Although coexistence with wildlife is a key goal of conservation, little is known about it or how to study it. By coexistence we mean a sustainable though dynamic state in which humans and wildlife coadapt to sharing landscapes, where human interactions with wildlife are effectively governed to ensure wildlife populations persist in socially legitimate ways that ensure tolerable risk levels. Problems that arise from current conflict‐oriented framing of human–wildlife interactions include reinforcing a human–nature dichotomy as fundamentally oppositional, suggesting coexistence requires the absence of conflict, and skewing research and management toward direct negative impacts over indirect impacts and positive aspects of living with wildlife. Human behavior toward wildlife is framed as rational calculus of costs and benefits, sidelining emotional and cultural dimensions of these interactions. Coexistence is less studied due to unfamiliarity with relevant methodologies, including qualitative methods, self‐reflexivity and ethical rigor, and constraints on funding and time. These challenges are illustrated with examples from fieldwork in India and Africa. We recommend a basic approach to case studies aimed at expanding the scope of inquiries into human–wildlife relations beyond studies of rational behavior and quantification of costs and benefits of wildlife to humans. Humans and wildlife are increasingly coming into contact due to climate change, habitat conversion, and species recovery and reintroductions. Thus, it is urgent to facilitate coexistence with wildlife in shared multiuse landscapes. Coexistence is, however, too seldom defined and rarely studied. In this essay, we define coexistence and then discuss why current framings of human–wildlife relations focused on conflict hinder the study of coexistence. We provide recommendations for reconceptualizing coexistence, and for studying coexistence, based on our fieldwork in India and South Africa.coexistence has become more prominent in conservation science  dimension here. Coexistence does not imply there is no risk; rather, it requires tolerance of risks and the management of risks such that they remain within tolerable limits. Effective institutions and social legitimacy allow for management actions to deal with the inevitable challenges—for humans  and wildlife —when they occur  is not new  is regarded as passive and less directly linked to action or behavior than intolerance. Seeing wildlife as a hazard suggests people formulate their judgements of the acceptability of these animals in accordance with the perceived risks and benefits associated with living alongside them. Although Bruskotter & Wilson  acknowleWe do not suggest this is not important and interesting work. We do suggest that the framework used is oriented to negative impacts and relationships predicated on rational calculus of costs and benefits. This line of thinking permeates recent ideas on coexistence. In a special section of this journal on human–wildlife conflict and coexistence, König et al.  provide The emphasis across the special section (12 articles) is mostly on reducing damages, involving relevant stakeholders in management, and providing co‐benefits calculated within a cost–benefit framework  negative interactions. Although both risks and benefits are in the frame, this conception still obscures reasons for coexistence that are not directly related to the costs or benefits of living with particular wild animals. It is also better suited to scenarios involving charismatic species or those with commercial potential in iconic landscapes where economic benefits really count. This partial view focuses on conservation goals and outcomes and excludes dimensions not relevant to this framing. It also implies an overly rational and universal view of human decision‐making.Possibly influenced by a much‐cited paper by St John et al. , conservResearch by psychologists shows that human decision‐making is not primarily or even most frequently rational, however. This is especially the case when it comes to infrequent, vivid, and traumatic events. Neurological research shows that “the emotional brain” responds to sensory inputs faster, and more simply, than the neocortex or “rational brain”  to address both rational and emotional dimensions of human responses to wildlife has been an important development in human–wildlife relations studies  that conflicts arise. It is also where coexistence is found. We agree with König et al.  that conA key challenge is to approach human–animal relations within a coherent conceptual and interdisciplinary framework, rather than splitting it into studies of human dimensions by ethnologists and of wildlife by ethologists and ecologists. We agree with Carter and Linnell :575 thatOur conception of coexistence assumes wild animals have the capacity to adjust to human presence in the landscape; it is not only humans who can adapt. This capacity can be individual and social. Brakes et al.  and KühlThe challenge is to identify and delineate the communities of cross‐species interest—rather than focus as Brakes et al. :1034 sugLestel et al.  object tattraction, habituation, sensitization, tolerance, and avoidance—and to consider the value judgments attached to these terms  results in a reduction in response in individual wild animals because they learn there are neither costs nor benefits to the presence of humans  that have no external indicators  are seldom provided (interviews recorded rigorously as data). Transcriptions of interviews or focus groups are seldom referred to. Methods sections are silent on the social contexts in which data were collected, by whom, and how this could have influenced the information gathered.Self‐reflexivity is an important dimension of field research, particularly research on sensitive topics such as human–wildlife conflict and coexistence. Sometimes noted, it is seldom explored in depth. In essence, it refers to researchers reflecting on their identity and how this positions them (and results in them being positioned) relative to their interviewees . Not doing so, however, and arriving with preformulated ideas and prestructured research instruments seriously compromises researchers’ abilities to discover concepts and questions they had not already thought of. Conceptually, ethnographic researchers try to avoid preconceptions and biases in questions and analyses based on predetermined categories and theoretical perspectives.victims, perpetrators, or demographic variables. This work requires giving the care and attentiveness to people that naturalists give to observing nature.Studying coexistence requires slow research and a willingness and capacity to listen carefully to and learn from others. It requires researchers to take the time to approach communities appropriately, get the necessary permissions, make good contacts, win peoples’ trust, learn about their lives beyond just how they interact with wildlife, and above all empathize with them. Interviewees are individuals with unique biographies; they are not simply It is remarkable how little attention has been paid to the experiences of (and posttraumatic effects on) people involved in life‐changing encounters with wild animals, including attacks and disastrous losses of livestock, food, or crops .It is not sufficient to gather demographic information on, for example, gender, age, or caste without understanding how these dimensions influence social interactions, including focus groups and interviews. Caste, for example, is a complex and fluid concept that nevertheless shapes social interactions in rural India de Zwart . Access Crocodylus palustris), the diversity of interview situations became quickly apparent. Very seldom were we alone with our select interviewee: relatives and friends would be present, and passers‐by would join in. Retaining focus on the person of interest, particularly if young or female, was challenging. If an elder or senior relative, a higher caste individual, or men  were present, they tended to dominate conversations and inhibit some interviewees. In some rural communities, women are reluctant to speak to unfamiliar males. It makes sense to work in a team of men and women.Traveling around the districts of Kheda, Anand, and Vadodara in Gujarat, meeting locals known to A.V. and crocodile expert Raju Vyas from a prior survey of interactions with mugger crocodiles .sarpanch (mayor). In northeastern Vadodara District, we were told that scheduled castes were barred from some crocodile exclusion enclosures.Locals from different castes interacted with us differently. Some Darbar men  were confident and challenging, whereas some Waghari caste  were diffident. We were told that the Waghari community  in a certain village were responsible for problems with crocodiles because they sacrifice animals and put the waste in the village pond. Community members denied this, as did the village In northern KwaZulu‐Province, South Africa, S.P. interviewed a family where the adult son was killed by a leopard. The consequences of his inability to complete paying his bride price tore the family apart. His wife's family took his 2 middle children hostage until the remaining cattle were provided. It took 3 field visits to secure an informal conversation with the investigating official. He had evaded us for fear the details would be misreported in the press. Such actual and potential indirect consequences of the impacts of wildlife on humans, for victims and for others involved—which continue after the incident—are seldom explored . Dimensions include histories of land use and community–conservation interactions and consideration of the lives and interactions of humans and animals.Having identified the key concerns and motivations of those involved through a collaborative process and clearly defined what is to be described and explained, focused field research can commence. Investigations radiate out from the identified key effects of conflict and coexistence, back in time and outward in space, to reveal a widening circle of causes. Explanatory theories to be tested, including consideration of counterfactuals, emerge from the data ; cultures of  rescuing problem animals; levels of natural history knowledge about mugger behavior and perceptions of population trends; extent and nature of shared use of waterbodies; attacks on people or livestock; apparent differences in the behavior of muggers (mostly) resident in ponds and dams (where coexistence exists) compared with river mugger (where most conflicts arise); histories of interactions of forestry officials, locals, and nongovernmental organizations over bite incidents; and traumatic individual experiences. Comparative work on scenarios where coexistence exists and scenarios where conflicts are predominant will enable a fuller appreciation of factors influencing either outcome.Studying coexistence where it exists, in diverse social, cultural, and ecological contexts, with appropriate methodologies and research instruments, will widen understanding of the ways in which humans and wildlife coexist. It will reveal to what degree (in particular places) coexistence requires that people do not act (show tolerance) and to what degree coexistence requires action .Not subordinating coexistence studies within a conception of human–wildlife interactions dominated by conflict studies, not being preoccupied with quantification of direct impacts and costs and benefits, and not universalizing Western values systems will allow exploration of novel dimensions of coexistence. These dimensions will include some not encompassed by theories of behavior focused on rational decision‐making. Historical research, human–animal studies and ethnographies, and exploring the psychology of traumatic events and the work that diverse cultural traditions do in responding to them all offer promising ways forward.Fieldwork interviews, background information, and table of interviewees (Appendix S1) is available online. The authors are solely responsible for the content and functionality of these materials. Queries  should be directed to the corresponding author.Click here for additional data file.


Background and Objectives: Rotator cuff disease (RCD) is a prominent musculoskeletal pain condition that spans a variety of pathologies. The etiology and precise diagnostic criteria of this condition remain unclear. The current practice of investigating the biochemical status of RCD is by conducting biopsy studies but their invasiveness is a major limitation. Recent biochemical studies on RCD demonstrate the potential application of serological tests for evaluating the disease which may benefit future clinical applications and research. This systematic review is to summarize the results of available studies on serological biochemical investigations in patients with RCD. Methods: An electronic search on databases PubMed and Virtual Health Library was conducted from inception to 1 September 2021. The inclusion criteria were case-control, cross-sectional, and cohort studies with serological biochemical investigations on humans with RCD. Methodological quality was assessed using the Study Quality Assessment Tool for Observational Cohort and Cross-sectional studies from the National Heart, Lung, and Blood Institute. Results: A total of 6008 records were found in the databases; of these, 163 full-text studies were checked for inclusion and exclusion criteria. Nine eligible studies involving 984 subjects with RCD emerged from this systematic review. The quality of the studies found ranged from poor to moderate. In summarizing all the studies, several fatty acids, nonprotein nitrogen, interleukin-1 β, interleukin-8, and vascular endothelial growth factor were found to be significantly higher in blood samples of patients with RCD than with control group patients, while Omega-3 Intex, vitamin B12, vitamin D, phosphorus, interleukin-10, and angiogenin were observed to be significantly lower. Conclusions: This is the first systematic review to summarize current serological studies in patients with RCD. Results of the studies reflect several systemic physiological changes in patients with RCD, which may prove helpful to better understand the complex pathology of RCD. In addition, the results also indicate the possibility of using serological tests in order to evaluate RCD; however, further longitudinal studies are required.  Rotator cuff disease (RCD) spans a variety of pathologies including rotator cuff (RC) tendon impingement in the subacromial space, partial tendon tears, full-thickness tears, and cuff tear arthropathy . RCD is The etiology and precise diagnostic criteria of this condition are still unclear. Recently, multiple studies have observed significantly elevated levels of pro-inflammatory mediators in biopsies of rotator cuff tendons in patients with RCD ,6, indicSerological investigation is a more convenient, lower cost, less time-consuming, and less invasive means to evaluate systemic bio-physiological changes. Increasing evidence supports serological investigation for RCD, and raises the prospect of using serological biomarkers in monitoring the responsiveness of RCD to current treatments. At present, it remains unclear if any specific biomarker can reflect disease status, severity, and clinical implications. The aim of this systematic review is to summarize recent findings from available serological biochemical studies in patients with RCD compared to people without shoulder pathologies.This systematic review was conducted following procedures in the Cochrane Handbook , and theTo summarize and update available reports on physiological changes in patients with RCD, a literature search using electronic search engines PubMed  and Virtual Health Library  was conducted from inception to 1 September 2021. The language of articles chosen was limited to English only. The keywords and search strategy used are detailed in Student Design—inclusion criteria were case-control studies, cross-sectional studies, or cohort studies.Population—subjects of the studies comprised adult (>18 years old) humans with RCD, including diagnosis of RC tendinopathy, shoulder impingement, subacromial bursitis, and RC tears. The diagnoses of RCD were confirmed by radiological or surgical examinations. Study populations involving other shoulder pathologies such as fractures, frozen shoulders, and shoulder joint dislocations were excluded. Subjects with other systemic conditions or comorbidities which could affect the outcomes were excluded. In addition, the studies were accompanied by suitable control groups without pathologies in the shoulders or without systemic conditions such as inflammatory joint disease and without immunological or neoplastic disorders. All animal studies were excluded.Outcomes—the studies needed to have outcome measures that could objectively quantify physiological biomarkers in blood samples of the subjects. Studies that lacked statistical analyses to compare their outcomes with were excluded.https://access.clarivate.com, accessed on 6 September 2021) for duplication elimination. Based on the inclusion criteria, abstracts and titles were primarily screened by two independent reviewers (CL and BL), followed by screening of the full-text articles. A third reviewer (SN) resolved disagreements. Reviewer CL is a physiotherapist with more than 15 years of clinical experience, a masters degree with research training, and more than 10 years of experience in musculoskeletal clinical research. Reviewer BL is a researcher with a PhD degree in immunology and more than 25 years of research experience in biomarkers and inflammatory diseases. Reviewer SN is a researcher with a PhD degree in physiotherapy with specialized training in epidemiology and biostatistics, plus more than 15 years of research experience in exercise physiology. Manual searching of included studies’ reference lists was performed to identify additional eligible studies. Meta-analysis was planned to determine if selected articles have comparable outcome measures.Search records were imported into the referencing website EndNote Web . This assessment tool consists of 14 questions to evaluate each study’s internal validity and risks of selection bias, information bias, measurement bias, or confounding bias. Quality and risk of bias assessment were conducted by two reviewers (CL and BL) individually. Any inconsistent results were discussed and resolved together with the third reviewer (SN).Selected articles were appraised on quality using the Study Quality Assessment Tool for Observational Cohort and Cross-sectional studies from the National Heart, Lung, and Blood Institute (Data were extracted from selected papers by one reviewer (CL) and checked by a second reviewer (SN) using a piloted table designed by the authors. The data included study design, demographics of the subjects, sample size, diagnosis for RCD, types of serological measures, results, and statistical analysis. If data in a selected study were missing or not clear, its authors were contacted to request details. The primary focus of the results was on identifying differences in the average levels of serological biomarkers between study groups and control groups in addition to statistical significances, if any.The process flow of initial search results, screening, inclusion, and exclusion of full texts is illustrated in Characteristics of the included studies are presented in The levels of fatty acids, nonprotein nitrogen, interleukin-1β, IL-8, and VEGF were significantly higher in the blood samples of patients with RCD than those in the control group. In contrast, the levels of Omega-3 Index, vitamin B12, vitamin D, phosphorus, IL-10, and ANG were significantly lower. Although Hallgren et al. (2012) found elevated plasma levels of TIMP-1 in their study group, the result is uncertain because of differences reported between the investigations by Luminex and ELISA methods . Other bAccording to the Levels of Evidence for Prognostic Studies, the nine included studies were level III evidence . AssessmResults of RCD immunologic biomarker studies through biopsy show significant increases in pro-inflammatory markers cyclooxygenase COX-1 and COX-2, TNFα, IL-1β, IL-6, hypoxia-inducible factors (HIFs), VEGF, and degenerative enzymes MMP-1, MMP-9, and MMP-13 in patients with RCD ,42,43,44p < 0.01), average microvascular density , and visual analog scores . VEGF is a pro-inflammatory substance and signal protein that is produced by endothelial and mesothelial cells which can be found in blood vessels and internal organs [Importantly, Savitskaya et al. (2011) observed that changes in serum levels of IL-1β, IL-8, VEGF, ANG, and IL-10 are statistically significant and specific in distinguishing between patients with RCD and control subjects . As statl organs ,47,48. Il organs ,49,50. Tp = 0.03) [p = 0.006) for degenerative RC tears. Summarizing the results from Savitskaya et al. (2011), Park et al. (2018), Hudek et al. (2019), and Kim et al. (2021), we propose the hypothesis that the pathological mechanism of RCD may involve systemic inflammatory components. These substances correlate with diverse metabolic factors such as body composition, age, diet, and exercise habits. Further investigation is required in order to determine the exact pathological mechanism between these substances and RCD as well as their usefulness as specific indicators for detecting or monitoring RCD.Hypo-HDLemia was found to have a significant odds ratio of 2.17 when comparing patients with RCD to the control group . This fi = 0.03) . These r = 0.03) . In Kim  = 0.03) . In addip = 0.035) [A lower HDL level was statistically correlated with RCD   but its = 0.035)  but the = 0.035) . Further= 0.035) . Other fp = 0.012) and low-density lipoprotein  in the group with revision surgery [p > 0.05) [Although several recent studies did not meet the inclusion criteria of this systematic review as a result of their methodologies, their results provide important insights. Hedderson et al. (2020) investigated plasma samples of patients with acute (<48 h) shoulder muscle injuries not specific to RC. In contrast to Savitskaya et al.’s (2011) study which reported significantly lower levels of serum IL-10 in patients with RCD, significantly higher levels of plasma IL-6 and IL-10 were reported in Hedderson et al.’s (2020) study ,57. Thei surgery . The fin > 0.05) . Therefo > 0.05) .In addition to the inflammatory markers and biochemical substances mentioned in this review, a recent study has shown the presence of estrogen and progesterone receptors in supraspinatus tendon biopsies of patients with RCD . TherefoSerological assessment for biomarkers is convenient and less invasive than biopsy studies; however, techniques based on Enzyme-Linked Immunosorbent Assays (ELISA) may only be available in specialized laboratories, often at high costs. The use of biosensors such as electrochemical, optical, quartz crystal microbalance, and wearable biosensors can provide more rapid, non-invasive ways to detect nucleic acids, enzymes, antibodies, and peptides . Such teOverall, the number of serological studies included in this review is less than the previous review on biopsy studies ,6. For aIn most of the included studies diagnosis of RCD was confirmed by MRI, but in the study conducted by Hallgren et al. (2012), diagnosis was verified by sonographic examination . FurtherAs mentioned, several immune biomarkers were found to be elevated in the biopsy samples of RCD patients including COX-1, COX-2, TNFα, and HIFs, and should be considered for further serological studies. Additional longitudinal research on blood biomarkers including VEGF, ANG, IL-1β, IL-8, and IL-10 may determine their relevance as suitable and sensitive biomarkers in monitoring RCD disease status.This is the first systematic review to summarize the case-control and cohort studies of serological investigations in RCD patients. The results of the included studies demonstrate significant changes in the levels of some biochemical substances in blood samples of RCD patients. The findings indicate systemic changes occurring in patients with RCD, and the review’s results provide new insights in understanding the complex pathology of RCD. Secondly, the results suggest serological tests for certain biochemical substances can be possibly applied clinically to monitor the status of RCD, which could be helpful in management plans. Further longitudinal studies are expected to evaluate further the usefulness and sensitivity of serological tests for RCD.


A similar representation of the dead-zone operators is also described. With the proposed digitized representation, the model is more intuitive and the inversion calculation is avoided. An experiment with a piezoelectric stacked linear actuator is conducted to validate the proposed digitized MPI hysteresis model and it is shown that it has almost the same performance as compared to the classical representation.Piezoelectric actuators are widely used in micromanipulation and miniature robots due to their rapid response and high repeatability. The piezoelectric actuators often have undesired hysteresis. The Prandtl–Ishlinskii (PI) hysteresis model is one of the most popular models for modeling and compensating the hysteresis behaviour. This paper presents an alternative digitized representation of the modified Prandtl–Ishlinskii with the dead-zone operators (MPI) hysteresis model to describe the asymmetric hysteresis behavior of piezoelectric actuators. Using a binary number with  Piezoelectric actuators are widely used in micromanipulation applications due to their rapid response and high repeatability, for example, microsurgical robots ,2, autofVarious methods have been proposed for modeling and compensating the hysteresis behavior. The existing methods can be classified into physics-based models and phenomenology-based models . PhysicsThe phenomenology-based model can also be roughly divided into three main groups : differeThe PI hysteresis model is one of the most popular models because of its simple implementation and analytical inversion . Ang 2929 concluIn the above literature, the design procedure generally consists of parameters identification of the description model and the construction of the inverse model as a desired compensator. The mathematical complexity of the identification and inversion problem depends on the selected modeling approaches . The amoIn this paper, we present an alternative digitized representation with which the inverse model can be easily constructed to compensate for the hysteresis behavior. The inversion calculation is avoided. The proposed representation is also more intuitive due to the geometric meanings of the parameters of the operators.The paper is organized as follows: This section describes the classical representation and an alternative digitized representation of the classical PI hysteresis model. A similar representation of the dead-zone operators is also described, the construction of the inverse model with the proposed representation is also presented.ith elementary operator, ith elementary operator, n is the number of the elementary operators and ith elementary operator.The classical PI hysteresis model has a series of elementary operators, the system output can be obtained by a weighted sum of n elementary operators with different thresholds. As shown in When the parameter  follows :(3)yk=∑in segments, the value of the kth segment can be calculated using the following equation:The As The value of The paired property n digits. Each digit of the binary number is a elementary operator with a binary state that can be either 0 or 1. Each elementary operator H of a PI hysteresis model with n elementary operators can be expressed in one equation:The state of the classical PI hysteresis model with n operators is represented with a binary number A digit, let the least significant digit with a binary state of 1 at the current state be the Z digit.The model also has a paired property When the state of the system changes to its upper neighbor, the binary state of the Similarly, when the state of the system changes to its lower neighbor, the binary state of the The traditional PI hysteresis model with n elementary operators has x with the current state When the system input is changed to x, is greater than or equal to 1. If the system input value, ed using .x, is greater than 2. If the system input value, ed using  and 13)x, is grex, is less than 3. If the system input value, ed using .x, is is less than 4. If the system input value, ed using  and 15)x, is is C. The n paired properties can be used to help describe the values of the n dead-zone operators as shown in , is modeled using the classical representation as well as the proposed representation. Two experiments have been performed. The first experiment is to identify the parameters and to model the hysteresis behavior of the piezoelectric actuator. The second experiment is to test the performance of the proposed representation deploying the inverse model as a feedfoward compensator.As seen from The hysteresis behavior of the piezoelectric stacked linear actuator under periodic control inputs is recorded. The parameters of the digitized representation and the classical representation of the modified PI model with the dead-zone operators are then identified with The inverse model is constructed and is then applied to compensate for the hysteresis behavior of the system at a changing amplitude sinusoidal wave with Experimental results show that the proposed digitized representation performs almost the same as the classical representation while modeling the hysteresis behavior of the piezoelectric stacked linear actuator. This is because the digitized representation is derived from the classical representation and the two representation are equal mathematically. With n. The parameters of the proposed representation is also more intuitive with their geometric meanings; this may help with the parameters identification. The proposed representation is more intuitive and may be easier to be modified further.With the proposed digitized representation, the construction of the inverse model is less mathematically complicated and this improvement may be significant with a large value of The proposed digitized representation is an alternative to the classical representation. The inverse model can be easily constructed with the proposed representation and the inversion calculation is avoided. The proposed representation is also more intuitive. The proposed representation and its inverse model are validated with description and compensation experimental results.


Neuropsychological studies have demonstrated that the preferential processing of near-space and egocentric representation is associated with the self-prioritization effect (SPE). However, relatively little is known concerning whether the SPE is superior to the representation of egocentric frames or near-space processing in the interaction between spatial reference frames and spatial domains. The present study adopted the variant of the shape-label matching task  to establish an SPE, combined with a spatial reference frame judgment task, to examine how the SPE leads to preferential processing of near-space or egocentric representations. Surface-based morphometry analysis was also adopted to extract the cortical thickness of the ventral medial prefrontal cortex (vmPFC) to examine whether it could predict differences in the SPE at the behavioral level. The results showed a significant SPE, manifested as the response of self-associated color being faster than that of stranger-associated color. Additionally, the SPE showed a preference for near-space processing, followed by egocentric representation. More importantly, the thickness of the vmPFC could predict the difference in the SPE on reference frames, particularly in the left frontal pole cortex and bilateral rostral anterior cingulate cortex. These findings indicated that the SPE showed a prior entry effect for information at the spatial level relative to the reference frame level, providing evidence to support the structural significance of the self-processing region. However, individuals had a different preference weight for the frame of reference. Evidence from behavioral and neuropsychological studies has supported that individual preferentially adopt different reference frames to represent spatial information in different depth locations7.The ability to represent surrounding spatial information is an essential requirement of living beings because individuals must represent spatial orientation information at all times in the real three-dimensional world. Generally, different spatial representation strategies have been used to represent spatial orientation information as quickly and accurately as possible9. According to the perception/action model, the dorsal stream transforms visual information into sensorimotor representation and the ventral stream transforms visual information into perceptual representation11. Therefore, the dorsal stream is implicated in near-space processing when individuals conduct an action and manipulation representation, and the ventral stream is implicated in far-space processing when individuals conduct a perception representation11. However, extant studies suggested that the differential activations in the dorsal/ventral stream associated with near space and far space processing were independent of the type of task but related to the frame of reference15. Evidence from clinical studies has shown that egocentric representation is usually transformed into the corresponding sensorimotor representation through the dorsal stream and the allocentric representation is usually transformed into the corresponding perceptual representation through the ventral stream19. For instance, it has been proved that patient with a damaged ventral stream had a poor performance on an allocentric task; likewise, a patient who injured the dorsal stream had a poor performance on an egocentric task21. Based on the perception/action model, egocentric representation and near-space shared a common neural mechanism ; similarly, allocentric representation and far-space shared common a neural mechanism . Therefore, theoretically, individuals are prone to use egocentric references in near space and allocentric references in far space.Previous studies have suggested that the space domain is divided into near (within the range of the arm) and far (beyond the range of the arm) spaces based on the hand-reaching distance22. For example, Chen and colleagues4 found that participants preferred egocentric representation, with a faster response in egocentric tasks regardless of near or far space. Additionally, the fMRI results by Chen and colleagues revealed that the parietal-occipital junction (POJ) shows enhanced neural activity in near-space processing, indicating a near-space preference. The study of Wang et al.7 further supported the view that the POJ acts as an interface between the dorsal and ventral streams in near and far space processing, showing higher activity to the target in near space than in far space. Therefore, individuals actually showed a priority for near-space processing and egocentric representation when reference frames interacted with spatial domains.Nevertheless, studies on the interaction between spatial domains and reference frames have found that individuals show processing precedence for egocentric presentation and near-space processing26. Briefly, the objects in the near space could automatically attract attention compared to those in far space30. For instance, Cosman and Vecera27 implied that individuals took precedence to process objects in near space because of the processing order determined by attention. Therefore, due to the high attention priority and strong self-relevancy of objects in near space, individuals tend to show a self-prioritization effect (SPE) in near-space processing. SPE is the phenomenon in which individuals focus on self-related information or objects and respond faster (or more accurately) relative to information associated with others34, such as the self-face advantage effect35 and self-reference effect39.Because objects that unexpectedly approach the observer have higher self-relevancy and farther unexpected objects involve less self-related thoughts, previous studies have indicated that attentional reorientation along 3D space involves self-related processing51 and found a faster response of self-association pairings than stranger-association pairings and higher activation of the ventral medial prefrontal cortex (vmPFC) in self-referential processing55. Existing studies suggested that the self gave priority not only to near-space processing but also to egocentric representation44. Specifically, participants tended to adopt an egocentric bias (self-reference bias) to represent internal representation, as reflected in the priority of the SPE for egocentric representation55, which might be because individuals were prone to perceive scenes from a first-person perspective57. It was suggested that taking an embodied perspective  could enhance the self-bias in perceptual matching43. In addition, from the view of the cognitive map, the flow of allocentric representation through ownership to the self  requires more brain regions than that of egocentric representation 2. Altogether, the self had a higher priority for the information of near-space processing and egocentric representation.Currently, converging studies have established the SPE using a shape-label matching taskConsidering the role of the SPE in near space processing and egocentric representation, the present study was specifically designed to address how the SPE controls the interaction between spatial domains and spatial reference frames. Specifically, participants addressed the conflict between performing allocentric visuospatial judgments in near space and egocentric visuospatial judgments in far space. Addressing this issue would allow a better understanding of the priority of the SPE and clarify the role of the SPE within the real 3D spatial domain. In the present study, all the participants were randomly assigned to either the self-association group or stranger-association group, and both groups were required to complete the spatial reference frame task in near and far spaces. The self-association group only needed to respond to the self-associated object, while the stranger-association group only needed to respond to the stranger-associated object. To further investigate whether the cortical thickness of self-processing regions could predict the SPE on spatial reference frames, we set the vmPFC as a region of interest (ROI) and extracted the cortical thickness of the vmPFC using surface-based morphometry analysis to correlate with the performance in the spatial reference frame task. We hypothesized that the SPE could affect the performance of egocentric representation and near-space processing in the self-association group and showed a preference for the process of the object in near space, followed by egocentric representation. Additionally, the cortical thickness of the vmPFC might be correlated with the performance of near-space processing and egocentric representation.To ensure that the samples were representative and unbiased, nine participants were excluded from the statistical analysis because they had low accuracy (lower than 90%) in the spatial reference frame judgment task, possibly because of the lack of attention or motivation during the experiment. Because the overall accuracy of all the participants was high , the present study focused more on reaction time (RT) in the statistical analysis  = 11.10, p = 0.001, ηp2 = 0.10, and the RTs of the self-association group (592 ms) were faster than those of the stranger-association group (645 ms), indicating a significant SPE in the self-association group. The main effect of spatial domains was not significant, F < 1. The main effect of reference frame judgment tasks was significant, F = 35.02, p < 0.001, ηp2 = 0.27, and the RTs of the allocentric judgment task (604 ms) were significantly faster than those of the egocentric judgment task (633 ms). The interaction effect between groups and spatial domains was significant, F = 61.70, p < 0.001, ηp2 = 0.39. The interaction effect between groups and reference frame judgment tasks was significant, F = 4.89, p = 0.03, ηp2 = 0.05. The interaction effect between the spatial domains and reference frame judgment tasks was not significant, F = 1.12, p = 0.29. The three-way interaction effect among groups, spatial domains, and reference frame judgment tasks was significant, F = 4.59, p = 0.04, ηp2 = 0.05. To investigate the potential interaction between ownership groups and reference frames in near and far spaces, further simple effect analyses should be conducted.For the RT data, 2 (groups: self-association vs. stranger-association) × 2  × 2  mixed ANOVA was conducted see Fig. . The maiF = 25.57, p < 0.001, ηp2 = 0.33, and the RTs of near-space processing (579 ms) were significantly faster than those of far-space processing (606 ms). The main effect of reference frame judgment tasks was significant, F = 6.35, p = 0.02, ηp2 = 0.12, and the RTs of the allocentric judgment task (583 ms) were significantly faster than those of the egocentric judgment task (602 ms). The interaction effect between spatial domains and reference frame judgment tasks was not significant, F < 1. To examine whether the participants performed better in allocentric judgment tasks in near space or egocentric judgment tasks in far space, a paired sample t test was conducted in the self-association group. The RTs of the allocentric judgment task in near space (571 ms) were faster than those of the egocentric judgment task in far space (617 ms), t(50) = 5.02, p < 0.001, Cohen’s d = 0.56. For the stranger-association group, the main effect of spatial domains was significant, F = 38.62, p < 0.001, ηp2 = 0.45, and the RTs of near-space processing (629 ms) were faster than those of far-space processing (660 ms). The main effect of reference frame judgment tasks was significant, F = 36.16, p < 0.001, ηp2 = 0.43, and the RTs of the allocentric judgment task (624 ms) were faster than those of the egocentric judgment task (665 ms). The interaction effect between spatial domains and reference frame judgment tasks was significant, F = 4.24, p < 0.045, ηp2 = 0.08. Further analysis found that the RTs of the allocentric judgment task (636 ms) were faster than those of the egocentric judgment task (685 ms) in far space, F = 34.41, p < 0.001, ηp2 = 0.42, and the RTs of the allocentric judgment task (613 ms) were also faster than those of the egocentric judgment task (645 ms) in near space, F = 19.66, p < 0.001, ηp2 = 0.29, exhibiting faster allocentric processing. These findings indicated that individuals showed a preference for allocentric representation in near space compared with egocentric representation in far space.First, to examine the role of groups in the three-way interaction effect, 2  × 2  repeated ANOVA was conducted in the self-association group and stranger-association group. For the self-association group, the main effect of spatial domains was significant, F = 12.57, p = 0.001, ηp2 = 0.12, and the RTs of the self-association group (602 ms) were significantly faster than those of the stranger-association group (665 ms). The main effect of spatial domains was not significant, F < 1. The interaction effect between groups and spatial domains was significant, F = 41.37, p < 0.001, ηp2 = 0.30. Further analysis found that the RTs of the self-association group in near space (587 ms) were faster than those of the stranger-association group (685 ms), F = 26.68, p < 0.001, ηp2 = 0.22, and no significant difference was found in the RTs between the self-association (617 ms) and stranger-association (645 ms) groups in far space. For the allocentric judgment task, the main effect of groups was significant, F = 7.61, p = 0.007, ηp2 = 0.07, and the RTs of the self-association group (583 ms) were significantly faster than those of the stranger-association group (624 ms). The main effect of spatial domains was not significant, F < 1. The interaction effect between groups and spatial domains was significant, F = 49.42, p < 0.001, ηp2 = 0.34. Further analysis found that the RTs of the self-association group in near space (571 ms) were faster than those of the stranger-association group (636 ms), F = 18.06, p < 0.001, ηp2 = 0.16, and no significant difference was found in the RTs between the self-association (595 ms) and stranger-association (613 ms) groups in far space. The above findings revealed that the SPE strongly affected near-space processing compared with far-space processing.Second, to examine the role of reference frame judgment tasks in the three-way interaction effect, a 2 (groups: self-association vs. stranger-association) × 2  mixed ANOVA was conducted in the egocentric and allocentric judgment tasks. For the egocentric judgment task, the main effect of groups was significant, F = 2.02, p = 0.16. The main effect of reference frame judgment tasks was significant, F = 27.12, p < 0.001, ηp2 = 0.22, and the RTs of the allocentric judgment tasks (604 ms) were significantly slower than those of the egocentric judgment tasks (631 ms). The interaction effect between groups and reference frame judgment tasks was not significant, F = 1.17, p = 0.28. In the near space condition, the main effect of groups was significant, F = 25.46, p < 0.001, ηp2 = 0.21, and the RTs of the self-association group (579 ms) were significantly faster than those of the stranger-association group (660 ms). The main effect of reference frame judgment tasks was significant, F = 28.65, p < 0.001, ηp2 = 0.23, and the RTs of the allocentric judgment task (603 ms) were significantly faster than those of the egocentric judgment task (636 ms). The interaction effect between groups and reference frame judgment tasks was significant, F = 7.50, p = 0.007, ηp2 = 0.07. Further simple effect analysis showed that the RTs of the egocentric judgment task (685 ms) were slower than those of the allocentric judgment task (636 ms) in the stranger-association group, t(48) = 5.87, p < 0.001, Cohen’s d = 0.54. However, no significant difference was found between allocentric (571 ms) and egocentric (587 ms) judgment tasks in the self-association group, t(49) = 1.81, p = 0.08. To further examine whether the SPE was more beneficial for egocentric representation or allocentric representation, we obtained the reaction time difference  by comparing the RT difference between allocentric and egocentric judgment tasks in near space. The independent-sample t test results showed a significant difference between the self-association group and stranger-association group, t(97) = 2.74, p = 0.007, Cohen’s d = 0.55, and the RT difference in the self-association group (16 ms) was less than that in the stranger-association group (49 ms), indicating that the self-association group had a faster response on the egocentric judgment task in near space. These findings suggested that the SPE only benefited egocentric representation more than allocentric representation.Third, to examine the role of spatial domains in the three-way interaction effect, a 2 (groups: self-association vs. stranger-association) × 2  mixed ANOVA was conducted in near and far spaces. In the far space condition, the main effect of groups was not significant, 55. Additionally, the behavioral results benefited the SPE more on the allocentric reference frame in near space than on the egocentric reference frame in far space. Therefore, we focused on examining whether the cortical thickness of the vmPFC  could predict the preference of the SPE on reference frames.As discussed in the Introduction section, the vmPFC region is supported by self-referential materialr(50) = − 0.30, p = 0.036; other regions showed little or no significant associations with RTs of the allocentric judgment tasks (ps > 0.05). Likewise, Pearson correlation analysis showed that the thickness of the left rostral ACC was positively correlated with the RTs of egocentric judgment tasks in far space  = 0.32, p = 0.026; the thickness of the right rostral ACC was also positively correlated with the RTs of egocentric judgment tasks in far space  = 0.28, p = 0.049. A significant association was no longer found between the thickness and RTs of the egocentric judgment task (ps > 0.05).Pearson correlation analysis was conducted between the RTs of allocentric judgment tasks in near space and thickness of the vmPFC. Only the thickness of the left FPC was negatively associated with the RTs of the allocentric judgment task see Fig. a, r(50) see Fig. b, r(50) The present study used the color-label matching paradigm to establish an SPE and combined a conjunction visual search task to probe how the SPE influenced the judgment of the reference frames in different spatial domains. Participants were randomly divided into the self-association group and stranger-association group. The self-association group was required to respond to the object associated with themselves, while the stranger-association group was required to respond to the object associated with strangers. As expected, a significant SPE was found in the self-association group. Besides, the SPE showed preference processing for the allocentric reference frame in near-space compared with the egocentric reference frame in far space, revealing a preference for near-space processing, followed by egocentric representation. More importantly, correlation analysis showed a significant correlation between the cortical thickness of the vmPFC and RTs of reference frame tasks in near and far spaces, indicating that the thickness of the vmPFC could predict the difference in the SPE on reference frames.46. One point to note here is that the present study modified the associative-learning task and adopted the color-label matching task to familiarize participants and inform them about a stable color-label association, an approach that was different from the classic shape-label matching paradigm42. Yin and colleagues45 first adopted this novel color-label matching paradigm to establish a self-/friend-/stranger-association in a spatial working memory task, and participants responded faster to the working memory probes of self-associated colors than to those of friend-associated and stranger-associated colors. Recently, their following study replicated the SPE in the matching paradigm46. Thus, these findings suggest that the SPE in the self-association matching paradigm works at a conceptual level, regardless of the attribution of associated stimuli47.First, the present study found a robust SPE in the self-association group compared with the stranger-association group. More specifically, the RTs of the spatial reference frame judgment task in the self-association group (592 ms) were significantly faster than those in the stranger-association group (645 ms). In accordance with the present study, previous studies have demonstrated that self-relevance automatically enhances stimulus processing, particularly in the form of a shape-label matching paradigm42, the present study found that the SPE affected the interaction between spatial reference frames and spatial domains. More importantly, the SPE showed a preference for information of the allocentric reference frame in near space compared with the egocentric reference frame in far space. Specifically, the performance of the allocentric judgment task in near space (571 ms) was faster than that of the egocentric judgment task in far space (617 ms) in the self-association group, with performance exhibiting faster RTs. Moreover, further analysis suggested that the SPE was only observed in near-space processing, particularly in egocentric judgment tasks. Specifically, the performance of near-space processing (579 ms) was faster than that of far-space processing (606 ms) in the self-association group, and improvement of the SPE on the egocentric reference frame (16 ms) was better than that on the allocentric reference frame (49 ms) in near space. Therefore, we observed that the SPE benefited egocentric representation more based on near space, a finding that has not previously been described44. In other words, near-space precedence was observed compared with egocentric representation during the information processing between spatial-level and reference frame-level information, revealing a near prior entry effect.Second, consistent with the findings of previous studies of a close relationship among the SPE, near-space processing, and egocentric reference frame41, developing an egocentric bias to represent objects in daily lives revealed that self-related objects (information) captured more endogenous attention than unfamiliar objects45. The participants focused more on the self-related stimuli cues when they adopted the egocentric strategy in the egocentric reference frame judgment task. However, the processing of information in near space still automatically captures more attention than egocentric representation information. Many current views have posited that objects in near space tend to attract extensive attention and be processed preferentially, and objects in near space acquire high attentional priority and automatically draw exogenous attention30. For example, Abrams et al.28 argued that individuals tend to process objects in near space or those close to them because objects in near space automatically capture their attention, revealing a near prior entry effect. Furthermore, from the perspective of evolutionary psychology, the memory and visuospatial attention of humans are selective58. Focusing on stimuli in near space is important for an organism to survive and thrive, and individuals generally tend to focus on information or objects closely related to adaptability59, likely because information in near space is more urgent and threatening to individuals. In summarize, individuals had higher attention priority in the processing of near space than in egocentric representation.Here, we believe that at least three factors should be considered for this consequence. In the first place, the attention priority to objects in near space may explain this consequence. Although the self-associated stimuli assigned increased personal significance and became perceptually more salient26. Moreover, the POJ showed enhanced neural activity in near-space processing22. Furthermore, because of the urgency and immediacy of objects in near space, near-space processing showed high self-relevancy26. Chen et al. found that the default-mode network, including the posterior cingulate cortex, orbital prefrontal cortex, and left angular gyrus, showed higher activation of attentional orientation when participants completed the task in near space48. Given that the region of the POJ overlapped with self-processing regions, a common neural mechanism likely exists between the SPE and near-space processing. Thus, the SPE having a prior entry effect in near space processing is not surprising.Next, the common neural mechanism between the SPE and near-space processing may be the other possible underlying consideration. Evidence from neuropsychological studies has implied that the POJ, a neural interface for integrating and processing different kinds of information, is significantly activated when the egocentric reference frame interacts with far space and the allocentric reference frame interacts with near space47 but have not measured the action movement time. To further measure the response execution and examine whether response execution can be modulated by self-associations, Desebrock and colleagues60 combined a motor-variant shape-label paradigm with a response box to measure the reaction time and movement time of perceptual tasks and found that the SPE could modulate the response execution. Because near space has been related to action more than far space13, the arm-movement response was actually an action representation61. That is why the SPE showed more priority to the processing of near space.Afterwards, the execution of arm-movement responses may be the last consideration. Previous studies have found a performance advantage in matching the self label with an action representation62. Specifically, the thickness of the left FPC was negatively correlated with the RTs of the allocentric judgment task in near space, and the thickness of the bilateral rostral ACC was positively correlated with the RTs of the egocentric judgment task in far space, a finding that contrasted the closed relationship between the SPE and ACC. Cortical thickness measures whether the brain structure is damaged or reveals normal development in morphological analysis of brain structure66. Better development of the brain area is generally associated with a higher cortical thickness. For example, Fleming et al. indicated that the thicker the right anterior cingulate cortex was, the better the cognitive control performance64. Because of the dominance of spatial-level information processing, it is not surprising that the thicker the FPC is, the faster the response of the allocentric reference frame in near space. However, notably, the positive correlation in the present study may be due to processing conflict between the information of the spatial level and reference frame level. Many studies have demonstrated that vmPFC activity (such as the ACC) is involved in various self-processing tasks53. The present study found superiority in information processing at the spatial level compared with the reference frame level. In other words, our brains prioritized processing far space information and then processed the information of the egocentric reference frame when the egocentric judgment task was conducted in far space. Therefore, an individual with a thicker ACC will have stronger competition  in the information processing between far-space processing and egocentric representation, exhibiting slower RTs with thicker thickness.Third, regarding correlation analysis, our results supported the view that the SPE was associated with the cortical midline structure, particularly the vmPFCIn conclusion, the present study revealed that the SPE could modulate the interaction between spatial domains and spatial reference frame representation. Additionally, the information at the spatial level before the reference frame level manifested with near-space processing first, followed by egocentric representation. Furthermore, the cortical thickness of the left FPC and bilateral ACC could predict the difference in the SPE on the reference frame. These findings reveal the role of the SPE in reference frames in the real three-dimensional world and provide evidence to support the relationship between the vmPFC and the SPE in humans regarding brain structure.68. According to a previous study69, a hybrid design should have a medium effect size (f = 0.25). With α = 0.05 and power = 0.80, the appropriate sample size was calculated to be at least 82. Nine participants were excluded from the statistical analysis because of lower accuracy.A total of 108 undergraduate and graduate students  participated in the experiment. The participants were randomly assigned to the self-association group and stranger-association group, with fifty-four participants in each group. All the participants were right-handed and had normal hearing, vision (or corrected vision), and color vision, with no history of neurological or psychiatric disorders. None of the participants had participated in any similar experiment. The present study was conducted according to the Declaration of Helsinki and was approved by the Ethics Committee of Soochow University. All the participants provided written informed consent. The sample size was calculated using the G-Power 3.1 toolbox40. During the color-label matching task, the visual stimuli were presented on a laptop screen with a gray background  in E-prime 2.0 software. The visual stimuli comprised colored forks  and social labels . The black fork  and white fork  were presented above a fixation cross (0.8° × 0.8°) at the center of the screen  with a screen resolution of 1024 × 768 pixels and a refresh rate of 60 Hz. The experiment comprised a delayed match-to-sample task  and a spatial reference frame task Fig. a. The cosee Fig. b. The wo4. The spatial reference frame judgment task involved two parts. The first part was a reference frame judgment task  in near space. The second part was a reference frame judgment task in the far space. During the spatial reference frame judgment task  × 2 (matching: matched vs. not matched) within-subjects design, divided into a training stage and a matching stage. First, in the training stage, the participants were required to code colored forks (black or white) as self or stranger. Specifically, the participants were told, “you are represented by a black fork, and a stranger is represented by a white fork”. After that, the participants had to judge whether the color-label pairings were correct in the matching stage. Specifically, each trial started with the presentation of a central fixation cross for 500 ms. Next, a pairing of color and label (you or stranger) was presented for 100 ms. The participants had to determine whether the color was correctly assigned to the person as accurately and quickly as possible within the timeframe (ranging from 800 to 1200 ms). The feedback  was presented for 500 ms at the end of each trial. The participants were required to perform 240 trials over three blocks, and they were informed of their overall accuracy at the end of the block. All the participants were explicitly informed that they could only conduct the spatial reference frame judgment tasks when their overall accuracy was higher than 90%. The color-label matching task served as training to familiarize the participants with the color-label associations. All the pairing conditions were counterbalanced across participants.The spatial reference frame judgment task was a 2  × 2  × 2 (groups: self-association vs. stranger-association) hybrid design. This task had two stages. First, the participants were randomly assigned to either the self-association group or stranger-association group. The self-association group was required to judge the position of the self-associated fork, and the stranger-association group was required to judge the position of the stranger-associated fork. Both groups were provided with verbal instruction that was the same as that provided in the color-label matching task . In the egocentric judgment task, each trial started with the presentation of instructions for 3000 ms. Afterward, the stimulus (a colored fork intersecting an orange plate) was presented for 150 ms. The participants had to determine whether the self- or stranger-association fork was on the left or right side of the midline of their body by pressing the response button with the right index finger or middle finger as accurately and quickly as possible within 1500 ms. The duration of each trial was 1650 ms with a 250 ms interstimulus interval. In the allocentric judgment task, the participants were required to determine whether the fork was on the left or right side of the midline of the plate. Except for the task instruction, the procedure of the allocentric representation task was the same as that of the egocentric judgment task. The participants needed to complete 384 trials of egocentric and allocentric judgment tasks in near and far spaces. Presentation order was counterbalanced across stimuli, tasks, spatial locations, and groups. In addition, the visual angle between the near space and far space was counterbalanced across participants. To ensure that the midline of the participants was aligned with the midline of the monitor, the participants’ head position was stabilized using a chin rest throughout the experiment.The participants were scanned on a 3.0 T Magnetom Prisma scanner with a commercial 64-element sensitivity encoding head coil array. For each participant, T1-weighted volumes were acquired using a magnetization-prepared gradient echo (MPRAGE) in an MRI room .https://www.nitrc.org/projects/mricron). After that, the oriented and neck-cut T1-weighted images were processed to obtain cortical thickness measures using FreeSurfer 6.0 software. FreeSurfer provides a full processing stream for T1-weighted MR images, including the removal of nonbrain tissue, automated Talairach transform computation, intensity normalization, skull stripping, white matter segmentation, filling and cutting, smoothing, inflation, spherical registration, and cortical parcellation statistics (https://surfer.nmr.mgh.harvard.edu/fswiki).The original T1-weighted images were converted from the DICOM format to the NIfTI format using MRIcroN software . Because the vmPFC acts as an ROI, the cortical thickness of the vmPFC in the medial orbitofrontal cortex (OFC), rostral and caudal anterior cingulate cortex (ACC), insular cortex, and frontal pole cortex (FPC) of the left and right hemispheres were extracted74.Brain structure measurements for cortical thickness were obtained using the semiautomated segmentation tool FreeSurfer. Cortical thickness maps were created using both signal intensity and continuity information from the 3D volume of magnetic resonance images, where the thickness was calculated as the closest distance from a pial to the white matter boundary at each vertex


Create a new definition of near-occlusion with full collapse to predicting recurrent stroke.Pooled analysis of two studies. Patients with symptomatic ≥ 50% carotid stenoses were included. Outcome was preoperative recurrent ipsilateral ischemic stroke or retinal artery occlusion within 28 days of presenting event. We analyzed several artery diameters on computed tomography angiography and stenosis velocity on ultrasound.p = 0.047). Distal internal carotid artery (ICA) diameter, ICA ratio, and ICA-to-external carotid artery ratio were associated with the outcome. Best new definition of full collapse was distal ICA diameter ≤ 2.0 mm and/or ICA ratio ≤ 0.42. With this new definition, 36% with full collapse and 4% without full collapse reached the outcome (p < 0.001).A total of 430 patients with symptomatic ≥ 50% carotid stenosis were included, 27% had near-occlusion. By traditional definition, 27% with full collapse and 11% without full collapse reached the outcome (Defining near-occlusion with full collapse as distal ICA diameter ≤ 2.0 mm and/or ICA ratio ≤ 0.42 seems to yield better prognostic discrimination than the traditional appearance-based definition. This novel definition can be used in prognostic and treatment studies of near-occlusion with full collapse. Carotid near-occlusion is a severe carotid stenosis where the internal carotid artery (ICA) distal to the stenosis is reduced in size (“collapsed”) –3. The dGuidelines recommend conservative treatment of symptomatic near-occlusion based on trials where 94% of near-occlusion were without full collapse –5. Two sThe aim of this study was to create a new definition of near-occlusion with full collapse based on angiographic and/or ultrasound measurements, aimed at predicting preoperative recurrent ipsilateral ischemic stroke.This was a pooled individual patient data analysis of two previously reported studies , 7. The The outcome was defined the same way as in both underlying studies and major trials , 6, 7: rBoth previously published and unpublished data were available for analysis. Available data included baseline factors, recurrent events, CTA assessments, CTA measurements, and velocity data from carotid ultrasound. In Gu et al., CTAs were performed locally or at any of 11 referring hospitals, in Johansson et al., only the referring hospital. In both, various machines and clinical protocols were used for CTA. In both studies, ultrasound was performed at the local hospital. The ultrasound exams were performed by several experienced sonographers using a standardized protocol including long- and short-axis assessment of common, internal, and external carotid arteries, with color doppler, pulsed doppler in duplex mode, and power doppler. Main emphasis was assessment of highest peak systolic velocity (PSV) in the stenosis, with adjustable angle correction ≤ 60°. Various ultrasound machines were used during the studies.In Gu et al., near-occlusion was diagnosed on CTA by two observers  using an approach of systematic interpretation of features, not over interpreting anatomical variance as near-occlusion , 13. CasFive parameters were candidates for novel definitions of full collapse. Four were CTA-based: stenosis diameter, distal ICA diameter, ipsilateral to contralateral distal ICA diameter ratio (ICA ratio), and distal ICA to ipsilateral external carotid artery diameter ratio (ECA ratio). Stenosis PSV was based on ultrasound. CTA measurements were gathered by one observer (EJ) with a random selection of 49 cases measured twice for reliability analyses. Stenosis PSVs were extracted from reassessment of images by several overlapping observers. All measurement extraction was done blinded to the outcome.Individual patient data were assessed in a pooled database. The analysis was conducted in four steps. (1) We assessed if any of the five candidate parameters was significantly associated with the outcome among near-occlusions. (2) Possible thresholds of the significant parameters were assessed, balancing high sensitivity (maximum number of outcomes in the full collapse group) with having the smallest full collapse group possible. (3) Combinations of thresholds of the significant parameters were assessed in a similar fashion as in step 2. In cases with one parameter was missing, the other parameter was used alone. (4) The risk of the outcome in the traditional and new near-occlusion groups was compared with conventional ≥ 50% stenosis as reference in both unadjusted and multivariable analyses.χ2-test, one-way ANOVA, Mann–Whitney test, and Kruskal–Wallis test. Reliability of CTA measurements was assessed with two-way mixed interclass correlation (ICC) for absolute agreement. The outcome was assessed with Kaplan–Meier (with log rank test) and Cox regression, using revascularization and death as censor. Two multivariable models were assessed: one adjusting for age & sex, the other included baseline parameters and step-wise removing the co-variate with the highest p-value until all variables had p < 0.05. Two risk markers have been suggested in this context: age and type of presenting event [p < 0.05 and IBM SPSS 26.0 was used in the calculations.Where appropriate, we used 95% confidence interval (95%CI), mean, median, standard deviation (SD), interquartile range (IQR), 2-sided ng event . Age wasp = 0.047, Table There were 19 outcome events  among the 116 near-occlusions. By traditional definition, the 28-day risk of the outcome was higher in near-occlusion with full collapse (27%) than near-occlusion without full collapse  and adjusted for degree of stenosis HR 1.2  per 10-year increment, when defining full collapse as distal ICA diameter ≤ 2.0 mm and/or ICA ratio ≤ 0.42.Multivariable analyses were conducted on the traditional and two of the new full collapse definitions Table . With alp = 0.002). All but one missing PSV data was due to no ultrasound exam, the exception was due to echo shadow. Median time between presenting event and the outcome tended to be longer for those examined with ultrasound  than those not examined with ultrasound , p = 0.15.None of the near-occlusion cases with missing data of stenosis diameter or ICA ratio reached the outcome. However, 58% of near-occlusions with the outcome lacked stenosis PSV data, compared to 21% of near-occlusion without the outcome  had an ECA ratio ≤ 0.96, but none had distal ICA ≤ 2.4 mm or ICA ratio ≤ 0.47.Intra-rater ICC was excellent for stenosis diameter , distal ICA diameter , and ICA ratio . Inter-rater ICC was very good for ECA ratio .The main finding of this study was that novel measurement–based definitions of near-occlusion with full collapse seem to provide better prognostic outcomes than the traditional appearance-based approach.Near-occlusion was defined in NASCET by necessity because the reduction of distal ICA diameter in near-occlusions would lead to stenosis underestimation if the percent comparison was applied –3. Near-Of the three significant parameters, one was an absolute measurement  and two were relative , which have different pros and cons: Absolute measurements can vary with study quality, windowing, and handling of the fuzzy edge. While intra-rater reliability was very good, it is not necessarily transferable to raters in routine practice. Relative measurements require a relevant comparison and the comparison can sometimes be misleading, such as bilateral near-occlusion affecting ICA ratio and ECA size vary between patients. Stenosis diameter was not associated with the outcome among near-occlusions, but this could be false-negative due to the use of CTA as stenosis diameter similar to voxel size make assessment difficult. A conventional angiography-based study might yield a positive association. The non-association between stenosis PSV and outcome was possibly due to lacking data. Further study into the prognostic potential of carotid ultrasound in near-occlusion should reasonably include the assessment of distal velocity .Near-occlusion without full collapse had no substantial benefit with CEA in NASCET and ECST due to a relatively low long-term risk of stroke in the medical arm –5. This p = 0.02). We showed a strong association for full collapse (p < 0.001) with similar number of cases included (n = 430), suggesting degree of stenosis being more important than age [We found that for all symptomatic ≥ 50% stenosis, only degree of stenosis (near-occlusion with full collapse) was associated with the outcome. Higher age and cerebral  presenting event have been suggested, but without assessment of near-occlusion . We founthan age .Our study had several weaknesses. The use of medical treatment could not be assessed as it was gathered with different definitions in the underlying studies , 7. HoweIn summary, defining near-occlusion with full collapse as distal ICA diameter ≤ 2.0 mm and/or ICA ratio ≤ 0.42 seems to yield better prognostic discrimination than the traditional appearance-based definition. This novel definition can be used in prognostic and treatment studies of near-occlusion with full collapse.


Considerable progress has been made over the past years to better understand the genetic nature and pathophysiology of brain AVM. For the actual review, a PubMed search was carried out regarding the embryology, inflammation, advanced imaging, and fluid dynamical modeling of brain AVM. Whole-genome sequencing clarified the genetic origin of sporadic and familial AVM to a large degree, although some open questions remain. Advanced MRI and DSA techniques allow for better segmentation of feeding arteries, nidus, and draining veins, as well as the deduction of hemodynamic parameters such as flow and pressure in the individual AVM compartments. Nonetheless, complete modeling of the intranidal flow structure by computed fluid dynamics (CFD) is not possible so far. Substantial progress has been made towards understanding the embryology of brain AVM. In contrast to arterial aneurysms, complete modeling of the intranidal flow and a thorough understanding of the mechanical properties of the AVM nidus are still lacking at the present time. Arteriovenous malformations of the brain are classically considered tangles of low-resistance channels between arteries and veins. In contrast to arterial aneurysms, relatively little efforts have been made to understand the complexities of hemodynamics and their relation to rupture. Massoud and colleagues elaborated possible flow patterns in analogy to electrical networks . These sSince possibilities of invasive measurements during endovascular or surgical therapy are limited, calculations based on models appear mandatory. For the case of arterial aneurysms, the advent of computational fluid dynamics (CFD) has brought a major breakthrough for our understanding. For the case of AVM, on the other hand, this method has so far not resulted in similar progress, since the exact geometry of the AVM compartments, that must been known for CFD calculation, still eludes current imaging methods.Nonetheless, much progress has been made towards better detail imaging of AVM, including estimation of pressure profiles in the feeding arteries and draining veins. Furthermore, a better understanding of defunct cell signal pathways and somatic mutations allowed for establishing tissue culture models of AV fistulas, resulting in a better understanding of the principles of emergence and growth. The purpose of the current review was to collect the recent scientific results regarding the embryological development of AVM, and regarding advanced imaging and fluid dynamic modeling. The recent literature was surveyed based on a PubMed search on Nov. 20, 2020, with the search terms “brain arteriovenous malformation” and “pathophysiology hemodynamics” (97 hits), “inflammation” (326 hits), “genetic mutation” (131 hits), “hemodynamics MRI” (152 hits), “4D” (44 hits), or “feeding artery pressure” (52 hits).There is little doubt that AVM are of dysembryological nature. Based on embryological data of normal brain angiogenesis, Mullan and other colleagues believed that AVM develop from a fistula created when during embryogenesis, the developing transverse veins are crossed at right angles by developing longitudinal arteries . The corEndoglin (ENG), Activin receptor-like kinase 1 (ALK1 or ACVRL1), and Mothers Against Decapentaplegic Homolog 4 (SMAD4). HHT is classified into HHT1, HHT2, and JP (juvenile polyposis)-HHT, depending on the causative gene mutations. HHT1 (ENG mutations) and HHT2 (ALK1 mutations) cover over 90% of all HHT cases. Although clinical presentations are indistinguishable between HHT1 and HHT2, genotype–phenotype correlation studies have shown that HHT1 has a higher prevalence of AVMs in the brain and lungs, while HHT2 has a higher prevalence of AVMs in the liver and gastrointestinal tract. Brain AVMs are present in 10–16% of patients with HHT [Bone Morphogenic Protein BMP9 and BMP10 could induce AVM development in the retinal vasculature, but it is not entirely clear whether both BMP9 and BMP10 are needed for ENG-ALK1 signaling. Nishida analyzed the prevalence of genetic variants in HHT and the correlations to phenotype in 171 patients with HHT and brain AVMs [About 5% of brain AVMs are linked to a genetic disorder, Hereditary Hemorrhagic Telangiectasia , which is an autosomal dominant vascular disease that affects approximately 1 in 5000 people worldwide . The majwith HHT , 37. HHTain AVMs . NeonataBernabeu and team tried to explain the focal nature of vascular malformations in HHT . They poCapillary Malformation-Arteriovenous Malformation (CM-AVM) syndrome [Ephrin-Typ-B-Rezeptor 4 (EPHB4) or RAS p21 Protein Activator 1 (RASA1) identified by molecular genetic testing. CM-AVM syndrome is inherited in an autosomal dominant manner. For RASA1-CM-AVM syndrome, about 70% of affected individuals have an affected parent; about 30% have a de novo pathogenic variant. For EPHB4-CM-AVM syndrome, some 80% of affected individuals have an affected parent; about 20% have a de novo pathogenic variant. Each child of an individual with CM-AVM syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal and preimplantation genetic testing is possible if the pathogenic variant has been identified in an affected family member.A more recently described rare systemic disorder associated with AVM is syndrome , 12. ThiRat Sarcoma (RAS)/Mitogen-Activated Protein Kinase (MAPK)/Extracellular-Signal-Regulated Kinase (ERK) cascade couples signals from cell surface receptors to transcription factors, which regulate gene expression. This pathway regulates several critical cellular functions, including proliferation, growth, survival, and senescence [Kirsten Rat Sarcoma (KRAS) mutations are present in colorectal, lung, and biliary tract carcinogenesis, while mutations in Neuroblastoma RAS (NRAS) and Harvey RAS (HRAS) are frequently present in melanomas and salivary gland tumors, respectively. Interestingly, almost all pancreatic adenocarcinomas harbor a RAS mutation. Furthermore, it has been shown that ERK5 regulates several signaling pathways involved in angiogenesis, whereby it can inhibit the expression of VEGF during the hypoxic response.The nescence . It has B-Rat Fibro sarcoma (BRAF) gene somatic mutations in brain and spinal cord arteriovenous malformations [P = 0.54). There were no histologic differences between KRAS-mutant and non-mutant cases.Regarding truly sporadic brain AVM, Nikolaev from the University of Geneva, and colleagues examined tissue and blood samples of patients with brain arteriovenous malformations to detect somatic mutations . The resrmations . Similarrmations . Priemerrmations . They soBone Morphogenic Protein (BMP) pathway in the arteriovenous malformation of a 14-year-old girl who developed a recurrent brain AVM [Walcott described a rare somatic mutation of the rain AVM . Whole-erain AVM . They foSummarizing these genetic analyses, it can be concluded that sporadic AVM are consequences of local somatic mutations affecting the endothelium. The situation is more complex in the situation of the rare familial cases, mainly in context with HHT. Here, in addition to a germline mutation, local additional factors must be postulated for the emergence of AVMs. These second factors are not well understood at the present time.P = 0.003). The authors also concluded that strong inflammation is present in both unruptured and ruptured AVMs.Comparable to intracranial aneurysms, inflammatory processes have been suspected for years to have a potential influence for the development and rupture of arteriovenous malformations , 33, 55.The finding that microhemorrhages are common in ruptured as well as unruptured AVMs corroborates well with the microscopic observations made by McCormick already more than 50 years ago. He described AVMs histopathologically as follows: “Microscopically, the variable and extremely complex nature of the lesion becomes evident. The vessels may range from relatively well-differentiated arteries and veins to malformed, thick and thin-walled, hyalinized vessels apparently neither artery nor vein. Segmental dilatations of these vessels are often seen. Large, irregular nodules of hyalinized intima and smooth muscle often project into the lumens. A peculiar, amyloid-like material is at times found in the vessel walls. Ossification may also occur, but is uncommon. Degeneration of the parenchyma about and within the malformation is almost constant, and may be the most conspicuous feature in some cases. Hemosiderin pigment is commonly found, indicating at least minor hemorrhage from the malformation” . HemosidHauer et al. recently used RNA sequencing to study upregulation of inflammatory cytokines . They usCarcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1), which is associated with infiltrating neutrophils, in tissues samples of 60 brain AVM [Neyazi and collaborators studied rain AVM . The assP = 0.003) than IL6-174C carriers. In a multivariate logistic regression model, IL6-174G > C genotype, as well as the known predictors small BAVM size, and exclusively deep venous drainage were independent predictors of ICH presentation [Pawlinowska and her team genotyped 180 AVM patients for 5 polymorphisms in 3 inflammatory cytokine genes, and 9 polymorphisms in 5 angiogenesis-related genes . They hoentation .Summarizing the present state regarding the importance of inflammation for rupture of AVM, we can conclude that inflammation in AVM does certainly occur. However, further studies are needed to define the role of inflammatory cytokines in the pathogenesis of AVM hemorrhage, before possible preventive use of anti-inflammatory drugs can be considered , 57.Advanced time-resolved MRI analysis has considerably advanced our understanding of AVM hemodynamics. Phase contrast imaging provides a vector field of the velocity and yields additional hemodynamic information, including volume flow rate and intravascular pressure. Color-coded images can separate feeding arteries, nidus, and draining veins. Theoretically, the images provide local flow velocities. In combination with the measured vascular diameters and lengths, the pressure drop along the feeding arteries and draining veins can be calculated. Ansari and coworkers were among the first to introduce this method. They aimed to determine whether time-resolved (4D) flow MR could provide insights into arteriovenous malformation hemodynamics and the changes in flow observed during staged embolization . They foThe abovementioned results show that advanced MRA provided some progress regarding analysis of flow through the AVM. The method does, however, not allow a detailed analysis of the highly complex flow patterns in the nidus. Furthermore, calculations of pressure profiles along the feeding arteries and highly sensitive to small errors concerning measured vessel diameters.Several groups have propagated advanced DSA imaging including visualization of flow fields , 23, 39.Summarizing the results of advanced DSA, similar limitations appear to apply as with time-resolved MRI. The detailed flow patterns in the nidus appear still difficult to grasp in detail.Fogarty-Mack and colleagues measured feeding artery pressure during embolization in order to examine the distribution of arterial hypotension surrounding arteriovenous malformations . Mean arSome additional insight regarding AVM hemodynamics might also be gained from less advanced technical methods. We used simple native and contrast CT to estimate the cumulative vessel diameter at the nidal and draining vein level. In 10 AVMs measured, we found an average ratio of total nidal vascular diameter to draining vein cross-area of 5.8 . This suggests, on the other hand, that net flow velocity in the nidus is almost 6 times slower than in the draining veins, and that pressure drop along the nidus is relatively small Fig. .Fig. 3PPathophysiologically, AVMs have been commonly modeled as tangles or networks of small channels , 22, 38.A certain stability is a mandatory precondition for an AVM structure to persist to adulthood. This precondition still leaves a number of structures as possible AVMs. In the end, there are probably also various possible angio-architectures, a fact that is also reflected by the histopathological variants, e.g., direct arteriovenous fistula, compact nidus, racematous plexiform nidus, capillary type of nidus. Generally speaking, the intranidal pressure is contained by (1) the vessel walls and (2) the gliotic interstitial tissue. If nidal vessels are not contained by the gliotic interstitial tissue, the wall tension and risk of rupture are likely to be governed by Laplace’s law , suggesting that rupture would preferentially occur close to the arterial side, with higher intravasal pressure. On the other hand, if the channels of the nidus are glued together by the gliotic interstitial tissue, the dynamics are somewhat different , 51. RupIf the nidal channels are glued together by the interstitial tissue, this has also some other consequences. First, the interstitial pressure would correspond to the intravasal pressure. Second, the pressure in adjacent channels must be almost identical in order to prevent compression of one lower pressure channel by the neighboring higher-pressure channel. This concept would render true tangles or knots inside the nidus unlikely and therefore suggest a clear polarity and alignment in the nidus of an AVM. This picture appears also to be in agreement with the usual angiographic appearance.Theoretically, a spherical structure of an AVM can be imagined, with the feeding arteries entering to the center and the draining veins draining from the surface of the sphere. Such a nidus could hardly bleed, since the nidal pressure would approach normal venous pressure at the surface. Such a structure is not known to occur in reality. The reason is probably that draining veins cannot encompass the entire nidus. Draining veins appear rather to develop from a venous pole in a fingerlike fashion toward an arterial pole, or in other words, the venous side develops as a fractal tree-like branching structure with all of the branches accepting direct AV-Shunts from an arterial network developing between the tree branches.Flow instabilities and even frank turbulence are well known from intracranial aneurysms, although the significance for growth and rupture remains unclear , 49. In Substantial advancements have been made during recent years to understand the embryological origin of brain AVM and the somatic and germline genetic mutations involved. Advances of imaging modalities allowed also better understanding the blood flow in feeding arteries and draining veins. Nonetheless, in contrast to arterial aneurysms, complete modeling of the intranidal flow by computational fluid dynamics (CFD) is not possible so far and a thorough understanding of the mechanical properties of the AVM nidus is still lacking for the time being. The relation of inflammation and flow pattern and to the risk of hemorrhage remains incompletely understood.