately showed higher rates of delayed care-seeking by those with self-reported food insecurity in Burkina Faso as well as those with self-reported fears of household COVID-19 infection in both Ghana and Sierra Leone. Among the households who reported delays in care-seeking, both cost and fear of infection were broadly noted as reasons for delays in care-seeking by a large number of participants in all three countries.Food insecurity was common among survey respondents and was frequently linked with delaying care-seeking and, among those delaying in Ghana and Sierra Leone, with financial reasons for the delays. There is newly emerging research investigating the relationship between food insecurity during COVID-19 and delayed care-seeking in other parts of the world. In the United States, those with food insecurity had significantly higher odds of delaying or forgoing medical care, including specifically due to cost concerns . AdditioParticipants’ perceived risk of themselves or their family members contracting COVID-19 was also significantly associated with decreased care-seeking behavior in Ghana and Sierra Leone. Our findings support existing evidence that fear of COVID-19 infection contributed to delays in care-seeking during the early COVID-19 pandemic in Ghana  and SierSierra Leone had a lower overall rate of delays in care than Burkina Faso and Ghana. Of note, Sierra Leone was one of the primary locations for the Ebola outbreak in 2014, resulting in the enhancement of disease surveillance and mitigation systems. It is possible that such developments helped mitigate the delay in healthcare-seeking due to effective communication and trust in healthcare authorities in Sierra Leone . Sierra In contrast to a number of telephone surveys that have included primarily men , our weBivariate analyses showed that in Ghana, older age groups showed increased rates of delays in care-seeking. We do not have the knowledge to understand the cause of these delays, but possible reasons include that during COVID-19, older people may have needed additional financial and social support, as they may have been disproportionately impacted by social distancing and the decreased wages of those in their social network , 73. In There were a number of limitations to our study. The survey data were limited to participants with a mobile phone, affecting generalizability of results for individuals with less access to technology and mobile phone coverage. However, 75% of Ghanaians aged 15 and older reported owning a cell phone for personal use . Cell phAdditionally, the surveys in Burkina Faso and Ghana did not explicitly assess urbanicity of participants. Our approach of inferring urban versus non-urban location based on reporting living in the largest city of certain regions may have led to misclassification by underestimating the number of people in urban environments but smaller cities. This notable limitation may have affected our power to detect a relationship between location and delays in care-seeking.Importantly, the surveys were collected from participants at a single time point. The available data cannot determine causality and does not assess any relationship between delays in care-seeking and harmful outcomes such as missed preventative care, disease diagnoses, and treatment of illness. Additionally, all analyses of factors were done within countries without statistical comparison between countries. Further studies that assess socioecological factors and policy in greater detail are needed to statistically assess potential differences between countries.Many countries recognized challenges related to food insecurity early during the COVID-19 pandemic and provided food and other support. Ongoing and future research should assess if and how these factors or rates in delayed care-seeking changed throughout the subsequent waves of the pandemic and as a result of changes in government supports, health system changes, and infection prevention responses. Our power to identify associated factors was low due to the low percentage of participants reporting a delay in care-seeking. This may have limited our ability to detect links between care-seeking and other factors, such as education. Finally, our ability to better understand the causes of delays in care-seeking was limited by the data available from survey questions, which did not delineate whether healthcare was needed in the studied time frame, and, if so, what were the types, length, and outcomes of delayed care-seeking. Further exploration of these causes as well as the purpose and consequences of the delayed care will be vital to recognize those most at risk for poor outcomes and inform to support uninterrupted care-seeking in future health system shocks.In conclusion, we found that there were notable rates of self-reported delays in care-seeking and several factors that related to these delays during the early COVID-19 pandemic in West Africa. Food insecurity and perceived risk of developing COVID-19 infection had significant relationships with delays in care-seeking, with those reporting increased food insecurity and/or perceived risk of developing COVID-19 having higher rates of delays in care-seeking. Increasing trust and safety of the health systems and patient education while addressing social determinants of health, such as ability to access and afford care, is necessary to improve overall care-seeking before, during, and after future pandemics. Further investigation into these factors and the sustained public health impacts of COVID-19 is ongoing and will likely also show variations in healthcare access and delivery over time in the ever-evolving landscape of COVID-19.Additional file 1: Appendix A. Consort diagrams for data collection, by country. Figure 1. Consort diagram for Burkina Faso. Figure 2. Consort diagram for Ghana. Figure 3. Consort diagram for Sierra Leone.Additional file 2: Appendix B. Unadjusted bivariate and multivariate analyses by country. Table 4. Unadjusted bivariate analyses, by country, of sociodemographic information, COVID-19 perceptions, food insecurity, and self-reported delays in care-seeking using chi-square tests. Table 5. Unadjusted multivariate logistic regression of associations of delays in care-seeking with sociodemographic information, COVID-19 beliefs, income, and food insecurity, by country. Table 6. Unadjusted bivariate country analyses of self-reported reasons for delays in care-seeking and access, sociodemographic information, and food insecurity among individuals who reported delays in care-seeking.