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We are grateful to Eker et al. for their thoughtful analysis and response to our publication titled Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT [...].

Research on interactions involving police officers foregrounds the importance of their communicative practices for fostering civilians’ perceptions of police legitimacy. Building on this research, we describe a pattern of conduct that is a recurrent source of trouble in such encounters, which we call sequential standoffs. These standoffs emerge when two parties persistently pursue alternative courses of action, producing a stalemate in which neither progress in, nor exit from, either course of action appears viable. They are routinely resolved by officers (re)casting civilians’ pursuit of one course of action as constituting resistance to the officers’ proposed course of action, and thus as warranting officers’ use of coercive violence to resolve the stalemate. In some cases, however, officers resolve standoffs cooperatively using sequentially accommodative methods. We consider how these findings advance approaches to communicative dilemmas in policing, and their broader significance for scholars of social interaction, and of the interactional organization of conflicts.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease characterized by the development of vascular malformations (VMs) in organs such as the brain and lungs, as well as telangiectases on mucosal surfaces. Prophylactic treatment of organ VMs may prevent potential complications, such as hemorrhage. However, brain VM treatment-surgical resection, embolization, and/or radiosurgery-is not recommended for all patients due to the associated risks. Given the scarcity of data regarding HHT-related brain VM presentation and treatment trends in pediatric patients, we aim to describe the clinical presentations and the patterns of treatment of HHT-related brain VMs in a pediatric cohort, and compare pediatric trends to those of adults. Demographic and clinical data were analyzed in 114 pediatric patients with HHT-related brain VMs and compared with a cohort of 253 adult patients enrolled in the multicenter Brain Vascular Malformation Consortium HHT Project. Our data demonstrated that a higher proportion of pediatric patients with HHT-related brain VMs were symptomatic at presentation (p = 0.004). Moreover, a higher proportion of pediatric patients presented with intracranial hemorrhage (p < 0.001) and seizure (p = 0.002) compared to adult patients. Surgical resection was the most common brain VM treatment modality in both children and adults. We conclude that pediatric patients may be more likely to present with symptoms and complications from brain VMs, supporting the case for screening for brain VMs in children with HHT.

AbstractMembership categories such as ‘doctor’, ‘customer’, and ‘girl’ can form a set of alternative ways of referring to the same person. Moreover, speakers can select from this array of correct alternatives that term best fitted to what is getting done in their talk. In contrast, self-references alone ordinarily do not convey category membership, unless the speaker specifically employs some sort of category-conveying formulation. This report investigates how speakers manage the categorical relevance of these simplest self-references (e.g. ‘I’, ‘me’, ‘my’) as a practical means of self-presentation. We first describe how speakers forestall recipient attribution of membership categories. We then consider cases where simple self-references are subjected to subsequent elaboration—via self-categorization—in the face of possible recipient misreading of the speaker's category membership. Thereafter, we introduce the practice of contrastive entanglement, and describe how speakers employ it to fashion tacitly categorized self-references that serve the formation of action. (Person reference, conversation analysis, membership categorization devices, race, gender)*

Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac ventricular myocyte-specific developmental deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium causes severe impairment in excitation-contraction coupling by altering both intracellular and mitochondrial calcium signaling. We also observed adverse cardiac remodeling which progressed to severe cardiomyopathy and death. Reintroduction of VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype. Activation of VDAC2 by efsevin increased cardiac contractile force in a mouse model of pressure-overload induced heart failure. In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing cellular calcium signaling. Through this unique role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.

Background The value of MRI in pediatric congenital heart disease (CHD) is well recognized; however, the requirement for expert oversight impedes its widespread use. Four-dimensional (4D) multiphase steady-state imaging with contrast enhancement (MUSIC) is a cardiovascular MRI technique that uses ferumoxytol and captures all anatomic features dynamically. Purpose To evaluate multicenter feasibility of 4D MUSIC MRI in pediatric CHD. Materials and Methods In this prospective study, participants with CHD underwent 4D MUSIC MRI at 3.0 T or 1.5 T between 2014 and 2020. From a pool of 460 total studies, an equal number of MRI studies from three sites (n = 60) was chosen for detailed analysis. With use of a five-point scale, the feasibility of 4D MUSIC was scored on the basis of artifacts, image quality, and diagnostic confidence for intracardiac and vascular connections (n = 780). Respiratory motion suppression was assessed by using the signal intensity profile. Bias between 4D MUSIC and two-dimensional (2D) cine imaging was evaluated by using Bland-Altman analysis; 4D MUSIC examination duration was compared with that of the local standard for CHD. Results A total of 206 participants with CHD underwent MRI at 3.0 T, and 254 participants underwent MRI at 1.5 T. Of the 60 MRI examinations chosen for analysis (20 per site; median participant age, 14.4 months [interquartile range, 2.3-49 months]; 33 female participants), 56 (93%) had good or excellent image quality scores across a spectrum of disease complexity (mean score ± standard deviation: 4.3 ± 0.6 for site 1, 4.9 ± 0.3 for site 2, and 4.6 ± 0.7 for site 3; P < .001). Artifact scores were inversely related to image quality (r = -0.88, P < .001) and respiratory motion suppression (P < .001, r = -0.45). Diagnostic confidence was high or definite in 730 of 780 (94%) intracardiac and vascular connections. The correlation between 4D MUSIC and 2D cine ventricular volumes and ejection fraction was high (range of r = 0.72-0.85; P < .001 for all). Compared with local standard MRI, 4D MUSIC reduced the image acquisition time (44 minutes ± 20 vs 12 minutes ± 3, respectively; P < .001). Conclusion Four-dimensional multiphase steady-state imaging with contrast enhancement MRI in pediatric congenital heart disease was feasible in a multicenter setting, shortened the examination time, and simplified the acquisition protocol, independently of disease complexity. Clinical trial registration no. NCT02752191 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Roest and Lamb in this issue.

Cerebrovascular malformations occur in both sporadic and inherited patterns. This paper reviews imaging and clinical features of cerebrovascular malformations with a genetic basis. Genetic diseases such as familial cerebral cavernous malformations and hereditary hemorrhagic telangiectasia often have manifestations in bone, skin, eyes, and visceral organs, which should be recognized. Genetic and molecular mechanisms underlying the inherited disorders are becoming better understood, and treatments are likely to follow. An interaction between the intestinal microbiome and formation of cerebral cavernous malformations has emerged, with possible treatment implications. Two-hit mechanisms are involved in these disorders, and additional triggering mechanisms are part of the development of malformations. Hereditary hemorrhagic telangiectasia encompasses a variety of vascular malformations, with widely varying risks, and a more recently recognized association with cortical malformations. Somatic mutations are implicated in the genesis of some sporadic malformations, which means that discoveries related to inherited disorders may aid treatment of sporadic cases. This paper summarizes the current state of knowledge of these conditions, salient features regarding mechanisms of development, and treatment prospects.

Abstract Membership categories such as ‘doctor’, ‘customer’, and ‘girl’ can form a set of alternative ways of referring to the same person. Moreover, speakers can select from this array of correct alternatives that term best fitted to what is getting done in their talk. In contrast, self-references alone ordinarily do not convey category membership, unless the speaker specifically employs some sort of category-conveying formulation. This report investigates how speakers manage the categorical relevance of these simplest self-references (e.g. ‘I’, ‘me’, ‘my’) as a practical means of self-presentation. We first describe how speakers forestall recipient attribution of membership categories. We then consider cases where simple self-references are subjected to subsequent elaboration—via self-categorization—in the face of possible recipient misreading of the speaker's category membership. Thereafter, we introduce the practice of contrastive entanglement, and describe how speakers employ it to fashion tacitly categorized self-references that serve the formation of action. (Person reference, conversation analysis, membership categorization devices, race, gender)*

While the specification of situating context(s) is commonly treated as an indispensable part of social scientific research, the choices this involves are rarely directly explicated. An exception is conversation analysis (CA), which differs from many other approaches in its privileging of participants’ orientations as a basis for empirically grounding analytic specifications of context. In this article, I demonstrate how this approach to context, along with CA methods and findings, can be employed in addressing challenges associated with identifying and analyzing (possible) instances of the implicit relevance of racial categories in everyday social interaction. Using the case of implicit whiteness in post-apartheid South Africa as a site for considering these challenges, I examine a collection of interactions in which race becomes (possibly) relevant during the course of complaints about violent crime. I begin with an ambiguous case of a speaker’s possible implicit orientation to whiteness, demonstrating the use of CA for the close examination of available evidence for this orientation. I then describe how an approach based on a collection of cases, constituted by similar sequential and action environments to those that characterize the ambiguous case, can be employed to strengthen the analysis of the ambiguous case. The analysis thereby demonstrates the powerful resources CA offers for addressing ambiguity with respect to social categories and the value of detailed examinations of interactional practices for documenting how participants manage and thereby reproduce the consequentiality of their position in a racialized social order.

Hereditary hemorrhagic telangiectasia (HHT), a rare autosomal dominant disease mostly caused by mutations in three known genes (ENG, ACVRL1, and SMAD4), is characterized by the development of vascular malformations (VMs). Patients with HHT may present with mucocutaneous telangiectasia, as well as organ arteriovenous malformations (AVMs) of the central nervous system, lungs, and liver. Genotype-phenotype correlations have been well described in adults with HHT. We aimed to investigate genotype-phenotype correlations among pediatric HHT patients. Demographic, clinical, and genetic data were collected and analyzed in 205 children enrolled in the multicenter Brain Vascular Malformation Consortium HHT Project. A chi-square test was used to determine the association between phenotypic presentations and genotype. Among 205 patients (age range: 0-18 years; mean: 11 years), ENG mutation was associated with the presence of pulmonary AVMs (p < 0.001) and brain VM (p < 0.001). The presence of a combined phenotype-defined as both pulmonary AVMs and brain VMs-was also associated with ENG mutation. Gastrointestinal bleeding was rare (4.4%), but was associated with SMAD4 genotype (p < 0.001). We conclude that genotype-phenotype correlations among pediatric HHT patients are similar to those described among adults. Specifically, pediatric patients with ENG mutation have a greater prevalence of pulmonary AVMs, brain VMs, and a combined phenotype.

A growing body of research, examining a wide spectrum of reference forms across diverse languages, cultures, and identities, has shown how references to persons can be selected for context-specific interactional outcomes. This report describes how even such simple forms of person reference as somebody (along with someone and a/the person) can be selected on the basis of their relevance for the specific interactional context in which they are employed. We consider how the particular circumstances of some person reference occasions can make these generic person reference forms specially relevant (even when other, more elaborated forms of reference, either recognitional or non-recognitional, were evidently available to the speaker), and we demonstrate how even these barest forms of person reference can be called on to perform delicate, context-sensitive interactional work. Specifically, we show that speakers can select these generic reference forms for non-recognitional references that a) contribute to the formation of the action of a turn, and, when used in a story, b) contribute to the story’s telling. Finally, we show how a generic person reference can be selected in place of a recognitional reference, thereby openly concealing a referent’s identity.

This report uses audio recorded telephone calls and textual data from an emergency medical services call center to examine the interactional practices through which speakers produce what we call “extraordinary emergencies”, treating the events concerned as requiring moral, as well as medical, attention. Since one of the overarching institutional aims of emergency call centers is to facilitate the efficient provision of medical services, call-takers typically treat reported emergencies as routine events. However, in some instances speakers produce practices that do not contribute toward the institutional agenda of providing medical assistance, thereby treating them as extraordinary cases. These practices occurred recurrently in calls involving reports of emergencies relating to child sexuality, including sexual assaults against children and obstetric emergencies where the mother was particularly young. We discuss the implications of these findings for the situated reproduction of particular moral norms, especially with respect to the category of the child in society.

Background Ferumoxytol is approved for use in the treatment of iron deficiency anemia, but it can serve as an alternative to gadolinium-based contrast agents. On the basis of postmarketing surveillance data, the Food and Drug Administration issued a black box warning regarding the risks of rare but serious acute hypersensitivity reactions during fast high-dose injection (510 mg iron in 17 seconds) for therapeutic use. Whereas single-center safety data for diagnostic use have been positive, multicenter data are lacking. Purpose To report multicenter safety data for off-label diagnostic ferumoxytol use. Materials and Methods The multicenter ferumoxytol MRI registry was established as an open-label nonrandomized surveillance databank without industry involvement. Each center monitored all ferumoxytol administrations, classified adverse events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events (grade 1-5), and assessed the relationship of AEs to ferumoxytol administration. AEs related to or possibly related to ferumoxytol injection were considered adverse reactions. The core laboratory adjudicated the AEs and classified them with the American College of Radiology (ACR) classification. Analysis of variance was used to compare vital signs. Results Between January 2003 and October 2018, 3215 patients (median age, 58 years; range, 1 day to 96 years; 1897 male patients) received 4240 ferumoxytol injections for MRI. Ferumoxytol dose ranged from 1 to 11 mg per kilogram of body weight (≤510 mg iron; rate ≤45 mg iron/sec). There were no systematic changes in vital signs after ferumoxytol administration (P > .05). No severe, life-threatening, or fatal AEs occurred. Eighty-three (1.9%) of 4240 AEs were related or possibly related to ferumoxytol infusions (75 mild [1.8%], eight moderate [0.2%]). Thirty-one AEs were classified as allergiclike reactions using ACR criteria but were consistent with minor infusion reactions observed with parenteral iron. Conclusion Diagnostic ferumoxytol use was well tolerated, associated with no serious adverse events, and implicated in few adverse reactions. Registry results indicate a positive safety profile for ferumoxytol use in MRI. © RSNA, 2019 Online supplemental material is available for this article.

Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in KRIT1, CCM2, or PDCD10 Disease onset is earlier and more severe in individuals with PDCD10 mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kinase kinase 3 (MEKK3) signaling downstream of Toll-like receptor 4 (TLR4) stimulation by lipopolysaccharide derived from the gut microbiome. These findings suggest a gut-brain CCM disease axis but fail to define it or explain the poor prognosis of patients with PDCD10 mutations. Here, we demonstrate that the gut barrier is a primary determinant of CCM disease course, independent of microbiome configuration, that explains the increased severity of CCM disease associated with PDCD10 deficiency. Chemical disruption of the gut barrier with dextran sulfate sodium augments CCM formation in a mouse model, as does genetic loss of Pdcd10, but not Krit1, in gut epithelial cells. Loss of gut epithelial Pdcd10 results in disruption of the colonic mucosal barrier. Accordingly, loss of Mucin-2 or exposure to dietary emulsifiers that reduce the mucus barrier increases CCM burden analogous to loss of Pdcd10 in the gut epithelium. Last, we show that treatment with dexamethasone potently inhibits CCM formation in mice because of the combined effect of action at both brain endothelial cells and gut epithelial cells. These studies define a gut-brain disease axis in an experimental model of CCM in which a single gene is required for two critical components: gut epithelial function and brain endothelial signaling.

BACKGROUNDCerebral cavernous angiomas (CAs) with a symptomatic hemorrhage (CASH) have a high risk of recurrent hemorrhage and serious morbidity.METHODSEighteen plasma molecules with mechanistic roles in CA pathobiology were investigated in 114 patients and 12 healthy subjects. The diagnostic biomarker of a CASH in the prior year was derived as that minimizing the Akaike information criterion and validated using machine learning, and was compared with the prognostic CASH biomarker predicting bleeding in the subsequent year. Biomarkers were longitudinally followed in a subset of cases. The biomarkers were queried in the lesional neurovascular unit (NVU) transcriptome and in plasma miRNAs from CASH and non-CASH patients.RESULTSThe diagnostic CASH biomarker included a weighted combination of soluble CD14 (sCD14), VEGF, C-reactive protein (CRP), and IL-10 distinguishing CASH patients with 76% sensitivity and 80% specificity (P = 0.0003). The prognostic CASH biomarker (sCD14, VEGF, IL-1β, and sROBO-4) was confirmed to predict a bleed in the subsequent year with 83% sensitivity and 93% specificity (P = 0.001). Genes associated with diagnostic and prognostic CASH biomarkers were differentially expressed in CASH lesional NVUs. Thirteen plasma miRNAs were differentially expressed between CASH and non-CASH patients.CONCLUSIONShared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in CA are mechanistically linked to lesional transcriptome and miRNA. The biomarkers may be applied for risk stratification in clinical trials and developed as a tool in clinical practice.FUNDINGNIH, William and Judith Davis Fund in Neurovascular Surgery Research, Be Brave for Life Foundation, Safadi Translational Fellowship, Pritzker School of Medicine, and Sigrid Jusélius Foundation.

Telangiectases and arteriovenous malformations (AVMs) are the characteristic lesions of Hereditary Hemorrhagic Telangiectasia (HHT). Somatic second-hit loss-of-function variations in the HHT causative genes, ENG and ACVRL1, have been described in dermal telangiectasias. It is unclear if somatic second-hit mutations also cause the formation of AVMs and nasal telangiectasias in HHT. To investigate the genetic mechanism of AVM formation in HHT, we evaluated multiple affected tissues from fourteen individuals. DNA was extracted from fresh/frozen tissue of 15 nasal telangiectasia, 4 dermal telangiectasia, and 9 normal control tissue biopsies, from nine unrelated individuals with HHT. DNA from six formalin-fixed paraffin-embedded (FFPE) AVM tissues (brain, lung, liver, and gallbladder) from five individuals was evaluated. A 736 vascular malformation and cancer gene next-generation sequencing (NGS) panel was used to evaluate these tissues down to 1% somatic mosaicism. Somatic second-hit mutations were identified in three in four AVM biopsies (75%) or half of the FFPE (50%) samples, including the loss of heterozygosity in ENG in one brain AVM sample, in which the germline mutation occurred in a different allele than a nearby somatic mutation (both are loss-of-function mutations). Eight of nine (88.9%) patients in whom telangiectasia tissues were evaluated had a somatic mutation ranging from 0.68 to 1.96% in the same gene with the germline mutation. Six of fifteen (40%) nasal and two of four (50%) dermal telangiectasia had a detectable somatic second hit. Additional low-level somatic mutations in other genes were identified in several telangiectasias. This is the first report that nasal telangiectasias and solid organ AVMs in HHT are caused by very-low-level somatic biallelic second-hit mutations. [ABSTRACT FROM AUTHOR]

This article addresses some ways in which stereotypes and stereotyping are treated as morally accountable by social psychologists, their research participants, and participants in everyday interactions. I focus in particular on closely examining some deployments and responses to stereotypes in everyday interactions by applying conversation analytic and discursive psychological approaches to recorded interactions from radio call-in shows. My analysis considers the different interactional trajectories that follow the production of (possible) racial stereotypes, demonstrating how participants treat their “inaccuracy” as a central basis for the production of challenges and moral sanctioning in response to their deployment. In addition, the analysis demonstrates some cases in which apparent stereotypes are accepted or aligned with, including those grounded in personal experiences, “self-stereotypes,” and humorous uses of stereotypes. I conclude by considering the implications of attending to the social–moral contexts in which stereotypes are produced, and the participant-administered accountability associated with these contexts.

Previous research examining online support forums has tended to focus either on evaluating their effectiveness while paying limited or no attention to the details of the interactions therein, or on features of their social organization, without regard to their effectiveness in fulfilling their stated purposes. In this article, we consider both the interactional features of a forum and participants' treatment thereof as being effective (or otherwise), thus adopting a view of effectiveness grounded in participants' proximate orientations and actions. Our analysis demonstrates some ways in which participants produce ratified displays of empathy in response to troubles expressed by another, as well as considering some designedly supportive actions that are treated by their recipients as unsupportive or antagonistic. Our findings indicate some structural features of such forums that facilitate the production of support, while suggesting that claims of knowledge tend to be treated as a basis of resistance to ostensibly supportive actions.

Background: A large body of research has produced vast quantities of empirical data on risk factors for violence in a range of countries and community contexts. Despite the unquestionable successes of this research in cataloguing these risk factors, relatively little is known about the situational factors and mechanisms that translate risks for violence into enactments of violence itself. Without stronger explanations of these situational pathways to violence, understandings of violence remain “fuzzy”. This special issue aims to address this important limitation through a focus on the situational dimensions of violence. Key points: Although directly observing violence is often ethically and methodologically challenging, the studies in this special issue demonstrate the value of better understanding the situational contexts that shape the well-documented affective, interactional and behavioral variables and processes that constitute violent enactments. Examining these processes and factors as they unfold in situ can advance and deepen theoretical and empirical research on general risks for violence. Implications: Situations in which violence is enacted, and the mechanisms through which it is realized, can and should be systematically studied as part of any attempt to enhance the resolution of existing knowledge with respect to violence. Empirical and theoretical research that attempts to get “closer” to violence offers important and innovative insights and opportunities for understanding violence itself, alongside its causes, correlates and consequences. Investing in the design of robust studies of the situational dimensions of violence is important for advancing the field of violence scholarship and potentially informing policy and intervention practices.

Objectives: The objective of this report was to consider some ways in which a range of phenomena commonly treated as “risk factors” for violence (including social asymmetries based on factors such as gender, race and class; and drug or alcohol intoxication) become observable in violent (or potentially violent) interactions. In doing so, we contribute to a growing body of research focused on moving beyond cataloguing factors abstractly associated with risk for violent outcomes, toward specifying the ways in which these risk factors are constituted in “doing violence” itself. Methods: We employed an ethnomethodological and conversation analytic approach to examine the sequential unfolding of interactions in which violent actions are projected and/or realized, drawing on a collection of 105 videos downloaded from the video sharing site YouTube. Results: Our analysis demonstrates how participants in the interactions orient to or deploy “risk factors” as resources for the production of actions and/or for interpreting or accounting for the actions of themselves and others both prior to, during or following the production of violent actions. Conclusions: The findings demonstrate that the target phenomena, rather than simply being abstracted “risk factors” (in a distal or “upstream” sense), are constitutive features of the in situ unfolding of conflicts in which violence comes to be projected (if not always realized) as an outcome. As a result, the ontological distance between “risk” and “enactments” of violence effectively dissolves when episodes in which these phenomena appear are subjected to detailed analysis.

Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3-KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment.