Chemosensory cues are vital for social and sexual behaviours and are primarily detected and processed by the vomeronasal system (VNS), whose plastic capacity has been investigated in mice. However, studying chemosensory plasticity outside of laboratory conditions may give a more realistic picture of how the VNS adapts to a changing environment. Rabbits are a well-described model of chemocommunication since the discovery of the rabbit mammary pheromone and their vomeronasal organ (VNO) transcriptome was recently characterised, a first step to further study plasticity-mediated transcriptional changes. In this study, we assessed the plastic capacity of the rabbit male and female VNO under sex-separation vs. sex-combined scenarios, including adults and juveniles, to determine whether the rabbit VNO is plastic and, if so, whether such plasticity is already established at early stages of life. First, we characterised the number of differentially expressed genes (DEGs) between the VNO of rabbit male and female under sex-separation and compared it to sex-combined individuals, both in adults and juveniles, finding that differences between male and female were larger in a sex-separated scenario. Secondly, we analysed the number of DEGs between sex-separated and sex-combined scenarios, both in males and females. In adults, both sexes showed a high number of DEGs while in juveniles only females showed differences. Additionally, the vomeronasal receptor genes were strikingly downregulated in sex-separated adult females, whereas in juveniles upregulation was shown for the same condition, suggesting a role of VRs in puberty onset. Finally, we described the environment-modulated plastic capacity of genes involved in reproduction, immunity and VNO functional activity, including G-protein coupled receptors. Our results show that sex-separation induces sex- and stage-specific gene expression differences in the VNO of male and female rabbit, both in adults and juveniles. These results bring out for the first time the plastic capacity of the rabbit VNO, supporting its functional adaptation to specifically respond to a continuous changing environment. Finally, species-specific differences and individual variability should always be considered in VNO studies and overall chemocommunication research. Chemosensory communication controls many vital social and sexual behaviours such as fighting or mating and strongly impacts individual behaviour. It demands accuracy and a dynamic range of stimuli perception as well as highly sensitive transduction mechanisms. In mammals, chemical stimuli are predominantly detected through the vomeronasal system (VNS), considered as a hardwired system in charge of detecting innate and stereotyped chemosignals . HoweverChemical stimuli are released by one individual to the external world and detected by conspecifics, predominantly by vomeronasal receptors (VRs) located in vomeronasal sensory neurons (VSNs) within the vomeronasal organ (VNO) . Vomeronin situ Hybridization) and gene expression [RNA sequencing (RNAseq)] of VSNs and VRs  male and female rabbits that were separated at birth (sex-separated) so that males and females did not have contact with members of the opposite sex, and compared their VNO transcriptome to (2) male and female rabbits that were reared together since birth (sex-combined). Two experimental time points [juveniles (40 days) and adults (6 months)] were considered. The two sampling points were selected following On day 0, kits were re-distributed among mothers, so that each mother took care of eight kits coming from different mothers. For the sex-separated condition, female and male kits were separated since birth in different litters. We employed 50 litters/condition  to ensure that animals were surrounded by individuals under the same condition, but only three individuals per condition/sex/stage were analysed for gene expression.A detailed scheme of the organisation of animals per rooms can be found in ad libitum feeding and drinking. All individuals were humanely sacrificed by an abattoir of the same company, following strict ethical farm conditions and in accordance with the current legislation. Sex-separated animals were sacrificed at the beginning of the day to avoid any type of contact with members of the opposite sex, and males and females were sacrificed in consecutive different days for the same reason. Their heads were separated from the carcasses in the slaughtering line and the whole double VNO structure was immediately dissected out after opening the lateral walls of the nasal cavity and removing the palate and nasal turbinates. Samples were immersed in Trizol and kept in ice (∼4°C). Tissue was homogenised at the sampling point using a mixer to guarantee the whole tissue sample was soaked by Trizol–due to the double bone and cartilage envelope of the rabbit VNO. After 20 min, all samples were stored at −80°C for further RNA extraction.Twenty-four animals, separated in 12 juveniles and 12 adults of 40 and 180 days, respectively, were used including the same number of males and females within each group. All animals pertained to a commercial hybrid  and were maintained on a farm  under the same temperature conditions (18–24°C), dark-light cycles of 12:12 h and 1 and on Trimmomatic v.0.39  using the Bioconductor package DESeq2 v.1.28.1  in R v.3In parallel, we also performed our analysis using kallisto , which pThe main goal of this study was to analyse the plasticity and capacity for sensorial adaptation of the VNO in response to diverse socio-environmental conditions. We characterised gene expression in the VNO for the four conditions  and two stages (adults and juveniles) using RNAseq.We first identified DEGs (FDR < 0.05) between females and males under sex-separated (SF vs. SM) or sex-combined conditions (CF vs. CM) in the rabbit VNO of adults and juveniles . We founIn juveniles, all the 39 DEGs found were specific of the sex-separated scenario, suggesting that sex-separation induces much greater differences between sexes at this stage than sex-combined. Only 3 of these DEGs were also detected in the same comparison in adults , therefoAll in all, results indicate that sex-separation induces VNO gene expression differences between males and females in the adult and juvenile rabbit VNO. Adult rabbits exhibit the largest divergence in the number of genes expressed (111 genes) and therefore, a higher plasticity under the two environmental scenarios.The differential gene expression detected between females and males subjected to different environmental conditions (sex-separated vs. sex-combined) could arise via changes in one sex or in both sexes. To decipher the influence of each sex, we compared DEGs between sex-separated and sex-combined females (SF vs. CF) and males (SM vs. CM), both in adults and juveniles (DEGs combined vs. separated). In adults, 235 (SF vs. CF) and 380 (SM vs. CM) DEGs were detected, while in juveniles the difference was much higher in females  than in males  . It may A higher overlap was observed when comparing the results of juveniles and adults of the same sex, especially in females, which shared 34 DEGs . GPA1 waThese results indicate that adults of both sexes exhibit specific responses of their overall gene repertoires depending on the environmental conditions (sex-separated and sex-combined scenarios), which is also true for juvenile females. Therefore, when studying how environmental modulation affects VNO gene expression, variations in sex and stage are highly expected and should be carefully considered.p < 0.01 (unadjusted) considering the low transcript abundance of VRs, as previously suggested (p < 0.05 (unadjusted) to broadly deepen into the VRs gene repertoire. First, we compared the number of VR DEGs between male and female under sex-separated or sex-combined conditions in adults and juveniles. In adults, we found four consistent  and 17 suggestive  differentially expressed (DE) VRs in the sex-separated condition, all of them downregulated in females (p < 0.05).We specifically analysed the gene expression of the vomeronasal receptor (VRs) repertoire considering its relevance for chemocommunication, especially on reproductive behaviour. We used a more conservative significance threshold of uggested . We also females . Convers females . Contrarp < 0.05), underscoring that the DE VRs are highly sex- and stage-specific, and that the environment critically influences VRs expression. Remarkably, these results contrast with those found by We then aimed to evaluate whether the DE VR repertoire is shared between adults and juveniles. We found no overlapping VRs in the four comparisons  could originate from changes in one sex or in both sexes. In female adults, we found three consistent  and 12 suggestive (eight V1R and four V2R) DE VRs between sex-separated and sex-combined individuals (SF vs. CF), whereas in male adults, we detected two consistent (one V1R and one V2R) and eight suggestive (three V1R and five V2R) DE VRs for the same comparison (SM vs. CM) . So, aduTwo main conclusions can be extracted from the VRs gene expression results: (1) rabbit VRs gene expression is sex- and stage-specific under different socio-environmental conditions (sex-separated vs. sex-combined) and (2) adult females in a sex-separated scenario showed the lowest VRs expression among all comparisons. For a more refined evaluation of VRs gene expression, we then visualised all V2R and V1R showing differential expression (consistent or suggestive) in any comparison . V2Rs exIndividual variation of VRs expression has been previously described , but mos3 A similar expression pattern (CM > SM) was found for the female-specific lacrimal gland protein , a gene previously identified as a lipocalin in hamsters which shows 85% protein sequence identity with male-specific submandibular salivary gland proteins (MSP) secreted in saliva and urine of male hamsters (p = 0.057 (adjusted) and p = 0.014 (unadjusted), respectively. Other genes related to steroid-binding  showed differential gene expression between conditions (p < 0.05 (unadjusted)], were differentially expressed between conditions (SF > CF)  , suggestSF > CF) , was sigSF > CF) , and theSF > CF) , and herTaken together, these results indicate that, in the adult and juvenile VNO, expression of several reproduction-related genes changes according to the environmental conditions  and some of them are sex-specific.We next sought to determine whether the functional activity of the VNO varies among the experimental groups. Enrichment analyses revealed overrepresentation of G-protein related terms such as “G protein-coupled chemo attractant receptor activity” and “G protein-coupled receptor signalling pathway” among DEGs detected in sex-separated vs. sex-combined females (SF vs. CF), both in adults and juveniles . In juveOther enriched functions were detected under environmental changes . We founThese results support that the VNO of male and female rabbits undergoes transcriptional changes according to environmental conditions, which might represent an adaptation of sensory responses to upcoming signals. These results are consistent with recent data by The VNO is capable of detecting a broad range of chemical cues which fluctuate depending on given environmental scenarios. We found enriched molecular function GO terms related to “response to chemical/biotic stimuli and to other organisms” and “regulation of response to external stimulus,” especially in sex-separated vs. sex-combined females (SF vs. CF), both in juveniles and adults, but also in sex-separated females vs. sex-separated males (SF vs. SM) in adults . The VNOp < 0.01 (unadjusted)]. These results indicate that FPR2 and FPR1 are environment-modulated and therefore its immune function could be more complex than previously thought. Additionally, we found many molecular function GO terms related to “response to bacterium” and “defense response” involving DEGs of several comparisons  confirmed that VNO plasticity, via transcriptional modulation, follows a different rationale according to species. Then, we discussed the potential role in pheromone perception of two important gene families–lipocalins and sex-steroids–broadly expressed in the VNO. Finally, we argued that VNO activity, and in particular VRs expression, might be linked to puberty onset, a fundamental question which needs to be further explored. Altogether, our study may serve as a bottom line for future studies of VNO chemocommunication, in which specie-specificity as well as VNO plasticity should always be considered.Our results proved that sex-separation induces sex-specific differences in the rabbit VNO gene expression, and this is consistent with previous results in adult mice . HoweverDespite males and females exhibit striking sexually dimorphic behavioural responses to pheromones, and VNO shows sexually dimorphic anatomical features , its VRsWe then aimed at determining whether this sex-specific VNO expression is environmentally modulated. To do so, we compared the differential gene expression of the adult VNO between males and females considering both environmental conditions (sex-separated vs. sex-combined). We detected a rather small overlap between sex-separation and sex-combined scenarios . This result indicates that different environmental conditions give rise to different DEGs repertoires in the VNO of male and females rabbits, thus supporting the importance of environmental context in the overall VNO gene expression. In contrast, in the mice VNO, Considering that chemical stimuli detected through vomeronasal receptors may vary depending on a given environment, other important point was to decipher whether VRs expression in males and females is also environmentally modulated. By performing a similar comparison as above, we did not find overlap between sex-combined and sex-separation scenarios (CF vs. CM and SF vs. SM), both in adult and juvenile rabbits. In contrast, Additionally, All in all, we found little DEGs overlap in the rabbit VNO between males and females in both juveniles and adults, and in all scenarios tested. These results indicate that environmental modulation changes the VNO gene expression in a sex- and stage-specific manner in this species. This leads us to conclude that sex-separation is a condition which induces sex- and stage-VNO specific differences, and which is influenced by species (mouse vs. rabbit) tissues  and individual variability. Our observations are consistent with the plastic capacity of the VNO to cope with different environmental scenarios, but further studies are needed to clarify the rationale behind this overwhelming gene expression heterogeneity.Different members of the lipocalin family are involved in pheromone transport and can be found in a variety of body fluids such as urine , tears , or salip = 0.013 (unadjusted), which could reflect saturation when males are continually exposed to the putative female pheromones. This would follow a similar rationale to the theory described for VRs “use it and lose it” . Therefore, its expression appears to be sex-specific and clearly depends on the environment. This could prepare separated males to be ready (receptors not saturated) to bind female-pheromones, eliciting copulatory behaviour in the presence of females. Also, it could selectively modulate the activation of vomeronasal receptors. Interestingly, when both sexes are reared together, the expression of this gene is lower (CM < SM), lose it” , which cSteroids are well-known for their essential role in animal physiology, particularly regarding the internal state of the individual. Less studied but also vital for animal behaviour is the role of steroids in chemosensation. These compounds are excreted by animals in urine or faeces, releasing a readout of its own biological state, and therefore acting as chemosignals/pheromones to be detected through the VNO of conspecifics . SpecifiThe complexity of steroid chemosensation suggests that there is not a universal rule governing sex-steroid pheromone vs. receptor activity . HoweverFemales exposed to urine odours of males during pre-pubertal period accelerate puberty, a phenomenon known as Vandenbergh effect . RemovalOur results indicate that the VNO expression pattern of juvenile females greatly differs between sex-separated and sex-combined conditions (SF vs. CF), whereas that of juvenile males remains almost unchanged. These results highlight the plasticity of the VNO in juvenile females exposed to different environmental conditions, which might be linked to female puberty. Regarding VRs, juvenile males and females showed similar VR gene expression repertoire when sex-combined (CM vs. CF). However, such VR repertoire vary in sex-separated conditions, showing overall upregulation in sex-separated females when compared to males and also when compared to their sex-combined counter partners.We speculate that this VR upregulation in juvenile separated females might follow the theory “use it and lose it” , suggestAll in all, this study shows the plastic capacity of the rabbit VNO, and that in mammals this feature is not limited to mice. Our experimental design of sex-separation vs. sex-combined scenarios is a suitable model of environmental modulation to study VNO plasticity. We demonstrated that the rabbit VNO exhibits significant gene expression differences between male and female under sex-separation but not sex-combined scenarios. These differences are not only remarkable for the vomeronasal receptor repertoire but also for many genes involved in sensory perception, reproduction, immunity and VNO functional activity. Additionally, the low overlap between the different comparisons suggests that variation in the VNO gene expression under environmental conditions is both sex- and stage-specific.Regulation of transcription arises as a mechanism that the VNO may use to adapt sensory responses to specific external stimuli. Further studies should approach the molecular logic of such transcriptional changes as well as its possible relationship with variation in the VNO cellular and neuron abundance.https://www.ncbi.nlm.nih.gov/, PRJNA720622.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: The animal study was reviewed and approved by Comité de Bioética da Universidade de Santiago de Compostela, Edificio CACTUS, CAMPUS DE LUGO, 27002 LUGO.PM, PS-Q, and PRV conceived and designed the experiments and RNAseq assay. PRV, JG, LQ, and PS-Q were involved in the experimental sampling. PRV and DR carried out the sequencing, transcriptomic analyses, bioinformatic work, and data analysis. PRV wrote the original draft. DR and PM participated in the reviewing and critical analysis of the manuscript. All authors provided critical input and approved the final version.


Currently, brain-computer interface (BCI) is the research focus and hotspot in the field of neuroscience. Related technologies are widely used in various scenarios such as clinical use, rehabilitation, engineering, and daily life. The BCI uses different brain signals, recording methods, and signal-processing algorithms to build a link between the brain and external software/hardware platforms. With the development of hardware  and algorithms , BCI is becoming more practical and stable.We publish this Research Topic to collect the latest research worldwide in BCI. Researchers from all over the world actively participate and contributed a lot of manuscripts. After carefully and professionally reviewing all submissions, 14 high-quality manuscripts are accepted.Zhang et al. propose a Multi-Scale 3D-CNN Approach for EEG-based Identity Authentication. The experimental results show that the classification performance of the proposed framework is excellent, and the multi-scale convolution method is effective to extract high-quality identity characteristics across feature domains. Qiu et al. use Electroencephalogram (EEG) and Functional Near Infra-red Spectroscopy (fNIRS) to track the brain activities evoked by neutral and preferred music. The authors conclude that music can promote brain activities, especially in the prefrontal lobe with preferred music. Deng et al. propose SparNet, a CNN composed of five parallel convolutional filters and the Squeeze-and-Excitation Networks (SENet), to learn EEG space-frequency domain characteristics and distinguish between depressive and normal control. The computational results indicate that SparNet achieves a sensitivity of 95.07%, and a specificity of 93.66%. Wang and Cerf combine common spatial pattern (CSP) features and radial basis function neural network (RBFNN) to classify motor imagery EEGs. The algorithm provided high variability within- and across-subjects in EEG-based action decoding. The computational accuracies are higher or close to 90% on two datasets, i.e., BCI competition IV-2a, and -2b. Chen L. et al. transform the EEG signals into symmetric positive definite (SPD) matrices and captures the features of SPD matrices by using CNN. Meta-transfer-learning (MTL) is used to avoid the time-consuming calibration. Chen G. et al. explore the feasibility of an audio-assisted visual BCI speller and a deep learning-based single-trial event-related potentials (ERP) decoding strategy. A spatial-temporal attention-based CNN (STA-CNN) is proposed to recognize the single-trial ERP components. The average classification accuracy of STA-CNN is 77.7% in the EEG dataset recorded from 10 subjects.In this topic, several of the contributions focus on the use of deep learning in EEG decoding for BCI, among which convolutional neural network (CNN) is the most widely used. Xu et al. use a simulated driving platform with an EEG data collection system for the evaluation of human trust in autonomous vehicles. The graphic theoretical analysis illustrates how human trust varies in EEG under semi-autonomous or fully autonomous driving modes. Wang J. et al. use non-linear dynamics of EEG Signals to Classify primary hand movement intent under opposite hand movement. Their experimental results show significant differences in movement-related cortical potentials between hand movement directions under an opposite hand movement. The results may lay a foundation for the future development of EEG-based human augmentation systems for both the handicapped and the healthy. Massé et al. investigate EEG-based alarm detection in the flight simulator. Cognitive fatigue and cognitive load are manipulated to trigger inattentional deafness, and brain activity is recorded via EEG. The results show that alarm omission and alarm detection can be classified based on time-frequency analysis of EEG. Triana-Guzman et al. combine filter bank CSP (FBCSP) and regularized linear discriminant analysis (RLDA) for decoding EEG rhythms offline and online during motor imagery for standing and sitting. The mean accuracy is higher than 80% in offline analysis, and higher than 90% in online experiments. Song et al. propose a rehabilitative motor imagery BCI system that focuses on rejecting false positive (FP) detection in stroke rehabilitation. A two-phase classifier is used to reject the FP. The algorithm achieved 71.76% selectivity and 13.70% FP rate by using only four EEG channels in the patient group with stroke. Kwon et al. propose a new hybrid visual stimuli for steady-state visual evoked potential (SSVEP)-based BCI, which incorporate various periodic motions into conventional flickering stimuli (FS) or pattern reversal stimuli (PRS). Results demonstrate that FS with sine-wave periodic motion and PRS with square-wave periodic motion could effectively improve the BCI performances compared to conventional FS and PRS.Other studies use traditional machine learning and statistical methods for BCI applications in certain modes. Wang Y. et al. classify the MEG data of patients with complex partial seizures (CPS) or simple partial seizures (SPS), using support vector machine. The algorithm obtained a classification accuracy higher than 80%. Cui et al. review the music-emotion recognition and analysis based on EEG signals.Finally, two studies provide clinical and human factor applications of magnetoencephalography (MEG) and EEG. Overall, we hope that this topic can provide some references and novel ideas for researchers in BCI. It should be emphasized that for such a rapidly developing research field, the work that has been done so far is only a drop in the ocean. The manuscripts we collect this time can only be a small leaf in the Amazon rainforest. For BCI, there is still a big gap between the current research and the actual use. Things that need to be solved go far beyond.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


During COVID-19, hospital capacity was significantly reduced to limit the spread of the pandemic. The limitations affected the efficiency of service delivery. We examined the effects of pandemic-related challenges on patient experience and hypothesize that digital health implementation increased patient satisfaction. We surveyed nationally aggregated data in hospital occupancy, hospital funding and patient experience, and plotted their correlation. We found digital health to contribute to patient experience and service-delivery effectiveness. We evaluate the benefits of digital health in context of hospital service delivery. Post-COVID-19, we recommend a continued implementation of digital health and offer suggestions to further improve its efficiency and cost-effectiveness. The coronavirus disease 2019 (COVID-19) pandemic has had tremendous impacts on healthcare systems worldwide. The World Health Organization (WHO) recommended healthcare services to limit in-person interactions to urgent services [Research to date has examined the effect of COVID-19 on healthcare services across jurisdictions, revealing COVID-19′s impact on various functions of healthcare services such as hospitals, healthcare provision and drug administrations. Globally, the World Health Organization revealed healthcare adoption priorities around clinical health systems in reaction to the pandemic . In the The Canadian healthcare system also largely conforms to COVID-19 prioritization in the jurisdictions highlighted above, implementing similar mechanisms in adaptation to pandemic-related constraints. The Canadian Institutes of Health Research’s Institute of Health Services and Policy Research (IHSPR) conducted a series of analyses of health-policy development, identifying virtual care as one of the seven COVID-19 priorities . Their fAlthough the research to date has highlighted the significant potential of digital healthcare, the lack of discussion on specific steps towards implementation hinders the ability to examine the practicality of implementation. Moreover, the lack of data analysis specific to the Canadian healthcare data limits the scope of discussion in Canadian implementation of digital healthcare. In this paper, we examine the effects of funding changes and pandemic restrictions on patient experience. We hypothesize digital health’s contribution to patient experience and advocate for broader implementations in the delivery of health services.Canadian Institute for Health InformationWe acquired the raw data for analysis from the following governmental resources:https://www.cihi.ca/sites/default/files/document/series-d1-2021-en.xlsx, accessed on 23 August 2022.https://www.cihi.ca/en/patient-experience/reporting-patient-experience-data, accessed on 21 August 2022.https://www.cihi.ca/sites/default/files/document/impact-covid-19-on-hospital-services-march-2020-to-june-2021-data-tables-en.xlsx, accessed on 23 August 2022.Financial Accountability Office of Ontariohttps://www.fao-on.org/en/Blog/Publications, accessed on 17 August 2022.http://www.fao-on.org/en/Blog/Publications/health-2020, accessed on 17 August 2022.Government of Albertahttps://www.alberta.ca/budget-highlights.aspx, accessed on 14 August 2022.Government of British Columbiahttps://bcbudget.gov.bc.ca/, accessed on 14 August 2022.Government of Canadahttps://health-infobase.canada.ca/covid-19/, accessed on 11 August 2022.Government of Manitobahttps://www.gov.mb.ca/sharethehealth/index.html, accessed on 10 August 2022.Government of New Brunswickhttps://www2.gnb.ca/content/gnb/en/departments/finance/budget.html, accessed on 10 August 2022.Government of Nova Scotiahttps://novascotia.ca/news/search/?deptnum=148&month=&year=2022&q=&condition=AND, accessed on 10 August 2022.The general workflow of this work is illustrated in Our data analysis was conducted with Microsoft Excel (version 16.44) and its built-in tools . Microsoft PowerPoint (version number 16) , GraphPad Prism (version 9.4.1) , and BioRender (version 2022)  were used to display results.Due to the reduction in hospital capacity under COVID-19 conditions, the hospital system was forced to adapt to prioritizing lifesaving treatments, shifting most of human resources to support areas of greatest need . In the Financially, COVID-19 impacted major spending categories, where spending increased for additional resources in personal protective equipment (PPE), intensive care unit ventilators and intensive care unit (ICU) beds . This leIn addition, we examined the patient experience data from provincial government . SurprisCOVID-19 had tremendous impacts on the funding and delivery of healthcare services. From our results, we found that hospital occupancy was significantly reduced in reaction to COVID-19 cases. With the reduced occupancy leading to delayed and cancelled services, we expect the patient service experience to be negatively implicated. However, survey results demonstrate that patients’ own assessments of their hospital experiences remained relatively unchanged and positive.This finding is different from some studies conducted in the United States, which found a negative correlation between patient satisfaction and wait time ,19,20. LCanada has started to implement digital health technologies since 1998 . DigitalAs a result of the decreased hospital capacity, virtual care became a key tool for primary care physicians and specialists to triage patients virtually. Physicians accelerated the adoption of virtual care, launching online diagnosis, outpatient appointments, and other services that allowed for physicians to connect with patients remotely. Between 27% and 57% of physician services were provided virtually during the pandemic across the five provinces where data are available . In thisSurveys on patient-clinician engagement further corroborate the effectiveness of remote diagnosis, finding equal engagement in virtual visits compared to in-person visits . NationaThe hypothesis that digital healthcare has served as an effective replacement for in-person visits is also supported by telehealth service providers data. The Center for Metabolic and Bariatric Surgery (CMBS), the sole bariatric surgery program in Manitoba, Canada, transitioned all appointments to being virtually offered. Using patient-reported experience measure (PREMs), patient satisfaction was concluded to be 81.7% . AdditioVarious results suggest that digital healthcare technology improves patient experience and enhances the delivery of hospital services. Its significance was highlighted in the pandemic, allowing for diagnosis without risk of transmission and risk of exposure for patients and physicians. Moreover, beyond its pandemic-contextualized benefits, digital health is cost-effective in and provides clear benefits in hospital systems.Digital healthcare reduces the cost of healthcare to patients and improves healthcare coverage. High treatment costs and geographical distance are major barriers to healthcare access . By fundBeyond cost reductions, digital health improves the overall efficiency of healthcare services. By eliminating the geographical barrier of healthcare access, patients can access a wider variety of providers, who will better match their medical needs . This alPost-pandemic, hospitals are resuming to pre-pandemic levels of capacity and offering of services. However, due to current inflationary pressures and limited funding allocations, hospital services have significant costs. By continuing the adoption and development of digital health tools, hospitals can improve their operations’ cost-effectiveness and enhance patient experience. With this in mind, we advocate for the broad use of digital healthcare tools in information management, service accessibility and service quality. In the discussion below, we analyzed these key pathways from regulatory, financial, and technological perspectives to advance the benefits brought by digital health integrations.Patient information management is a critical aspect in supporting the wide-scale use of digital healthcare. With more prevalence of digital health technologies, clear regulations must be set for uniform regulation. Currently, digital health is offered by hospitals individually, resulting in a variety of delivery formats through regulated and unregulated platforms. To ensure a secure system for wide-scale usage, guidelines and legislations should be established in accordance with privacy acts such as the Personal Information Protection and Electronic Documents Act (PIPEDA) and Personal Health Information Protection Act (PHIPA).In addition, support should be provided to simplify physician registration and licensure processes by regulatory bodies. The enhancement of physician information systems will further increase efficiency the of virtual care. Given physicians’ contrasted preferences in offering virtual care , physiciBlockchain technology can be incorporated in the information management recommendations. Due to the non-tamper ability characteristic of blockchain technology , its furBy bettering the fundamental identity management aspect of digital healthcare, the safety and quality of virtual care can be improved. Moreover, these recommendations improve the national standards for patient health information access and broadly enhance identity management.A critical issue with the current digital health system is the lack of equitable access; a demographic analysis of popular digital health platforms reveals the majority of users to be younger, healthier, and living in wealthier areas ,37. FeesAs outlined, increased digital health funding should be specifically targeted towards equitable access to digital healthcare. On a general level, digital health financing should implement widely agreed-on health-financing principles for funding expansion , includiThe information system and accessibility improvements will contribute to a better quality of service by standardizing the information and delivery of digital healthcare. In addition to these recommendations, service adaptations and technological integrations for virtual care will further improve patient experience. Beyond suggestions for clinicians’ service adaptations to integrate virtual care characteristics, we suggest that technological integrations virtually support patient experience. Healthcare providers face a challenge in supporting patients’ diagnosis needs in due to the difference in the meeting format. For example, in a physical diagnosis, the physician can ask the patient to reveal their injuries and lean closer to take a clearer examination. In a remote setting, would patients feel as comfortable undressing to show their injuries, and how would physicians adapt to a virtual examination? In a physical waiting room, patients could sit and wait until the physician called them. In a remote setting, who would give cues to these patients if another appointment is running late? Although the details could be highly specific, these are processes that have gained familiarity across physical healthcare settings. Virtual services require standardization so that patients can instill familiarity and trust in the system.In addressing such challenges, not only do physicians need to train and adapt their services, but technological integrations could also increase the efficiency of delivery. Due to the virtual setting, technological integrations could be used as effective substitutes for traditional walk-in methods. For example, AI-based chatbots are an efficient integration that are already being used by some digital healthcare systems, where physician signals would prompt chatbots to communicate with the patients. This would help manage patient tracking and system integration, improving the overall patient experience. Moreover, technological integrations extend to an adaptation of virtual devices to conduct virtual services. Wearable devices, a model under digital health, could aid in the continuation of remote health-monitoring. Remote patient-monitoring devices, such as smart watch, RPM, and tele-homecare, enable health providers to monitor patient conditions outside of physical clinical settings and could remotely extend related diagnoses. Such integrations provide alternatives to patients, who may feel more comfortable in virtual rather than physical care. Physicians can engage more efficiently and more deeply with patients because of these tools and improve the overall effectiveness of virtual care. Given that patient engagement is critical to improving the quality of healthcare , we suggWe analyzed various aspects of the Canadian healthcare system to realize significant funding allocation challenges in the pandemic period. Through compiling aggregate data on COVID-19 waves, hospitalization, patient experiences and hospital findings, we found that patients remained satisfied, despite setbacks in hospital services. We find that the results of the study support the claim that digital health effectively reduces costs and increases patient satisfaction when funding and service delivery are limited. We believe that the maintenance of the healthcare standard is, in part, a result of the digital health implantation in Canada. Our in-depth analysis and discussion further suggest three fundamental pathways to improve the effectiveness of digital healthcare. Our study offers insights to regulatory agencies regarding strategic decision-making, as well as hospitals, to improve the overall efficiency of services and reduce healthcare costs.


The term “carbon-based spintronics” mostly refers to the spin applications in carbon materials such as graphene, fullerene, carbon nitride, and carbon nanotubes. Carbon-based spintronics and their devices have undergone extraordinary development recently. The causes of spin relaxation and the characteristics of spin transport in carbon materials, namely for graphene and carbon nanotubes, have been the subject of several theoretical and experimental studies. This article gives a summary of the present state of research and technological advancements for spintronic applications in carbon-based materials. We discuss the benefits and challenges of several spin-enabled, carbon-based applications. The advantages include the fact that they are significantly less volatile than charge-based electronics. The challenge is in being able to scale up to mass production. In the 1990s, the term spintronics (short for spin electronics) was created to designate technologies that make use of an electron’s quantum mechanical feature known as “spin”, which has only two values: spin-up and spin-down. To keep up with the ever-increasing data generation, our society has dramatically boosted data storage capacity. Memory devices have shrunk in size concurrently . One of The carbon material research focuses on carbon nanotubes and graphene. Although carbon exists in a variety of allotropic forms, these two substances offer a low dimensionality and high crystalline purity, opening the door to several unusual quantum events . Spin inTo properly understand carbon-based spintronics, it is crucial to assess the most recent research in the area. This review article has explored the evolution of carbon-based spintronics and has also discussed some current problems and anticipated future developments. The preparation of the materials needed for carbon-based spintronic is covered in the first section. The second section illustrates the operation of carbon-based spintronic device operations. In this section, a few potential carbon-based spintronic devices for logic and memory applications are introduced along with other uses. The last section discusses the topic of prospective and challenges in carbon-based spintronics for real-world applications.The different carbon prototypes used in the synthesis serve as the foundation for most carbon-based spintronic devices. The carbon materials utilized are divided into four distinct types: graphene-based, carbon nanotubes-based, carbon nitride-based, and fullerenes-based . These aIt is possible to think about graphene as a single sheet of graphite since it produces a perfectly planar layer of carbon atom. Thus, the arrangement of carbon atoms results in a hexagonally symmetric, monatomic, two-dimensional lattice. Currently, there are three main methods for creating graphene nanoribbons (GNRs): cutting graphene using lithography, polycyclic bottom-up synthesis, and unzipping carbon nanotubes (CNTs). Chemical vapor deposition (CVD) on metal surfaces, mechanical exfoliation, electrochemical exfoliation, chemical exfoliation of graphite powder, epitaxial growth on single crystal SiC, chemical coupling processes, and intercalation/sonication are the common techniques used to produce graphene nanosheets (GNs) . GraphenArc discharge , chemica2 dissociation by selectively adhering to borders, lowering the barrier to graphene hydrogenation. The PHGr can therefore be used as a platform for single-atom catalysts and carbon-based spintronic devices. Additionally, when the size of the GNF fluctuates between 1.4 nm and 2.3 nm, it was discovered that the antiferromagnetic boundary states and semiconducting characteristics remain unaltered. The impact of magnetic coupling engineering on the spin transport characteristics of covalently coupled nanographene dimer-based molecular devices has been investigated by Jing Zeng and Xiaohui Deng. Their findings demonstrate that the magnetic coupling strength of the covalently connected, five-membered ring-decorated nanographene is a key factor in the superior spin transport capabilities 2[p-terphenyl3], is isolated by Gadjieva N.A. et al. [The conduction electron spin lattice relaxation time (CESR), Tormation . In the ic field . During . et al. . MagnetoUsing liquid ammonia, Markus B.G. et al. reported synthesizing few-layer graphene (FLG) doped with Li and Na. Chemical exfoliation was used to prepare the FLG material . The app3C60 sample that has been well-characterized [3C60 is a promising three-dimensional superconducting magnet material with the advantage of the rich carbon abundance on the Earth due to the high upper critical field of 33.0 ± 0.5 T obtained from the direct electrical transport measurements, along with the relatively high critical temperature and large critical current density. The examination of all independently acquired parameters points to the peculiar nature of K3C60’s superconductivity, including contributions from electron correlations and electron–phonon coupling. By using the ESR technique, paramagnetic centers in heterofullerides with the compositions A2MC60 and AM2C60  were studied by Kytin V.G. and his collegues [The study by Ren-Shu Wang et al. provides a complete set of parameters through a thorough investigation on a Kcterized . K3C60 iollegues . The ESRThe electron spin resonance (ESR) signal of undoped and potassium-doped SWCNTs was investigated by Galambos M. et al. . They idCarbon-based, molecular, or polymeric semiconductors are used in organic electronics because they are inexpensive to produce, mechanically adaptable, and, most critically, have practically limitless and chemically tunable electrical and optical properties. The organic light-emitting device (OLED), which is utilized in displays, is the most widely used commercial organic electronic application (notably in smart phones). By combining organic materials into spintronics and spin dependent effects in organic electronics, organic spintronics strives to merge these two fields. According to Dediu et al. devices with ferromagnetic La0.7Sr0.3MnO3 (LSMO) electrodes and a sexithienyl (6T) spacer exhibit room-temperature magnetoresistance . In ordeTwisteronics is currently a popular issue in the study of 2D materials. Although the superconductivity in twisted graphene systems appears to be of an uncommon type, the underlying theoretical description is still elusive, which poses a significant issue for carbon-based spintronics. Increasing production rate, scalability, homogeneity, and quality control are problems for the industrial-scale synthesis of carbon-based spintronic materials. In general, varying quality across producers is a problem, and it is imperative to improve a single standard or grading system. Improving the quality and reproducibility of patterned nanostructures, effectively coupling light into and out of graphene, and expanding plasmon tunability to the vis-NIR range are challenges in plasmonic and optical qualities. Developing regulated fabrication processes that result in reliable and repeatable devices is another problem in electrical and spintronic applications. Of course, there are also significant challenges with scalability and wafer-scale integration. Nanotube-based electronics have two main difficulties that must be overcome. Connectability is one of the difficulties; while it is one thing to construct a single nanotube transistor, it is quite another to connect millions of them. A single component at a time is often used in the current techniques of nanotube electronics, which is not practical. The suggested theoretical research and experimental findings typically differ significantly, since the experiments are so complex. These disagreements suggest that elaborate physical mechanisms and precise theoretical models must be established to effectively direct research efforts and interpret experimental findings. The limitation in material science with carbon-based spintronics is that the majority of materials with thicknesses close to the atomic level are temperature-, oxygenation-, and moisture-sensitive. They need to operate above room temperature and be stable in the presence of air.Due to their unique spin-dependent characteristics, such as lengthy spin relaxation durations, long diffusion lengths, and high spin–orbit coupling, carbon-based materials have received a lot of attention in the field of spintronics. Because of its high charge carrier mobility, long spin lifetime, and long diffusion length, graphene has distinguished itself as a superior platform for future spintronic devices. Effective spin logic and non-volatile data storage are made possible by the tunable bandgap and robust spin–orbit coupling that carbonitrides show. The integration of spintronics and photonics into a single platform for both light-based and spin-based quantum computing is the goal of ongoing research and development. Researchers hope to be able to control the electron spin dynamics in nanostructured 2D magnetic materials activated using brief laser pulses by employing specially created photonic circuits. The rapidly developing field of spintronics, which has contributions from a wide range of nations and disciplines, including biology, chemistry, physics, electrical engineering, computer science, and mathematical information theory, promises to make fundamental discoveries in both pure and applied science as well as have a significant impact on future technology. In contrast to traditional charge-based information processing technologies, using spin as a state variable in logic devices has various benefits, including non-volatility, faster and more energy-efficient data processing, and higher integration densities. Spintronic computing has the potential to meet the constantly rising performance requirements of upcoming abundant-data applications.


Elderly patients exhibit a higher incidence of chronic heart failure (CHF). Patients with CHF can develop acute kidney injury (AKI) during follow-up, which can result in poor prognosis. This relationship between kidney dysfunction and levels of N-terminal pro-brain natriuretic peptides (NT-proBNP), with regard to prognosis, is complicated and has rarely been analyzed in elderly patients with CHF.We conducted a retrospective cohort study involving patients with a CHF history aged ≥ 65 years, who experienced an episode of AKI. Kaplan–Meier curves and Cox or logistic proportional hazards regression models were used to evaluate the association between serum NT-proBNP concentrations and mortality or renal recovery by day 90.A total of 1,160 eligible patients with AKI were available for the study. Of this sample, 41.5% of patients died within 90 days of the onset of AKI. Patients with a decreased change in NT-proBNP accompanying the episode of AKI had a lower risk  of more severe AKI (stage 2 and 3 vs. stage 1). The more severe AKI were associated with higher mortality and non-recovery of renal function in elderly patients with CHF, independent of NT-proBNP levels. Elevated levels of baseline lnNT-proBNP  predicted mortality in elderly patients with CHF within 90 days of AKI onset. Patients with a decrease in NT-proBNP accompanying AKI had a lower risk of mortality . However, a decrease in NT-proBNP is a risk factor  for the non-recovery of renal function following AKI–especially in elderly survivors with low baseline NT-proBNP levels.A decreased change in NT-proBNP maybe protective for elderly patients with CHF by improving survival outcomes and preventing severe AKI. However, an excessive decrease in NT-proBNP is a risk factor for the non-recovery of renal function following AKI. Avoiding excessive changes in NT-proBNP may be protective for survival and renal injury prognosis. The prevalence of chronic heart failure (CHF) is high and increasing in aging populations worldwide. The higher incidence of CHF in elderly persons can be attributed to aging and the high frequency of comorbidities, particularly coronary heart disease and hypertension. CHF with preserved ejection fraction is particularly prevalent in geriatric patients. The aging-related changes in the diastolic properties of the myocardium predispose older adults to develop CHF with preserved ejection fraction and atrial fibrillation . ElderlyB-type natriuretic peptide (BNP) and the precursor of BNP, N-terminal pro-brain natriuretic peptide (NT-proBNP), are produced mainly by cardiomyocytes in response to stretch from volume overload and myocardial ischemia. Circulating natriuretic peptides are widely used biomarkers that are indicative of HF and volume overload. In elderly patients with heart disease, elevated NT-proBNP levels are associated with a greater risk of cardiovascular mortality . In eldePatients with CHF are often characterized by impaired renal function, also referred to as cardiorenal syndrome (CRS). Cardiorenal syndrome is prevalent in the elderly, and a dynamic interplay between the heart and kidneys exists . PatientSince most of the randomized clinical trials for CHF and AKI were designed to exclude elderly patients, only limited data on elderly patients with cardiorenal syndrome are available. In the current analysis, we conducted a retrospective observational study to investigate the relationships between change in NT-proBNP, renal function and adverse outcomes in elderly patients with AKI in CHF.2) or incomplete medical histories were excluded from the study. Patients were also excluded if they lacked serum creatinine (SCr) or NT-proBNP data, either at baseline or at AKI onset. We followed all patients for 90 days after the initial AKI episode, to determine clinical outcomes relating to mortality and renal function.We conducted a retrospective cohort study at the Second Medical Center (Geriatric Department) of the Chinese PLA General Hospital to assess AKI outcomes in older patients with CHF. Patients 65 years of age or older, with a history of CHF with preserved and mildly reduced ejection fraction [left ventricular ejection fraction (LVEF) > 40%], were enrolled if they experienced an episode of AKI between 1 January 2008 and 31 December 2018. Patients with end-stage renal disease , and the requirement for informed consent was waived.The ICD10 codes I50.22 and I50.32 were used to retrieve data on patients with CHF history. The diagnosis of CHF was based on clinical findings, symptoms, abnormal electrocardiogram, elevation of brain natriuretic peptide level (NT-proBNP > 125 pg/mL), and structural cardiac abnormalities identified on echocardiography according to 2021 ESC guidelines . AKI is The secondary outcome of the study was non-recovery from AKI, defined as the last available SCr measurement (during the follow-up of 90 days) where SCr remained at more than 150% of the baseline value (thus still meeting the criteria for AKI).at AKI to NT-proBNP at baseline. The change in NT-proBNP was also analyzed as a binary variable. A decreased change in NT-proBNP was defined by the ratio of NT-proBNP at AKI to NT-proBNP at baseline < 1.All data were obtained from hospital electronic health records. Demographic characteristics (age and sex), medical history , accompanying conditions , and laboratory test results  were recorded. SCr levels were routinely measured in our clinical laboratory, using the Cobas c 501 analyzer (Roche Diagnostics). The serum NT-proBNP concentration was measured using Dimension EXL with an LM Integrated Chemistry System (Siemens). Within 3 months before AKI onset, the NT-proBNP level at baseline (NT-proBNP at baseline) was measured together with the baseline SCr value in a stable state. The NT-proBNP at AKI diagnosis (NT-proBNP at AKI) was measured together with the increased SCr value, which contributed to the diagnosis of AKI. The change in NT-proBNP (continuous) accompanying the episode of AKI was expressed as the ratio of NT-proBNP U test (continuous variables), or Pearson’s χ2 test . NT-proBNP concentrations were log-transformed to reduce skew, modeled as continuous variables, and divided into quartiles. Kaplan–Meier, log rank, and univariate and multivariate Cox regression analyses were used for the outcomes of 90-day mortality. Univariate and multivariate logistic regression models were used to evaluate the associations between NT-proBNP concentrations and the severity of AKI and the 90-day renal recovery. Multivariable models were constructed including NT-proBNP levels, severe AKI and confounding factors that were significantly associated with outcomes in the univariate analyses (P < 0.05). Interaction testing was performed between the direction of change in NT-proBNP, before and after AKI, and the quartiles of baseline NT-proBNP levels, with renal outcomes. The association between the change in NT-proBNP levels and non-recovery from AKI was further examined within different quartiles of baseline NT-proBNP levels. P-values of < 0.05 were considered statistically significant for all analyses, including interaction terms.Continuous variables were presented as mean ± standard deviation for normally distributed data or median [25−75% interquartile ranges (IQR)] for non-normal distributions. Discrete variables were presented as percentages. Patient characteristics were compared by the Student’s t-test, the Mann–Whitney at AKI/NT-proBNP at baseline) were found in the non-survivors. Stage 1 AKI occurred in 746 patients (64.3%), stage 2 in 245 patients (21.1%), and stage 3 in 169 patients (14.6%). In the non-surviving group, the percentage of patients with more severe AKI was higher than that in the surviving group . Moreover, non-survivors experienced a higher incidence of comorbidities including prior myocardial infarction, atrial fibrillation, COPD, and malignant tumors, as well as abnormal conditions including lower LVEF, proteinuria, extremity edema, infection, higher blood glucose, electrolyte disturbance, lower blood pressure, lower hemoglobin and higher cTnI. Additionally, survivors were more often treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), and non-survivors were more often treated with loop diuretics.A total of 1,160 eligible patients with CHF and AKI were enrolled and assessed in this study. Clinical characteristics and survival outcomes of the enrolled geriatric patients are shown in As shown in Severe AKI may result from several associated risk factors. P < 0.001; P < 0.001) and stage 3 (log rank P < 0.001) compared to stage 1.Kaplan–Meier curves for 90-day mortality showed that patients with higher NT-proBNP levels at baseline  survivors did not recover from AKI. Significant variables  from univariate logistic regression analyses and retained adjustors (NT-proBNP levels and AKI stages) were analyzed in multivariate models  as covarat AKI to NT-proBNP at baseline for non-recovery of renal function was not statistically significant. However, interaction testing was significant (adjusted P = 0.026) for the interaction between the direction of change in NT-proBNP and the quartiles of baseline NT-proBNP levels. In the lowest quartile of baseline NT-proBNP , patients with decongestion accompanied by an episode of AKI had significantly worse renal outcomes , which could contribute to the decline in heart and renal function, leading to the deterioration of systemic functions and worse outcomes . ElderlyElderly patients have the highest prevalence of HF, and a positive correlation between natriuretic peptides and age has been found . NatriurCardiorenal syndrome is a common clinical condition in the elderly. Cardiorenal syndrome occurs when dysfunction of either the heart or kidneys progresses to the other organ, leading to both cardiac and renal failure. Patients with CHF can develop AKI during follow-up . Pre-renThe role of kidney dysfunction in mortality has been frequently observed in patients with HF, especially acute decompensated HF. Improving renal function was previously reported to be paradoxically associated with worse outcomes in acute HF, but outcomes may differ based on the response to decongestion (decrease in NT-proBNP) . The relIn this study, 18% of survivors did not fully recover from AKI. Compared with non-elderly patients, impaired recovery of kidney function after AKI is more common in elderly patients . Non-recThere were several limitations of our study. This was a retrospective study in a single center that was restricted to a former member of the armed forces. Identified or unidentified confounders may have influenced the result. We lacked adequate data on the history of CHF  and the etiology of HF was difficult to precisely determine. We also lacked detailed data at AKI onset. In addition to BNP and extremity edema, lung congestion, liver congestion, and other indicators of volume and congestion status were unavailable and not included in our analyses. The causes of AKI and mortality in elderly patients with CHF are diverse and may have influenced the result. Subgroup analysis based on different causes is further required.In conclusion, a decreased change in NT-proBNP was associated with a lower risk of more severe AKI in elderly patients with CHF. Elevated levels of baseline NT-proBNP and increased change in NT-proBNP accompanying the episode of AKI predicted a higher 90-day mortality in elderly patients with a CHF history. However, an excessive decrease in NT-proBNP is a risk factor for the non-recovery of renal function following AKI–especially in elderly CHF patients with low baseline NT-proBNP levels. Continuous monitoring of NT-proBNP is recommended in elderly patients with CHF and avoiding excessive changes in NT-proBNP may be protective for survival and renal injury prognosis.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 Ethics Committee of Chinese People’s Liberation Army General Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JH and XZ contributed to the data analysis and drafting the manuscript. ZW contributed to the data collection and data analysis. YL, YZ, JZ, XW, HC, GY, and QM contributed to the data collection of the study. QC and QA contributed to the design of the study and data analysis. All authors reviewed the manuscript.


Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a major complication of methotrexate (MTX) therapy that can develop in patients with rheumatoid arthritis (RA), although primary hepatic MTX-LPD is extremely rare. Discontinuation of MTX results in remission in half of the patients with MTX-LPDs and is one treatment approach.A 64-year-old Japanese woman suffering from rheumatoid arthritis treated with MTX presented with upper abdominal pain.Pathological evaluation showed that the tumor contained geographic necrosis and proliferation of large atypical lymphocytes strongly positive for cluster of differentiation 20 (CD20) antigen with immunohistochemical staining and Epstein-Barr Virus-encoded RNA transcript by in situ hybridization. The tumor was finally diagnosed as a primary hepatic MTX-associated Epstein-Barr Virus positive B-cell LPD.Left hepatic lobectomy was performed for diagnosis and therapy.No sighs of recurrence were observed for 2 years.This patient demonstrated that MTX-LPD could arise in the liver, although it is rare. If liver tumors arise in patients taking MTX, examination of sIL-2R, Epstein-Barr virus-VCA IgG and EBNA might support the diagnosis of MTX-LPD. In this case, the primary hepatic MTX-LPD became necrotic without discontinuation of MTX. It is generally believed that withdrawal of MTX restores antitumor immunity resulting in tumor necrosis. This case indicates that spontaneous regression might occur without any treatment in some patients treated for RA with MTX-LPD. The relationship between MTX-LPD and spontaneous necrosis is unclear and further data is required to characterize the types of patients that will develop spontaneous regression without intervention. In 1991, Ellman et al first reported an association between lymphoma and the immunosuppression induced by MTX therapy in patients with RA. With the increasing frequency of MTX use in patients with RA, MTX has also been noted to cause methotrexate-associated lymphoproliferative disorder (MTX-LPD), a major complication of MTX therapy. Lymphoproliferative disorders (LPDs) are a group of disorders that include temporary lymphoid cell proliferations with spontaneous regression, benign lesions, borderline malignancies, and malignant lymphomas. The liver is rarely involved in MTX-LPDand the etiology of hepatic MTX-LPDs remains largely unknown. We report primary hepatic Epstein-Barr virus (EBV)-positive MTX-LPD in a patient with RA, in whom a large hepatic tumor developed with geographic necrosis without MTX withdrawal. Spontaneous regression may occur without intervention in some patients with MTX-LPD.Methotrexate (MTX), a commonly used immunosuppressive agent, is an important modality in the management of patients with rheumatoid arthritis (RA)A 64-year-old Japanese woman with a 14-year history of RA presented with upper abdominal pain. Administration of prednisolone and bucillamine was initiated for the management of RA at the time of disease onset. However, symptoms due to RA were not well controlled and MTX was started at 8mg/week, and the dose of MTX gradually increased to 12.5mg/week. Infliximab was started at 250mg/4 weeks at the same time. For the past 10 years, the symptoms have been controlled with MTX at 12.5mg/week, infliximab at 250mg/4weeks and prednisolone at 5mg/day. She had no family history of liver diseases or collagen diseases.Contrast-enhanced computed tomography (CT) scan of the abdomen was performed to evaluate the abdominal pain, which revealed a single 90mm nodular mass in the left lobe of the liver. A dynamic study revealed mild annular enhancement and a low-density area in the center of the tumor Fig. A. MagnetThe tumor was grossly composed of 2 well-defined mass lesions, which were contiguous within the liver Fig.A–B. LympMTX is widely used to treat patients with RA. LPDs develop in patients with autoimmune diseases receiving immunosuppressive agents such as MTX, which is associated with other iatrogenic immunodeficiency-associated LPDs. According to the World Health Organization classification of tumors of hematopoietic and lymphoid tissues, these disorders are categorized as lymphoid proliferations or lymphomas that arise in patients treated with immunosuppressive drugs for autoimmune diseases or conditions other than in post-transplant settings.,4 Although MTX-LPDs can arise in various extra-nodal organs, primary hepatic lesions are extremely rare. To date, only 12 patients with liver MTX-LPD have been reported. Nine patients had multiple lesions compared to three with single lesions. Five patients had lesions outside the liver, including the lung (n = 2), spleen (n = 2), abdominal para-aortic lymph nodes (n = 2), adrenal glands (n = 2), cervical lymph nodes (n = 1), and retroperitoneal lymph node (n = 1). Seven patients had lesions restricted to the liver. In the present patient, there was a single hepatic lesion. According to a report by Ono et al, liver function tests were slightly elevated, whereas sIL-2R, LDH, and CRP were more elevated in patients with liver MTX-LPD. In the present patient, liver function tests were slightly elevated, and sIL-2R levels were elevated, and LDH and CRP levels were not elevated. Imaging examinations of patients with PHL display various findings, including solitary, multiple, or infiltrative patterns, and there are no definitive diagnostic features. It is difficult to distinguish PHL from hepatocellular carcinoma or metastatic tumors and to obtain a correct diagnosis based on imaging studies alone. Characteristic imaging findings with hepatic MTX-LPD have not been delineated because of their rarity. Therefore, biopsy or surgical resection of suspected PHL and subsequent histological examination is necessary to make a definitive diagnosis. In the present patient, there was a single hepatic lesion and a definitive diagnosis could not be achieved based on imaging studies. Surgical resection was performed for diagnostic and therapeutic purposes. The development of MTX-LPD in various organs in patients taking MTX must be considered.Primary hepatic lymphoma (PHL) is very rare, accounting for just 0.4% of extra-nodal non-Hodgkin’s lymphomas. A number of recent reports have shown that patients suffering from RA treated with immunosuppressive agents, including MTX, have high prevalence of LPDs.-11 RA itself is associated with increased risk of lymphoma by 2.5 times compared to healthy people. The extent to which MTX contributes to a further increased risk of developing LPDs remains unclear. It is well known that immunosuppression predisposes patients to the development of EBV-associated lymphomas. EBV infection was detected in 12- 44% of lymphoma tissues that have emerged in patients with RA. It was reported that reactivation of EBV was detected in most patients with MTX-LPDs, and LPDs regressed in half of them after discontinuation of MTX therapy. Immunosuppression induced by MTX may be involved in the reactivation of EBV, which may lead to the development of MTX-LPD. In the present patient, serological tests for EBV-VCA IgG and EBNA were positive, and the test for EBV IgM was negative. These results indicate reactivation of EBV. Pathological specimens showed that the atypical large lymphoid cells infiltrating the tumor were positive for CD20 and EBVR. These results taken together led to the diagnosis of primary hepatic EBV-positive B-cell MTX-LPD.Immunocompromised patients have a higher risk of developing LPD than healthy individuals. Salloum et al reported that 62.5% of patients showed at least partial regression of the LPD in response to MTX withdrawal without additional antitumor therapy, and most of these patients were EBV-positive. If hepatic MTX-LPD is suspected based on the findings of oral MTX administration, EBV reactivation (elevation of EBV-VCA IgG and EBNA titers) and elevation of sIL-2R, pathological examination using a liver biopsy should be considered to avoid surgical intervention. If a definitive diagnosis is achieved, withdrawal of MTX with observation is 1 treatment option. In some cases, regression of liver tumors may not occur after MTX withdrawal, or the tumor might relapse even if withdrawal of MTX induces temporary regression of MTX-LPD. Chemotherapy administration should be considered in such patients.There is no established standard treatment for patients with MTX-LPD. Similar to the present patient, the patient in that report was EBER-positive and EBNA-positive.It is generally believed that the withdrawal of MTX restores antitumor immunity with resulting tumor necrosis. In other situations, necrosis can be attributed to the effects of chemotherapy or other treatment. In the present patient, pathological examination of the resected specimen revealed geographic necrosis in the tumor without MTX withdrawal. Ohkura et al reported that primary adrenal MTX-LPD became necrotic without any treatment, showing the possibility of tumor resolution without intervention. EBV-transformed B lymphocytes and EBV-infected lymphoma cells produce IL-12, a cytokine that promotes cellular immunity. IL-12 production by lymphoma cells may be involved in the spontaneous regression of EBV-infected lymphoma or lymphoproliferative disorders. A recent study that compared differences in gene analysis profiles and immunohistochemistry between DLBCL developing during MTX administration and DLBCL in the general population revealed a microenvironment with high numbers of cytotoxic T lymphocytes and M2 macrophages in MTX-DLBCL. Antitumor immune responses might occur concurrently with immunosuppression induced by MTX in some cases of MTX-LPD. Spontaneous regression has been observed in several types of malignant tumors, including low-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. These tumors appear to display spontaneous regression more frequently than other malignancies. MTX-LPD might be susceptible to spontaneous regression without intervention.In EBV-infected lymphoma or lymphoproliferation, anti-EBV immune responses are believed to induce responses against lymphoma resulting in spontaneous regression.A patient with primary hepatic EBV-positive MTX-LPD which underwent spontaneous necrosis without MTX withdrawal is reported. The relationship between MTX-LPD and spontaneous necrosis is unclear and further studies are required to characterize the types of tumors that will spontaneously regress without intervention. Understanding of the mechanisms associated with spontaneous regression may lead to development of new therapeutic approaches.The authors thank patients for their participation in this study.All authors have read and agree to publication of the manuscript.Conceptualization: Takahiko Omameuda, Hideyo Miyato.Drafting the manuscript: Takahiko Omameuda, Hideyo Miyato.Resources: Takahiko Omameuda, Hideyo Miyato.Supervision: Hideyo Miyato.Writing – original draft: Takahiko Omameuda, Hideyo Miyato.Writing – review & editing: Hideyo Miyato, Naohiro Sata, Alan Kawarai Lefor.


The family plays a key role on the development of children. One with low socioeconomic status was more likely to suffer childhood neglect, which might impact on development of self-continuity and win-win values. Using cross-sectional data from 489 participants, this study conducted a mediation model to examine the roles of childhood neglect and self-continuity between socioeconomic status and win-win values. Our results showed that childhood neglect and self-continuity fully mediated the effect of socioeconomic status on win-win values. Specifically, socioeconomic status might affect win-win values through three roles: the individual mediating role of childhood neglect, the individual mediating role of self-continuity, and the multiple mediation roles of childhood neglect and self-continuity. According to previous research, a high rate of childhood neglect was observed worldwide . The expValues were defined as wide motivational goals that guided one’s principles in life . RecentlFurthermore, SES might have a direct effect on win-win values. According to Bronfenbrenner ecosystem theory , the impThe pathways from SES to win-win values, however, were complex and multifaceted. First, self-continuity might also play the role of mediator between SES and win-win values. Self-continuity was defined as the connection between one’s self in different temporal dimensions, consisting of a fundamental aspect of identity –32. AccoThe aim of this study is to investigate the mediating roles of childhood neglect and self-continuity in the effect of SES on win-win values via structural equation modeling (SEM). Specifically, the present study proposed the following hypotheses: H1. Childhood neglect mediated the effect of SES on win-win values; H2. Self-continuity mediated the effect of SES on win-win values; H3. Childhood neglect and self-continuity played multiple mediating roles between SES and win-win values.M = 20.72, SD = 1.43). This study was approved by the Research Ethics Committee of the Faculty of Education of Henan University. The participants provided their written informed consent to participate in this study.Participants were recruited from three universities by cluster random sampling in Henan province in China. A total of 575 questionnaires were distributed, and all participants completed the questionnaire in the classroom. After excluding invalid questionnaires , data of 489 participants  remained. Their ages ranged from 17 to 26 years , parental occupation , and gross monthly family income (CNY) .Z-scores of parental education level, parental occupation, and gross monthly family income  self-report version of the neglect dimension extracted from the childhood trauma questionnaire (CTQ-SF) compiled by Fink and Bernstein , and ChiChildhood neglect scale included two dimensions: Emotional neglect and physical neglect . Participants scored each item on a 5-point Likert-type scale . The total scores per subscale ranged from 5-25, with the total scores ranging from 10 to 50. The Cronbach’s alpha coefficient of the childhood neglect scale in the current sample was 0.857.The self-continuity questionnaire  consisteParticipants completed the win-win scale  to asses2/df), root mean square error of approximation (RMSEA), comparative fit index (CFI), Tucker-Lewis index (TLI), and standardized root mean square residual (SRMR). In general, χ2/df should not exceed 3, RMSEA should be smaller than 0.08, CFI and TLI should be higher than 0.90, and SRMR should be smaller than 0.05 .In our structural equation model, gender and age were controlled as covariates. Before testing the mediation model, we conducted a structural equation modeling test on the relationship between SES and win-win values. The results showed that SES significantly predicted win-win values . ps < 0.05) except for the direct path from SES to win-win values.Then, we carried out a test of the mediation model. This model produced appropriate fit indices . First, chronic poverty was a significant risk factor for child neglect . Low SESWe found that self-continuity played a fully mediating role between SES and win-win values. The result confirmed our second hypothesis (H2). Additionally, our study revealed that childhood neglect and self-continuity played multiple mediating roles between SES and win-win values. The result confirmed our third hypothesis (H3). People from disadvantaged environments  were more likely to have experienced trauma . Trauma-exposed people tended to experience a wide range of negative outcomes  . Low selThere are some limitations in this study. Our data collection and study design were cross-sectional. We cannot obtain causal effect among these variables, so causal interpretation should be cautious here. Moreover, in the present research, we focused solely on the mediating roles of childhood neglect and self-continuity. Future research could investigate other mediator or moderator variables to explore the influence adverse childhood experiences on the relationship between SES and win-win values in depth. Finally, we did not explore the differences between individuals who had suffered other childhood adversities  and individuals who suffered childhood neglect. This issue should be explored in future studies.We concluded that socioeconomic status might influence win-win values by childhood neglect and self-continuity. Childhood neglect and self-continuity played multiple mediating roles between SES and win-win values.Our study shed light on the mediating roles of childhood neglect and self-continuity between SES and win-win values, and thus confirmed the indirect mechanisms of SES effect on win-win values. First, low SES affected an individual’s experiences that brought childhood neglect, and indirectly affected an individual’s values. Second, low SES individuals who suffered physical and emotional neglect would be difficult to develop high self-continuity, and so their win-win values might be impacted. These results extended previous studies between SES and values.At the same time, our results also suggested that low SES remained a significant risk factor for individual development. It was also prone to cause a series of subsequent problems of development. These problems would influence self-continuity and win-win values. Furthermore, values were meaningful predictors of mental health , we coulThe 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 Research Ethics Committee of the Faculty of Education of Henan University. The participants provided their written informed consent to participate in this study.FZ and SZ contributed to conception and design of the study. XG performed the statistical analysis. SZ wrote the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.