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Biological embedding occurs when life experience alters biological processes to affect later life health and well-being. Although extensive correlative data exist supporting the notion that epigenetic mechanisms such as DNA methylation underlie biological embedding, causal data are lacking. We describe specific epigenetic mechanisms and their potential roles in the biological embedding of experience. We also consider the nuanced relationships between the genome, the epigenome, and gene expression. Our ability to connect biological embedding to the epigenetic landscape in its complexity is challenging and complicated by the influence of multiple factors. These include cell type, age, the timing of experience, sex, and DNA sequence. Recent advances in molecular profiling and epigenome editing, combined with the use of comparative animal and human longitudinal studies, should enable this field to transition from correlative to causal analyses.

Adverse childhood experiences (ACEs) have consistently been associated with elevated risk of multiple adverse health outcomes, yet their contribution to coping ability and psychiatric resilience in adulthood is unclear. Cross-sectional data were derived from the ongoing Stress-And-Gene-Analysis cohort, representing 30% of the Icelandic nationwide female population, 18-69 years. Participants in the current study were 26,198 women with data on 13 ACEs measured with the ACE-International Questionnaire. Self-reported coping ability was measured with the Connor-Davidson Resilience Scale and psychiatric resilience was operationalized as absence of psychiatric morbidity. Generalized linear regression assuming normal or Poisson distribution were used to assess the associations of ACEs with coping ability and psychiatric resilience controlling for multiple confounders. Number of ACEs was inversely associated with adult resilience in a dose-dependent manner; every 1SD unit increase in ACE scores was associated with both lower levels of coping ability ( = -0.14; 95% CI-0.15,-0.13) and lower psychiatric resilience ( = -0.28; 95% CI-0.29,-0.27) in adulthood. Compared to women with 0 ACEs, women with ≥5 ACEs had 36% lower prevalence of high coping ability (PR = 0.64, 95% CI 0.59,0.70) and 58% lower prevalence of high psychiatric resilience (PR = 0.42; 95% CI 0.39,0.45). Specific ACEs including emotional neglect, bullying, sexual abuse and mental illness of household member were consistently associated with reduced adult resilience. We observed only slightly attenuated associations after controlling for adult socioeconomic factors and social support in adulthood. Cumulative ACE exposure is associated with lower adult resilience among women, independent of adult socioeconomic factors and social support, indicating that adult resilience may be largely determined in childhood. This work was supported by the European Research Council (Consolidator grant; UAV, grant number 726413), and the Icelandic Center for Research (Grant of excellence; UAV, grant number 163362-051). HBD was supported by a doctoral grant from the University of Iceland Research Fund.

Laboratory and animal studies indicate that melatonin exerts a negative impact on breast cancer progression and metastasis. These actions are both receptor-dependent and -independent. Of the two transmembrane melatonin receptors identified in humans, breast cancer expresses only MT1. The aim of this study was to investigate the expression of MT1 in hormone-receptor-positive, HER2-negative invasive ductal breast carcinoma in postmenopausal women and its possible correlations with clinicopathological parameters and survival. A total of 118 patients with luminal A/B primary breast cancer with or without axillary metastases were identified. The MT1 receptor expression was immunohistochemically assessed as a percentage of stained cells and a weighted index (WI) (percentage multiplied by staining intensity). Most tumor samples (84.7%) and metastasized lymph nodes (96%) stained positive for MT1, with varying intensity. No statistically significant correlations were found between the MT1 expression or the WI in the primary tumor and the patient and tumor characteristics, or the MT1 and WI in the metastasized lymph nodes. The survival analysis did not reveal a significant effect of MT1 expression or the WI on the risk of recurrence or survival.

Background Differential effects of the coronavirus SARS‐CoV‐2 (COVID‐19) pandemic and associated public restrictions on adolescent girls and boys are emerging but have not been elucidated. This study examined gender differences across broad indicators of adolescent well‐being during the COVID‐19 pandemic in Iceland, and explored potential explanations for these differences. Methods In total, 523 youth (56.5% girls) born in Iceland in 2004 completed measures on mental health problems (depressive symptoms, anger and suicide attempts) and measures designed for this study to assess broad indicators of adolescent well‐being (e.g., day‐to‐day life, academic performance, family and peer relationships, and mental and physical health) and behavioral changes during the COVID‐19 pandemic. Mental health problems during the pandemic were compared to expected scores based on nationwide ratings of same‐aged peers in 2018. Results Although both boys and girls appeared affected, girls reported a greater negative impact across all the broad indicators of well‐being and behavioral change during COVID‐19 than boys, and their depressive symptoms were above and beyond the expected nationwide scores (t(1514) = 4.80, p < .001, Cohen's d = 0.315). Higher depressive symptoms were associated with increased passive social media use and decreased connecting with family members via telephone or social media among girls, and decreased sleeping and increased online gaming alone among boys. Concern about others contracting COVID‐19, changes in daily and school routines, and not seeing friends in person were among the primary contributors to poor mental health identified by youth, particularly girls. Conclusions Adolescents were broadly negatively affected by the COVID‐19 pandemic and accompanying restrictions; however, this negative impact was more pronounced in girls. The findings suggest that a steady routine and remaining socially connected may help youth cope with the uncertainty and social restrictions associated with a pandemic. Moreover, healthcare providers, teachers, and other professionals should pay close attention to depressive symptoms among girls during a pandemic.

Substantial sex differences have been reported in the physiological response to stress at multiple levels, including the release of the stress hormone, cortisol. Here, we explore the genomic variants in 93 females and 196 males regulating the initial transcriptional response to cortisol via glucocorticoid receptor (GR) activation. Gene expression levels in peripheral blood were obtained before and after GR-stimulation with the selective GR agonist dexamethasone to identify differential expression following GR-activation. Sex stratified analyses revealed that while the transcripts responsive to GR-stimulation were mostly overlapping between males and females, the quantitative trait loci (eQTLs) regulation differential transcription to GR-stimulation was distinct. Sex-stratified eQTL SNPs (eSNPs) were located in different functional genomic elements and sex-stratified transcripts were enriched within postmortem brain transcriptional profiles associated with Major Depressive Disorder (MDD) specifically in males and females in the cingulate cortex. Female eSNPs were enriched among SNPs linked to MDD in genome-wide association studies. Finally, transcriptional sensitive genetic profile scores derived from sex-stratified eSNPS regulating differential transcription to GR-stimulation were predictive of depression status and depressive symptoms in a sex-concordant manner in a child and adolescent cohort (n = 584). These results suggest the potential of eQTLs regulating differential transcription to GR-stimulation as biomarkers of sex-specific biological risk for stress-related psychiatric disorders.

Background Childhood abuse and neglect have been associated with premenstrual disorders (PMDs), including premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). However, the associations of other adverse childhood experiences (ACEs) and the cumulative number of ACEs with PMDs remain to be explored. Methods To evaluate the associations of the cumulative number and types of ACEs with PMDs, we conducted a cross-sectional analysis with a subsample of menstruating women within the Stress-And-Gene-Analysis (SAGA) cohort, assessed for PMDs and ACEs ( N =11,973). The cumulative and individual exposure of 13 types of ACEs was evaluated by a modified ACE-International Questionnaire. A modified version of the Premenstrual Symptom Screening Tool was used to identify probable cases of PMDs, further sub-grouped into PMS and PMDD. Prevalence ratios (PRs) of PMDs in relation to varying ACEs were estimated using Poisson regression. Results At a mean age of 34.0 years (standard deviation (SD) 9.1), 3235 (27%) met the criteria of probable PMDs, including 2501 (21%) for PMS and 734 (6%) for PMDD. The number of ACEs was linearly associated with PMDs (fully-adjusted PR 1.12 per ACE, 95% CI 1.11–1.13). Specifically, the PR for PMDs was 2.46 (95% CI 2.21–2.74) for women with 4 or more ACEs compared with women with no ACEs. A stronger association was observed for probable PMDD compared to PMS ( p for difference <0.001). The associations between ACEs and PMDs were stronger among women without PTSD, anxiety, or depression, and without childhood deprivation and were stronger among women a lower level of social support ( p for interaction<0.001). All types of ACEs were positively associated with PMDs (PRs ranged from 1.11 to 1.51); the associations of sexual abuse, emotional neglect, family violence, mental illness of a household member, and peer and collective violence were independent of other ACEs. Conclusions Our findings suggest that childhood adverse experiences are associated with PMDs in a dose-dependent manner. If confirmed by prospective data, our findings support the importance of early intervention for girls exposed to ACEs to minimize risks of PMDs and other morbidities in adulthood.

Evidence supporting the association between posttraumatic stress disorder (PTSD) and cognitive impairment is accumulating. However, less is known about which factors influence this association. The aims of this meta-analysis were to (1) elucidate the association between PTSD and a broad spectrum of cognitive impairment, including the risk of developing neurocognitive disorder (NCD) later in life, using a multilevel meta-analytic approach, and (2) identify potential moderating factors of this association by examining the effects of age (20-39, 40-59, 60+), study design (cross-sectional or longitudinal), study population (war-exposed populations/veterans or the general population), neurocognitive outcome assessed (i.e. a diagnosis of NCD or type of cognitive domain as classified according to A Compendium of Neuropsychological tests), gender (≥50% women or <50% women), study quality (high vs low), type of PTSD measure (self-report or clinical diagnosis), as well as the presence of comorbidities such as traumatic brain injury (TBI), depression, and substance use (all coded as either present or absent). Peer-reviewed studies on this topic were extracted from PubMed and Web of Science with predetermined keywords and criteria. In total, 53 articles met the criteria. Hedge's effect sizes were calculated for each study and a three-level random effect meta-analysis conducted. After accounting for publication bias, the results suggested a significant association between PTSD and cognitive impairment,  = 0.13 (95% CI: 0.10-0.17), indicating a small effect. This association was consistent across all examined moderators, including various neurocognitive outcomes, age, gender, study design, study population, study quality, type of PTSD measure, and comorbidities such as depression, substance use, and TBI. These findings collectively suggest that PTSD is associated with both cognitive impairment and NCD. This emphasizes the need for early intervention (including prevention strategies) of PTSD, alongside monitoring cognitive function in affected individuals.International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42021219189, date of registration: 02.01.2021.

PurposeIdentifying and understanding modifiable risk and protective factors that can inform early detection and intervention to prevent adolescent emotional problems and harmful behaviours is among the most pressing modern-day public health challenges. This paper describes the rationale, objectives, methods, and anticipated outcomes of the LIFECOURSE study, a multi-level, bio-psychosocial prospective study designed to advance our understanding of factors that shape adolescent mental health and behaviour. MethodsConducted by the Icelandic Centre for Social Research and Analysis at Reykjavik University, LIFECOURSE is a longitudinal population-based developmental study of Icelandic adolescents born in 2004. The study utilizes a comprehensive multi-informant assessment of individual, societal and biological factors measured across the lifespan. Data assembly and collection were conducted from 2016–2020 and utilize both retrospective and prospective data sources: (a) retrospective registry data assembled from seven national databases, (b) prospectively collected social surveys and (c) biomarker samples. ResultsOf the 3914 eligible adolescents, 60.8% (n = 2378) provided informed parental consent and student assent to participate in the study, with approximately half of the participants being female (n = 1175, 49.4%) and the majority being born in the capital area (n = 1455; 61.2%). The coverage of available data from the national databases and participation in the social surveys ranged from 81.7 to 100%.ConclusionsMajor gaps remain in our knowledge of how individual, societal and biological factors across the lifespan—from early life to adolescence—interact and shape the risk for emotional problems and harmful behaviours during adolescence. The LIFECOURSE study was designed to address this knowledge gap.

ABSTRACT Background Cancer‐related cognitive impairment (CRCI), for example, impairments in reaction time, processing speed, memory and executive function, may be associated with breast cancer (BC) surgery which can disrupt biological and psychological stress markers. Evidence suggests that light therapy may ameliorate cognitive impairment and stress. In this double‐blind, randomized controlled trial, we investigated the efficacy of light therapy on mitigating the impact of BC surgery on CRCI in a national Icelandic cohort of women with BC. Methods Participants were randomly allocated to receive circadian‐effective blue light (BL, N = 60) or circadian‐ineffective dim light (DL, N = 57) for 4 weeks after surgery. The primary outcome was overall cognitive performance (assessed via global composite score), and secondary outcomes were specific cognitive domains, cognitive complaints, psychological (depressive symptoms, overall cancer‐related stress and its symptoms: hyperarousal, avoidance, and intrusive thoughts) and biological (cortisol and α‐amylase) stress markers. Linear regression and path analyses within structural equation modeling frameworks were conducted, adjusted for baseline cognitive performance, age, education, subsequent cancer treatment, cancer stage, and treatment credibility. Results No group differences were found in overall cognitive performance or in specific cognitive domains, except for a non‐significant trend for faster reaction times in the BL group (p < 0.11). Additionally, the BL group reported significantly fewer cognitive complaints compared with the DL group (p < 0.05), as well as a non‐significant trend for less intrusive thoughts (p < 0.11). No group differences were observed in the biological stress markers. Conclusion Overall, these findings suggest that light therapy may help mitigate the adverse effects associated with BC surgery on CRCI and intrusive thoughts, although further research is warranted. Trial Registration: NCT04418856

Background:Novel interventions should be developed for people who have undergone psychological trauma. In a previous case study, we found that the number of intrusive memories of trauma could be reduced with a novel intervention. The intervention included a brief memory reminder, a visuospatial task and mental rotation, and targeted trauma memory hotspots one at a time in separate sessions.Objective:This case series (N=3) extended the first case study with 3 new cases to determine whether a similar pattern of beneficial results is observed. We explored whether the brief intervention would result in reduced numbers of intrusive memories and whether it would impact symptoms of posttraumatic stress, depression and anxiety, and general functioning. Acceptability of the intervention was also explored.Methods:A total of 3 women completed the study: 2 with posttraumatic stress disorder and other comorbidities and 1 with subthreshold posttraumatic stress disorder. The primary outcome was the change in the number of intrusive memories from the baseline phase to the intervention phase and at the 1-month follow-up, with an assessment of the intrusion frequency at 3 months. Participants monitored the number of intrusive memories in a daily diary for 1 week at baseline, for maximum of 6 weeks during the intervention phase and for 1 week at the 1-month and 3-month follow-ups. The intervention was delivered in person or digitally, with guidance from a clinical psychologist. A repeated AB design was used (A was a preintervention baseline phase and B intervention phase). Intrusions were targeted individually, creating repetitions of an AB design.Results:The total number of intrusive memories was reduced from the baseline to the intervention phase for all participants. The total number for participant 3 (P3) reduced from 38.8 per week during the baseline phase to 18.0 per week in the intervention phase. It was 13 at the 3-month follow-up. The total number for P4 reduced from 10.8 per week at baseline to 4.7 per week in the intervention phase. It was 0 at the 3-month follow-up. The total number for P5 was reduced from 33.7 at baseline to 20.7 per week in the intervention phase. It was 8 at the 3-month follow-up. All participants reported reduction in posttraumatic stress symptoms in the postintervention phase. Depression and anxiety symptoms reduced in 2 of the 3 participants in the postintervention phase. Acceptability was favorable.Conclusions:We observed good compliance with the intervention and intrusive memory diary in all 3 cases. The number of intrusive memories was reduced for all participants during the intervention phase and at the 1-month follow-up, with some improvement in other symptoms and functioning. Further research should explore the remote delivery of the intervention and whether nonspecialists can deliver the intervention effectively.