Rare variants in complement system genes associate with endothelial damage after pediatric allogeneic hematopoietic stem cell transplantation.

Introduction: Complement system has a postulated role in endothelial problems after hematopoietic stem cell transplantation (HSCT). In this retrospective, singlecenter study we studied genetic complement system variants in patients with documented endotheliopathy. In our previous study among pediatric patients with an allogeneic HSCT (2001-2013) at the Helsinki University Children´s Hospital, Finland, we identified a total of 19/122 (15.6%) patients with vascular complications, fulfilling the criteria of capillary leak syndrome (CLS), venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS) or thrombotic microangiopathy (TMA). Methods: We performed whole exome sequencing (WES) on 109 patients having an adequate pre-transplantation DNA for the analysis to define possible variations and mutations potentially predisposing to functional abnormalities of the complement system. In our data analysis, we focused on 41 genes coding for complement components. Results: 50 patients (45.9%) had one or several, nonsynonymous, rare germline variants in complement genes. 21/66 (31.8%) of the variants were in the terminal pathway. Patients with endotheliopathy had variants in different complement genes: in the terminal pathway (C6 and C9), lectin pathway (MASP1) and receptor ITGAM (CD11b, part of CR3). Four had the same rare missense variant (rs183125896; Thr279Ala) in the C9 gene. Two of these patients were diagnosed with endotheliopathy and one with capillary leak syndrome-like problems. The C9 variant Thr279Ala has no previously known disease associations and is classified by the ACMG guidelines as a variant of uncertain significance (VUS). We conducted a gene burden test with gnomAD Finnish (fin) as the reference population. Complement gene variants seen in our patient population were investigated and Total Frequency Testing (TFT) was used for execution of burden tests. The gene variants seen in our patients with endotheliopathy were all significantly (FDR < 0.05) enriched compared to gnomAD. Overall, 14/25 genes coding for components of the complement system had an increased burden of missense variants among the patients when compared to the gnomAD Finnish population (N=10 816). Discussion: Injury to the vascular endothelium is relatively common after HSCT with different phenotypic appearances suggesting yet unidentified underlying mechanisms. Variants in complement components may be related to endotheliopathy and poor prognosis in these patients.

Clinically relevant germline variants in allogeneic hematopoietic stem cell transplant recipients.

Allogeneic hematopoietic stem cell transplantation (HSCT) provides patients with severe hematologic disease a well-established potential for curation. Incorporation of germline analyses in the workup of HSCT patients is not a common practice. Recognizing rare harmful germline variants may however affect patients' pre-transplantation care, choice of the stem cell donor, and complication risks. We analyzed a population-based series of germline exome data of 432 patients who had undergone HSCT. Our aim was to identify clinically relevant variants that may challenge the outcome of the HSCT. We focused on genes predisposing to hematological diseases, or solid tumors, and genes included in the American College of Medical Genetics secondary findings list v3.0. As population-specific controls, we used GnomAD non-cancer Finns (n = 10,816). We identified in our population-based analysis rare harmful germline variants in disease-predisposing or actionable toxicity-increasing genes in 17.8% of adult and pediatric patients that have undergone HSCT (15.1% and 22.9%, respectively). More than half of the patients with a family member as a donor had not received genetic diagnosis prior to the HSCT. Our results encourage clinicians to incorporate germline genetic testing in the HSCT protocol in the future in order to reach optimal long-term outcome for the patients.

A germline exome analysis reveals harmful POT1 variants in multiple myeloma patients and families.

Observations of inherited susceptibility to multiple myeloma have led to active research in defining predisposing genes to the disease. Here, we analysed 128 plasma cell dyscrasia patients' germline whole-exome sequencing data. Rare dominantly inherited pathogenic or likely pathogenic (P/LP) variant was found in 9.4% of the patients. Among the P/LP variants, CHEK2 (p. Thr410MetfsTer15) was the most prevalent (n = 5, 3.9%). Interestingly, P/LP variants in POT1 were identified in three patients (2.3%). Our findings broaden the spectrum of POT1-related cancers and demonstrate the importance of the germline genetic analysis in hematological malignancies.

Enrichment of cancer-predisposing germline variants in adult and pediatric patients with acute lymphoblastic leukemia.

Despite recent progress in acute lymphoblastic leukemia (ALL) therapies, a significant subset of adult and pediatric ALL patients has a dismal prognosis. Better understanding of leukemogenesis and recognition of germline genetic changes may provide new tools for treating patients. Given that hematopoietic stem cell transplantation, often from a family member, is a major form of treatment in ALL, acknowledging the possibility of hereditary predisposition is of special importance. Reports of comprehensive germline analyses performed in adult ALL patients are scarce. Aiming at fulfilling this gap of knowledge, we investigated variants in 93 genes predisposing to hematologic malignancies and 70 other cancer-predisposing genes from exome data obtained from 61 adult and 87 pediatric ALL patients. Our results show that pathogenic (P) or likely pathogenic (LP) germline variants in genes associated with predisposition to ALL or other cancers are prevalent in ALL patients: 8% of adults and 11% of children. Comparison of P/LP germline variants in patients to population-matched controls (gnomAD Finns) revealed a 2.6-fold enrichment in ALL cases (CI 95% 1.5-4.2, p = 0.00071). Acknowledging inherited factors is crucial, especially when considering hematopoietic stem cell transplantation and planning post-therapy follow-up. Harmful germline variants may also predispose patients to excessive toxicity potentially compromising the outcome. We propose integrating germline genetics into precise ALL patient care and providing families genetic counseling.

Reconsidering longstanding assumptions about the role of medial prefrontal cortex (MPFC) in social evaluation.

The psychological nature of the association between MPFC modulation and social evaluation remains poorly understood. Despite confounds, small samples, and mixed results in existing research, MPFC activation is often interpreted as a reflection of socioemotional association and/or perceived similarity between the self and an evaluation target. The present research addressed issues from the existing literature by examining whether MPFC is modulated by (a) socioemotional associations unconfounded by previous knowledge (memory effects (Study 1, N = 48), repetition suppression (Study 2, N = 43), multi-voxel pattern analysis (Study 1 & 2)) and (b) perceived similarity to self (Study 2). MPFC was modulated by self-reference and trait-relevance, but there was not significant empirical support for the interpretation that MPFC modulation reflects socioemotional association or perceived similarity. These findings highlight the weak basis for prevailing assumptions about the psychological significance of MPFC in social evaluation and the need for studies which test multiple mechanisms.

The functional role of ventral anterior cingulate cortex in social evaluation: disentangling valence from subjectively rewarding opportunities.

Despite robust associations between the ventral anterior cingulate cortex (vACC) and social evaluation, the role of vACC in social evaluation remains poorly understood. Two hypotheses have emerged from existing research: detection of positive valence and detection of opportunities for subjective reward. It has been difficult to understand whether one or both hypotheses are supported because previous research conflated positive valence with subjective reward. Therefore, the current functional magnetic resonance imaging study drew on a social evaluation paradigm that disentangled positive valence and subjective reward. Participants evaluated in-group and out-group politicians in a social evaluation paradigm that crossed trait valence with opportunity for subjectively rewarding affirmation (i.e. a chance to affirm positive traits about in-group politicians and affirm negative traits about out-group politicians). Participants rated in-group politicians more positively and out-group politicians more negatively. One subregion of vACC was modulated by positive valence and another relatively posterior region of vACC was modulated by opportunity for subjective reward (i.e. a politician × valence interaction). The current findings demonstrate the importance of incorporating vACC function into models of social cognition and provide new avenues for sharpening our understanding of the psychological significance of vACC function in social evaluation and related domains such as reward and affect.

The neural representation of social status in the extended face-processing network.

Social status is a salient cue that shapes our perceptions of other people and ultimately guides our social interactions. Despite the pervasive influence of status on social behavior, how information about the status of others is represented in the brain remains unclear. Here, we tested the hypothesis that social status information is embedded in our neural representations of other individuals. Participants learned to associate faces with names, job titles that varied in associated status, and explicit markers of reputational status (star ratings). Trained stimuli were presented in an functional magnetic resonance imaging experiment where participants performed a target detection task orthogonal to the variable of interest. A network of face-selective brain regions extending from the occipital lobe to the orbitofrontal cortex was localized and served as regions of interest. Using multivoxel pattern analysis, we found that face-selective voxels in the lateral orbitofrontal cortex - a region involved in social and nonsocial valuation, could decode faces based on their status. Similar effects were observed with two different status manipulations - one based on stored semantic knowledge (e.g., different careers) and one based on learned reputation (e.g., star ranking). These data suggest that a face-selective region of the lateral orbitofrontal cortex may contribute to the perception of social status, potentially underlying the preferential attention and favorable biases humans display toward high-status individuals.

An Analysis of Journey Mapping to Create a Palliative Care Pathway in a Canadian First Nations Community: Implications for Service Integration and Policy Development.

Providing palliative care in Indigenous communities is of growing international interest. This study describes and analyzes a unique journey mapping process undertaken in a First Nations community in rural Canada. The goal of this participatory action research was to improve quality and access to palliative care at home by better integrating First Nations' health services and urban non-Indigenous health services. Four journey mapping workshops were conducted to create a care pathway which was implemented with 6 clients. Workshop data were analyzed for learnings and promising practices. A follow-up focus group, workshop, and health care provider surveys identified the perceived benefits as improved service integration, improved palliative care, relationship building, communication, and partnerships. It is concluded that journey mapping improves service integration and is a promising practice for other First Nations communities. The implications for creating new policy to support developing culturally appropriate palliative care programs and cross-jurisdictional integration between the federal and provincial health services are discussed. Future research is required using an Indigenous paradigm.

Dynamic neural architecture for social knowledge retrieval.

Social behavior is often shaped by the rich storehouse of biographical information that we hold for other people. In our daily life, we rapidly and flexibly retrieve a host of biographical details about individuals in our social network, which often guide our decisions as we navigate complex social interactions. Even abstract traits associated with an individual, such as their political affiliation, can cue a rich cascade of person-specific knowledge. Here, we asked whether the anterior temporal lobe (ATL) serves as a hub for a distributed neural circuit that represents person knowledge. Fifty participants across two studies learned biographical information about fictitious people in a 2-d training paradigm. On day 3, they retrieved this biographical information while undergoing an fMRI scan. A series of multivariate and connectivity analyses suggest that the ATL stores abstract person identity representations. Moreover, this region coordinates interactions with a distributed network to support the flexible retrieval of person attributes. Together, our results suggest that the ATL is a central hub for representing and retrieving person knowledge.

More Than Meets the Eye: The Merging of Perceptual and Conceptual Knowledge in the Anterior Temporal Face Area.

An emerging body of research has supported the existence of a small face sensitive region in the ventral anterior temporal lobe (ATL), referred to here as the "anterior temporal face area". The contribution of this region in the greater face-processing network remains poorly understood. The goal of the present study was to test the relative sensitivity of this region to perceptual as well as conceptual information about people and objects. We contrasted the sensitivity of this region to that of two highly-studied face-sensitive regions, the fusiform face area (FFA) and the occipital face area (OFA), as well as a control region in early visual cortex (EVC). Our findings revealed that multivoxel activity patterns in the anterior temporal face area contain information about facial identity, as well as conceptual attributes such as one's occupation. The sensitivity of this region to the conceptual attributes of people was greater than that of posterior face processing regions. In addition, the anterior temporal face area overlaps with voxels that contain information about the conceptual attributes of concrete objects, supporting a generalized role of the ventral ATLs in the identification and conceptual processing of multiple stimulus classes.

Understanding social hierarchies: The neural and psychological foundations of status perception.

Social groups across species rapidly self-organize into hierarchies, where members vary in their level of power, influence, skill, or dominance. In this review, we explore the nature of social hierarchies and the traits associated with status in both humans and nonhuman primates, and how status varies across development in humans. Our review finds that we can rapidly identify social status based on a wide range of cues. Like monkeys, we tend to use certain cues, like physical strength, to make status judgments, although layered on top of these more primitive perceptual cues are sociocultural status cues like job titles and educational attainment. One's relative status has profound effects on attention, memory, and social interactions, as well as health and wellness. These effects can be particularly pernicious in children and adolescents. Developmental research on peer groups and social exclusion suggests teenagers may be particularly sensitive to social status information, but research focused specifically on status processing and associated brain areas is very limited. Recent evidence from neuroscience suggests that there may be an underlying neural network, including regions involved in executive, emotional, and reward processing, that is sensitive to status information. We conclude with questions for future research as well as stressing the need to expand social neuroscience research on status processing to adolescents.

Two rooms, two representations? Episodic-like memory in toddlers and preschoolers.

Episodic memory involves binding together what-where-when associations. In three experiments, we tested the development of memory for such contextual associations in a naturalistic setting. Children searched for toys in two rooms with two different experimenters; each room contained two identical sets of four containers, but arranged differently. A distinct toy was hidden in a distinct container in each room. In Experiment 1, which involved children between 15 and 26 months who were prompted with a very explicit cue (a part of the hidden toy), we found a marked shift in performance with age: while 15- to 20-month-olds concentrated their searches on the two containers that sometimes contained toys, they did not distinguish between them according to context, but 21-26-month-olds did. However, surprisingly, without toy cues, even the youngest children showed a fragile ability to disambiguate the two containers by room context. In Experiment 2, we tested 34- to 40-month-olds and 64- to 72-month-olds without toy cues. The 5-year-olds were nearly perfect, and the 3-year-olds showed a significant preference for the correct container given only the context. In Experiment 3, we filled in the age range, and also investigated the effects of the use of labels (i.e. names of experimenters and rooms) and of familiarization time, in groups of 34- to 40-month-olds, 42- to 48-month-olds, and 50- to 56-month-olds. Neither labels nor familiarization time had an effect. Across experiments, there was regular age-related improvement in context-based memory. Overall, the results suggest that children's episodic memory may undergo an early qualitative change, yet to be precisely characterized, and that continuing increments in the use of contextual cues occur throughout the preschool period. A video abstract of this article can be viewed at https://www.youtube.com/watch?v=DkwEFw0UEz4&list=PLwxXcOKHPC0llAPVcJyW4EtzlA934A2Rz&index=1.

'I'm just a walking eating disorder': the mobilisation and construction of a collective illness identity in eating disorder support groups.

The increasing visibility of support groups has prompted a flurry of sociological investigation, much of which explores how groups benefit participants. What researchers have failed to consider is the group itself. Bringing social movement theory to bear on the case of eating disorder support groups, this study seeks to explore how support groups attract and sustain adequate participation. Participant observation in an eating disorder support group reveals that broad diagnostic and prognostic frames, coupled with strong motivational framing and collective identification on the basis of a shared disordered self, promote support group participation. The very processes that enable support groups' successful mobilisation, however, simultaneously construct a collective illness identity, which in turn serves as the basis for participants' individual-level identity work. More specifically, support group mobilisation processes construct eating disorders as highly consequential, highly symptomatic, chronic, rooted in the self, and uncontrollable. Such findings suggest that support groups may have unanticipated and potentially adverse consequences for participants and thus build on previous work highlighting the unintended health consequences of framing processes. Such findings further contribute to our understanding of how macro-social forces shape illness experience.

Tracking the eyes to see what children remember.

Relational memory is a canonical form of episodic memory known to rely on the hippocampus. Several lines of evidence suggest that relational memory has a developmental trajectory in which it is fragile, inflexible, and error-prone until around 6 years of age, which seems to mirror maturational changes in the morphology of the hippocampus. However, recent findings from Richmond and Nelson (2009) challenge this idea as they provide evidence suggestive of adult-like relational memory in 9-month-old infants. In this study the authors measured the eye movements of infants and showed that they preferentially gazed at correct, as opposed to incorrect, face-scene pairings at test. The goal of the present study was to evaluate the development of relational memory by assessing 4-year-olds using Richmond and Nelson's task and stimuli, but gathering two dependent measures of relational memory: overt response as well as eye movements. The results show that, overall, preferential looking at correct face-scene pairings was at chance; however, preferential looking was observed when the correct face-scene pair was later explicitly identified. Thus, while eye movements do index explicit memory in 4-year-olds, behavioural data are necessary to obtain a full picture of the development of relational memory in childhood.