Explore the vast range of titles available.

Early life adversity and insecure attachment style are known risk factors for perinatal depression. The biological pathways linking these experiences, however, have not yet been elucidated. We hypothesized that overlap in patterns of DNA methylation in association with each of these phenomena could identify genes and pathways of importance. Specifically, we wished to distinguish between allostatic-load and role-transition hypotheses of perinatal depression. We conducted a large-scale analysis of methylation patterns across 5 × 10 6 individual CG dinucleotides in 54 women participating in a longitudinal prospective study of perinatal depression, using clustering-based criteria for significance to control for multiple comparisons. We identified 1580 regions in which methylation density was associated with childhood adversity, 3 in which methylation density was associated with insecure attachment style, and 6 in which methylation density was associated with perinatal depression. Shorter telomeres were observed in association with childhood trauma but not with perinatal depression or attachment insecurity. A detailed analysis of methylation density in the oxytocin receptor gene revealed similar patterns of DNA methylation in association with perinatal depression and with insecure attachment style, while childhood trauma was associated with a distinct methylation pattern in this gene. Clinically, attachment style was strongly associated with depression only in pregnancy and the early postpartum, whereas the association of childhood adversity with depression was time-invariant. We concluded that the broad DNA methylation signature and reduced telomere length associated with childhood adversity could indicate increased allostatic load across multiple body systems, whereas perinatal depression and attachment insecurity may be narrower phenotypes with more limited DNA methylation signatures outside the CNS, and no apparent association with telomere length or, by extension, allostatic load. In contrast, the finding of matching DNA methylation patterns within the oxytocin receptor gene for perinatal depression and attachment insecurity is consistent with the theory that the perinatal period is a time of activation of existing attachment schemas for the purpose of structuring the mother–child relationship, and that such activation may occur in part through specific patterns of methylation of the oxytocin receptor gene.

ObjectivesWe examined the association between breastfeeding difficulties and trajectories of bonding in the first 6 months postpartum.MethodsEach month for the first 6 months following birth, 121 mothers of newborn infants (age = 23–45 years, M = 32.31 ± 4.79, 57% White, 23% Asian, 11% Hispanic, 9% Multiracial, 1% Black/African American) were invited to complete self-assessments of bonding. At the first postpartum assessment, mothers who intended to breastfeed also reported whether breastfeeding was more difficult than they had anticipated. We conducted linear mixed modelling to test whether early breastfeeding difficulty was associated with bonding trajectories and examined whether effects remained when accounting for postnatal depression symptoms.ResultsWe found main effects of breastfeeding difficulty (β = − .20, 95% CI [ −  .34, − .06]) and postpartum month (β = .13, 95% CI [.07, .20]) on bonding. On average, women who reported breastfeeding difficulty reported lower bonding than women who did not (Cohen’s d = − 0.44, 95% CI [− 0.81, − 0.06]). Additional analyses indicated that, independent of breastfeeding difficulties, women who reported higher postnatal depressive symptoms across the first 6 months postpartum reported lower levels of bonding, on average. Further, within-individual decreases in postnatal depressive symptoms across the first six months were associated with relative improvements in bonding across this period.Conclusions for PracticeOur findings suggest that mothers who experience breastfeeding difficulties are at risk for reduced bonding with their infants in the first 6 months after birth. Moreover, while postnatal depressive symptoms are also associated with reduced bonding, the effect of breastfeeding difficulties on bonding persists over and above the effect of postnatal depressive symptoms.

The early environment, including maternal characteristics, provides many cues to young organisms that shape their long-term physical and mental health. Identifying the earliest molecular events that precede observable developmental outcomes could help identify children in need of support prior to the onset of physical and mental health difficulties. In this study, we examined whether mothers’ attachment insecurity, maltreatment history, and depressive symptoms were associated with alterations in DNA methylation patterns in their infants, and whether these correlates in the infant epigenome were associated with socioemotional and behavioral functioning in toddlerhood. We recruited 156 women oversampled for histories of depression, who completed psychiatric interviews and depression screening during pregnancy, then provided follow-up behavioral data on their children at 18 months. Buccal cell DNA was obtained from 32 of their infants for a large-scale analysis of methylation patterns across 5 × 106 individual CpG dinucleotides, using clustering-based significance criteria to control for multiple comparisons. We found that tens of thousands of individual infant CpGs were alternatively methylated in association with maternal attachment insecurity, maltreatment in childhood, and antenatal and postpartum depressive symptoms, including genes implicated in developmental patterning, cell-cell communication, hormonal regulation, immune function/inflammatory response, and neurotransmission. Density of DNA methylation at selected genes from the result set was also significantly associated with toddler socioemotional and behavioral problems. This is the first report to identify novel regions of the human infant genome at which DNA methylation patterns are associated longitudinally both with maternal characteristics and with offspring socioemotional and behavioral problems in toddlerhood.

Background and objectivesThe clinical diagnosis of Huntington disease (HD) is typically made once motor symptoms and chorea are evident. Recent reports highlight the onset of cognitive and psychiatric symptoms before motor manifestations. These findings support further investigations of cognitive function across the lifespan of HD sufferers.MethodsTo assess cognitive symptoms in the developing brain, we administered assessments from the National Institutes of Health Toolbox Cognitive Battery, an age-appropriate cognitive assessment with population norms, to a cohort of children, adolescents and young adults with (gene-expanded; GE) and without (gene-not-expanded; GNE) the trinucleotide cytosine, adenine, guanine (CAG) expansion in the Huntingtin gene. These five assessments that focus on executive function are well validated and form a composite score, with population norms. We modelled these scores across age, and CAP score to estimate the slope of progression, comparing these results to motor symptoms.ResultsWe find significant deficits in the composite measure of executive function in GE compared with GNE participants. GE participant performance on working memory was significantly lower compared with GNE participants. Modelling these results over age suggests that these deficits occur as early as 18 years of age, long before motor manifestations of HD.ConclusionsThis work provides strong evidence that impairments in executive function occur as early as the second decade of life, well before anticipated motor onset. Future investigations should delineate whether these impairments in executive function are due to abnormalities in neurodevelopment or early sequelae of a neurodegenerative process.

Attachment security may be a mechanism by which exposure to early life adversity affects subsequent generations. We used a prospective cohort design to examine this possibility in a convenience sample of 124 women (age = 23–45 years, M = 32.32 [SD = 4.83] years; 57.3% White, 22.6% Asian) who provided self-reports of attachment style during pregnancy using the Attachment Style Questionnaire, of whom 96 (age = 28–50 years, M = 36.67 [SD = 4.90] years; 60.4% White, 19.8% Asian) were reassessed when their child was preschool-age (M = 4.38 [SD = 1.29] years). Women self-reported on their own childhood maltreatment severity and their child’s current emotional and behavioral problems using the Childhood Trauma Questionnaire and the Child Behavior Checklist for ages 1.5–5, respectively. Maternal childhood maltreatment severity was associated with less secure, and more avoidant and anxious attachment. Mediation analyses revealed further that less secure maternal attachment, but not avoidant or anxious attachment, mediated the associations between maternal childhood maltreatment and offspring emotional and behavioral problems. These findings suggest that improving maternal attachment security, which can be identified even prior to the child’s birth, is an important target to consider for intervention efforts aimed at minimizing adverse intergenerational effects of early life adversity.

Exposure to risks throughout life results in a wide variety of outcomes. Objectively judging the relative impact of these risks on personal and population health is fundamental to individual survival and societal prosperity. Existing mechanisms to quantify and rank the magnitude of these myriad effects and the uncertainty in their estimation are largely subjective, leaving room for interpretation that can fuel academic controversy and add to confusion when communicating risk. We present a new suite of meta-analyses—termed the Burden of Proof studies—designed specifically to help evaluate these methodological issues objectively and quantitatively. Through this data-driven approach that complements existing systems, including GRADE and Cochrane Reviews, we aim to aggregate evidence across multiple studies and enable a quantitative comparison of risk–outcome pairs. We introduce the burden of proof risk function (BPRF), which estimates the level of risk closest to the null hypothesis that is consistent with available data. Here we illustrate the BPRF methodology for the evaluation of four exemplar risk–outcome pairs: smoking and lung cancer, systolic blood pressure and ischemic heart disease, vegetable consumption and ischemic heart disease, and unprocessed red meat consumption and ischemic heart disease. The strength of evidence for each relationship is assessed by computing and summarizing the BPRF, and then translating the summary to a simple star rating. The Burden of Proof methodology provides a consistent way to understand, evaluate and summarize evidence of risk across different risk–outcome pairs, and informs risk analysis conducted as part of the Global Burden of Diseases, Injuries, and Risk Factors Study. A new Burden of Proof meta-analytic method that accounts for between-study heterogeneity and corrects for bias between different study designs is used to interpret the strength of evidence between different pairs of risk factors and health outcomes.

Immunoglobulin G3 (IgG3) has an uncertain role in the response to infection with and vaccination against human immunodeficiency virus (HIV). Here we describe a regulatory role for IgG3 in dampening the immune system–activating effects of chronic HIV viremia on B cells. Secreted IgG3 was bound to IgM-expressing B cells in vivo in HIV-infected chronically viremic individuals but not in early-viremic or aviremic individuals. Tissue-like memory (TLM) B cells, a population expanded by persistent HIV viremia, bound large amounts of IgG3. IgG3 induced clustering of B cell antigen receptors (BCRs) on the IgM + B cells, which was mediated by direct interactions between soluble IgG3 and membrane IgM of the BCR (IgM-BCR). The inhibitory IgG receptor CD32b (FcγRIIb), complement component C1q and inflammatory biomarker CRP contributed to the binding of secreted IgG3 onto IgM-expressing B cells of HIV-infected individuals. Notably, IgG3-bound TLM B cells were refractory to IgM-BCR stimulation, thus demonstrating that IgG3 can regulate B cells during chronic activation of the immune system. Circulating IgG3 increases in chronic HIV infection. Moir and colleagues describe a negative regulatory role of secreted IgG3 in response to chronic HIV infection through its action on nonconventional CD27 – memory B cells.

Meningiomas are the most common primary intracranial tumors. Although most symptomatic cases can be managed by surgery and/or radiotherapy, a relevant number of patients experience an unfavorable clinical course and additional treatment options are needed. As meningiomas are often perfused by dural branches of the external carotid artery, which is located outside the blood–brain barrier, they might be an accessible target for immunotherapy. However, the landscape of naturally presented tumor antigens in meningioma is unknown. We here provide a T-cell antigen atlas for meningioma by in-depth profiling of the naturally presented immunopeptidome using LC–MS/MS. Candidate target antigens were selected based on a comparative approach using an extensive immunopeptidome data set of normal tissues. Meningioma-exclusive antigens for HLA class I and II are described here for the first time. Top-ranking targets were further functionally characterized by showing their immunogenicity through in vitro T-cell priming assays. Thus, we provide an atlas of meningioma T-cell antigens which will be publicly available for further research. In addition, we have identified novel actionable targets that warrant further investigation as an immunotherapy option for meningioma.

Purpose Radiotherapy treatment planning is a complex process with multiple, dependent steps involving an interdisciplinary patient care team. Effective communication and real‐time tracking of resources and care path activities are key for clinical efficiency and patient safety. Materials and Methods We designed and implemented a secure, interactive web‐based dashboard for patient care path, clinical workflow, and resource utilization management. The dashboard enables visualization of resource utilization and tracks progress in a patient's care path from the time of acquisition of the planning CT to the time of treatment in real‐time. It integrates with the departmental electronic medical records (EMR) system without the creation and maintenance of a separate database or duplication of work by clinical staff. Performance measures of workflow were calculated. Results The dashboard implements a standardized clinical workflow and dynamically consolidates real‐time information queried from multiple tables in the EMR database over the following views: (1) CT Sims summarizes patient appointment information on the CT simulator and patient load; (2) Linac Sims summarizes patient appointment times, setup history, and notes, and patient load; (3) Task Status lists the clinical tasks associated with a treatment plan, their due date, status and ownership, and patient appointment details; (4) Documents provides the status of all documents in the patients' charts; and (5) Diagnoses and Interventions summarizes prescription information, imaging instructions and whether the plan was approved for treatment. Real‐time assessment and quantification of progress and delays in a patient's treatment start were achieved. Conclusions This study indicates it is feasible to develop and implement a dashboard, tailored to the needs of an interdisciplinary team, which derives and integrates information from the EMR database for real‐time analysis and display of resource utilization and clinical workflow in radiation oncology. The framework developed facilitates informed, data‐driven decisions on clinical workflow management as we seek to optimize clinical efficiency and patient safety.

Medulloblastoma is the most frequent malignant primary brain tumor in children. Despite recent advances in integrated genomics, the prognosis in children with high-risk medulloblastoma remains devastating, and new tumor-specific therapeutic approaches are needed. Here, we present an atlas of naturally presented T cell antigens in medulloblastoma. We map the human leukocyte antigen (HLA)-presented peptidomes of 28 tumors and perform comparative immunopeptidome profiling against an in-house benign database. Medulloblastoma is shown to be a rich source of tumor-associated antigens, naturally presented on HLA class I and II molecules. Remarkably, most tumor-associated peptides and proteins are subgroup-specific, whereas shared presentation among all subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) is rare. Functional testing of top-ranking novel candidate antigens demonstrates the induction of peptide-specific T cell responses, supporting their potential for T cell immunotherapy. This study is an in-depth mapping of naturally presented T cell antigens in medulloblastoma. Integration of immunopeptidomics, transcriptomics, and epigenetic data leads to the identification of a large set of actionable targets that can be further used for the translation into the clinical setting by facilitating the informed design of immunotherapeutic approaches to children with medulloblastoma. Medulloblastoma in children is a difficult cancer to treat and the immune response to this tumour is not fully understood. Here the authors characterise and validate T cell epitopes from these cancers using an immunopeptidomics approach, comparing different molecular subtypes.