The Impact of Early Childhood Life Adversity on Peripubertal Accelerated Epigenetic Aging and Psychopathology.

OBJECTIVE: To examine longitudinal associations between early life threat and deprivation on epigenetic age acceleration at ages 9 and 15 years, and to examine associations of age acceleration on later internalizing and externalizing symptoms. METHOD: The study examines a large (n = 2,039) and racially diverse (Black/African American = 44%, Latino = 18%, White = 5%) sample from a national dataset. Epigenetic age acceleration was estimated using the pediatric buccal epigenetic clock. Early life threat and deprivation were measured using composites from the Parent-Child Conflict Tactics Scale and county-level violent and property crime rate data. Internalizing and externalizing symptoms came from parent-reported Child Behavior Checklist. Path analysis models examined associations of threat and deprivation at age 3 years on epigenetic age acceleration at ages 9 and 15. Experiences of threat were further broken down into threat experienced in the home and in the community. RESULTS: Home threat experienced at age 3 years predicted age acceleration at 9 and 15, and community threat experienced at 3 predicted age acceleration at 15, but not at 9. Deprivation was not a significant predictor of accelerated aging. Age acceleration at age 9 predicted externalizing, but not internalizing, symptoms at age 15. Community threat had a direct effect on externalizing. No association emerged with internalizing. CONCLUSION: Findings revealed that threat, not deprivation, was predictive of age acceleration, demonstrating support for this pattern longitudinally, using an epigenetic clock that is accurate in children. The findings provide critical nuance to the examination of threat, and highlight associated risks and possible intervention points for externalizing symptoms.

Oral Immunotherapy: An Overview.

Oral immunotherapy (OIT) is an alternative treatment of IgE-mediated food allergy that has been shown to increase tolerance threshold to many of the top food allergens, although this effect may be dependent on age, dose, frequency, and duration. OIT has been shown to be effective and safe in infants, and early initiation can improve rates of desensitization even for those foods whose natural history favors loss of allergy. Studies looking at protocol modification to improve OIT success are ongoing as is the evaluation of clinical tools to help monitor OIT effects.

Sex-Specific Associations between Prenatal Exposure to Di(2-ethylhexyl) Phthalate, Epigenetic Age Acceleration, and Susceptibility to Early Childhood Upper Respiratory Infections.

Di(2-ethylhexyl) phthalate (DEHP) is a common plasticizer that can affect immune system development and susceptibility to infection. Aging processes (measured as epigenetic age acceleration (EAA)) may mediate the immune-related effects of prenatal exposure to DEHP. This study's objective was to examine associations between prenatal DEHP exposure, EAA at three months of age, and the number of upper respiratory infections (URIs) from 12 to 18 months of age using a sample of 69 maternal-child pairs from a Canadian pregnancy cohort. Blood DNA methylation data were generated using the Infinium HumanMethylation450 BeadChip; EAA was estimated using Horvath's pan-tissue clock. Robust regressions examined overall and sex-specific associations. Higher prenatal DEHP exposure (B = 6.52, 95% CI = 1.22, 11.81) and increased EAA (B = 2.98, 95% CI = 1.64, 4.32) independently predicted more URIs. In sex-specific analyses, some similar effects were noted for boys, and EAA mediated the association between prenatal DEHP exposure and URIs. In girls, higher prenatal DEHP exposure was associated with decreased EAA, and no mediation was noted. Higher prenatal DEHP exposure may be associated with increased susceptibility to early childhood URIs, particularly in boys, and aging biomarkers such as EAA may be a biological mechanism. Larger cohort studies examining the potential developmental immunotoxicity of phthalates are needed.

An integrative framework and recommendations for the study of DNA methylation in the context of race and ethnicity.

Human social epigenomics research is critical to elucidate the intersection of social and genetic influences underlying racial and ethnic differences in health and development. However, this field faces major challenges in both methodology and interpretation with regard to disentangling confounded social and biological aspects of race and ethnicity. To address these challenges, we discuss how these constructs have been approached in the past and how to move forward in studying DNA methylation (DNAm), one of the best-characterized epigenetic marks in humans, in a responsible and appropriately nuanced manner. We highlight self-reported racial and ethnic identity as the primary measure in this field, and discuss its implications in DNAm research. Racial and ethnic identity reflects the biological embedding of an individual's sociocultural experience and environmental exposures in combination with the underlying genetic architecture of the human population (i.e., genetic ancestry). Our integrative framework demonstrates how to examine DNAm in the context of race and ethnicity, while considering both intrinsic factors-including genetic ancestry-and extrinsic factors-including structural and sociocultural environment and developmental niches-when focusing on early-life experience. We reviewed DNAm research in relation to health disparities given its relevance to race and ethnicity as social constructs. Here, we provide recommendations for the study of DNAm addressing racial and ethnic differences, such as explicitly acknowledging the self-reported nature of racial and ethnic identity, empirically examining the effects of genetic variants and accounting for genetic ancestry, and investigating race-related and culturally regulated environmental exposures and experiences. Supplementary Information: The online version contains supplementary material available at 10.1007/s44155-023-00039-z.

Oral Immunotherapy: An Overview.

Oral immunotherapy (OIT) is an alternative treatment of IgE-mediated food allergy that has been shown to increase tolerance threshold to many of the top food allergens, although this effect may be dependent on age, dose, frequency, and duration. OIT has been shown to be effective and safe in infants, and early initiation can improve rates of desensitization even for those foods whose natural history favors loss of allergy. Studies looking at protocol modification to improve OIT success are ongoing as is the evaluation of clinical tools to help monitor OIT effects.

Rare diseases of epigenetic origin: Challenges and opportunities.

Rare diseases (RDs), more than 80% of which have a genetic origin, collectively affect approximately 350 million people worldwide. Progress in next-generation sequencing technology has both greatly accelerated the pace of discovery of novel RDs and provided more accurate means for their diagnosis. RDs that are driven by altered epigenetic regulation with an underlying genetic basis are referred to as rare diseases of epigenetic origin (RDEOs). These diseases pose unique challenges in research, as they often show complex genetic and clinical heterogeneity arising from unknown gene-disease mechanisms. Furthermore, multiple other factors, including cell type and developmental time point, can confound attempts to deconvolute the pathophysiology of these disorders. These challenges are further exacerbated by factors that contribute to epigenetic variability and the difficulty of collecting sufficient participant numbers in human studies. However, new molecular and bioinformatics techniques will provide insight into how these disorders manifest over time. This review highlights recent studies addressing these challenges with innovative solutions. Further research will elucidate the mechanisms of action underlying unique RDEOs and facilitate the discovery of treatments and diagnostic biomarkers for screening, thereby improving health trajectories and clinical outcomes of affected patients.

Associations of peripheral blood DNA methylation and estimated monocyte proportion differences during infancy with toddler attachment style.

Attachment is a motivational system promoting felt security to a caregiver resulting in a persistent internal working model of interpersonal behavior. Attachment styles are developed in early social environments and predict future health and development outcomes with potential biological signatures, such as epigenetic modifications like DNA methylation (DNAm). Thus, we hypothesized infant DNAm would associate with toddler attachment styles. An epigenome-wide association study (EWAS) of blood DNAm from 3-month-old infants was regressed onto children's attachment style from the Strange Situation Procedure at 22-months at multiple DNAm Cytosine-phosphate-Guanine (CpG) sites. The 26 identified CpGs associated with proinflammatory immune phenotypes and cognitive development. In post-hoc analyses, only maternal cognitive-growth fostering, encouraging intellectual exploration, contributed. For disorganized children, DNAm-derived cell-type proportions estimated higher monocytes -cells in immune responses hypothesized to increase with early adversity. Collectively, these findings suggested the potential biological embedding of both adverse and advantageous social environments as early as 3-months-old.

Sex differences in epigenetic age in Mediterranean high longevity regions.

Sex differences in aging manifest in disparities in disease prevalence, physical health, and lifespan, where women tend to have greater longevity relative to men. However, in the Mediterranean Blue Zones of Sardinia (Italy) and Ikaria (Greece) are regions of centenarian abundance, male-female centenarian ratios are approximately one, diverging from the typical trend and making these useful regions in which to study sex differences of the oldest old. Additionally, these regions can be investigated as examples of healthy aging relative to other populations. DNA methylation (DNAm)-based predictors have been developed to assess various health biomarkers, including biological age, Pace of Aging, serum interleukin-6 (IL-6), and telomere length. Epigenetic clocks are biological age predictors whose deviation from chronological age has been indicative of relative health differences between individuals, making these useful tools for interrogating these differences in aging. We assessed sex differences between the Horvath, Hannum, GrimAge, PhenoAge, Skin and Blood, and Pace of Aging predictors from individuals in two Mediterranean Blue Zones and found that men displayed positive epigenetic age acceleration (EAA) compared to women according to all clocks, with significantly greater rates according to GrimAge (ß = 3.55; p = 1.22 × 10-12), Horvath (ß = 1.07; p = 0.00378) and the Pace of Aging (ß = 0.0344; p = 1.77 × 10-08). Other DNAm-based biomarkers findings indicated that men had lower DNAm-predicted serum IL-6 scores (ß = -0.00301, p = 2.84 × 10-12), while women displayed higher DNAm-predicted proportions of regulatory T cells than men from the Blue Zone (p = 0.0150, 95% Confidence Interval [0.00131, 0.0117], Cohen's d = 0.517). All clocks showed better correlations with chronological age in women from the Blue Zones than men, but all clocks showed large mean absolute errors (MAE >30 years) in both sexes, except for PhenoAge (MAE <5 years). Thus, despite their equal survival to older ages in these Mediterranean Blue Zones, men in these regions remain biologically older by most measured DNAm-derived metrics than women, with the exception of the IL-6 score and proportion of regulatory T cells.

Association of Pediatric Buccal Epigenetic Age Acceleration With Adverse Neonatal Brain Growth and Neurodevelopmental Outcomes Among Children Born Very Preterm With a Neonatal Infection.

Importance: Very preterm neonates (24-32 weeks' gestation) remain at a higher risk of morbidity and neurodevelopmental adversity throughout their lifespan. Because the extent of prematurity alone does not fully explain the risk of adverse neonatal brain growth or neurodevelopmental outcomes, there is a need for neonatal biomarkers to help estimate these risks in this population. Objectives: To characterize the pediatric buccal epigenetic (PedBE) clock-a recently developed tool to measure biological aging-among very preterm neonates and to assess its association with the extent of prematurity, neonatal comorbidities, neonatal brain growth, and neurodevelopmental outcomes at 18 months of age. Design, Setting, and Participants: This prospective cohort study was conducted in 2 neonatal intensive care units of 2 hospitals in Toronto, Ontario, Canada. A total of 35 very preterm neonates (24-32 weeks' gestation) were recruited in 2017 and 2018, and neuroimaging was performed and buccal swab samples were acquired at 2 time points: the first in early life (median postmenstrual age, 32.9 weeks [IQR, 32.0-35.0 weeks]) and the second at term-equivalent age (TEA) at a median postmenstrual age of 43.0 weeks (IQR, 41.0-46.0 weeks). Follow-ups for neurodevelopmental assessments were completed in 2019 and 2020. All neonates in this cohort had at least 1 infection because they were originally enrolled to assess the association of neonatal infection with neurodevelopment. Neonates with congenital malformations, genetic syndromes, or congenital TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes and other agents) infection were excluded. Exposures: The extent of prematurity was measured by gestational age at birth and PedBE age difference. PedBE age was computed using DNA methylation obtained from 94 age-informative CpG (cytosine-phosphate-guanosine) sites. PedBE age difference (weeks) was calculated by subtracting PedBE age at each time point from the corresponding postmenstrual age. Main Outcomes and Measures: Total cerebral volumes and cerebral growth during the neonatal intensive care unit period were obtained from magnetic resonance imaging scans at 2 time points: approximately the first 2 weeks of life and at TEA. Bayley Scales of Infant and Toddler Development, Third Edition, were used to assess neurodevelopmental outcomes at 18 months. Results: Among 35 very preterm neonates (21 boys [60.0%]; median gestational age, 27.0 weeks [IQR, 25.9-29.9 weeks]; 23 [65.7%] born extremely preterm [<28 weeks' gestation]), extremely preterm neonates had an accelerated PedBE age compared with neonates born at a later gestational age (ß = 9.0; 95% CI, 2.7-15.3; P = .01). An accelerated PedBE age was also associated with smaller cerebral volumes (ß = -5356.8; 95% CI, -6899.3 to -2961.7; P = .01) and slower cerebral growth (ß = -2651.5; 95% CI, -5301.2 to -1164.1; P = .04); these associations remained significant after adjusting for clinical neonatal factors. These findings were significant at TEA but not earlier in life. Similarly, an accelerated PedBE age at TEA was associated with lower cognitive (ß = -0.4; 95% CI, -0.8 to -0.03; P = .04) and language (ß = -0.6; 95% CI, -1.1 to -0.06; P = .02) scores at 18 months. Conclusions and Relevance: This cohort study of very preterm neonates suggests that biological aging may be associated with impaired brain growth and neurodevelopmental outcomes. The associations between epigenetic aging and adverse neonatal brain health warrant further attention.

Study protocol for Attachment & Child Health (ATTACHTM) program: promoting vulnerable Children's health at scale.

BACKGROUND: Children's exposure to toxic stress (e.g., parental depression, violence, poverty) predicts developmental and physical health problems resulting in health care system burden. Supporting parents to develop parenting skills can buffer the effects of toxic stress, leading to healthier outcomes for those children. Parenting interventions that focus on promoting parental reflective function (RF), i.e., parents' capacity for insight into their child's and their own thoughts, feelings, and mental states, may understand help reduce societal health inequities stemming from childhood stress exposures. The Attachment and Child Health (ATTACHTM) program has been implemented and tested in seven rapid-cycling pilot studies (n = 64) and found to significantly improve parents' RF in the domains of attachment, parenting quality, immune function, and children's cognitive and motor development. The purpose of the study is to conduct an effectiveness-implementation hybrid (EIH) Type II study of ATTACHTM to assess its impacts in naturalistic, real-world settings delivered by community agencies rather than researchers under more controlled conditions. METHODS: The study is comprised of a quantitative pre/post-test quasi-experimental evaluation of the ATTACHTM program, and a qualitative examination of implementation feasibility using thematic analysis via Normalization Process Theory (NPT). We will work with 100 families and their children (birth to 36-months-old). Study outcomes include: the Parent Child Interaction Teaching Scale to assess parent-child interaction; the Parental Reflective Function and Reflective Function Questionnaires to assess RF; and the Ages and Stages Questionnaire - 3rd edition to examine child development, all administered pre-, post-, and 3-month-delayed post-assessment. Blood samples will be collected pre- and post- assessment to assess immune biomarkers. Further, we will conduct one-on-one interviews with study participants, health and social service providers, and administrators (total n = 60) from each collaborating agency, using NPT to explore perceptions and experiences of intervention uptake, the fidelity assessment tool and e-learning training as well as the benefits, barriers, and challenges to ATTACHTM implementation. DISCUSSION: The proposed study will assess effectiveness and implementation to help understand the delivery of ATTACHTM in community agencies. TRIAL REGISTRATION: Name of registry: https://clinicaltrials.gov/. REGISTRATION NUMBER: NCT04853888 . Date of registration: April 22, 2021.

Prenatal exposure to phthalates and peripheral blood and buccal epithelial DNA methylation in infants: An epigenome-wide association study.

BACKGROUND: Prenatal exposure to phthalates has been associated with adverse health and neurodevelopmental outcomes. DNA methylation (DNAm) alterations may be a mechanism underlying these effects, but prior investigations of prenatal exposure to phthalates and neonatal DNAm profiles are limited to placental tissue and umbilical cord blood. OBJECTIVE: Conduct an epigenome-wide association study (EWAS) of the associations between prenatal exposure to phthalates and DNAm in two accessible infant tissues, venous buffy coat blood and buccal epithelial cells (BECs). METHODS: Participants included 152 maternal-infant pairs from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Maternal second trimester urine samples were analyzed for nine phthalate metabolites. Blood (n = 74) or BECs (n = 78) were collected from 3-month-old infants and profiled for DNAm using the Infinium HumanMethylation450 (450K) BeadChip. Robust linear regressions were used to investigate the associations between high (HMWPs) and low molecular weight phthalates (LMWPs) and change in methylation levels at variable Cytosine-phosphate-Guanine (CpG) sites in infant tissues, as well as the sensitivity of associations to potential confounders. RESULTS: One candidate CpG in gene RNF39 reported by a previous study examining prenatal exposure to phthalates and cord blood DNAm was replicated. The EWAS identified 12 high-confidence CpGs in blood and another 12 in BECs associated with HMWPs and/or LMWPs. Prenatal exposure to bisphenol A (BPA) associated with two of the CpGs associated with HMWPs in BECs. DISCUSSION: Prenatal exposure to phthalates was associated with DNAm variation at CpGs annotated to genes associated with endocrine hormone activity (i.e., SLCO4A1, TPO), immune pathways and DNA damage (i.e., RASGEF1B, KAZN, HLA-A, MYO18A, DIP2C, C1or109), and neurodevelopment (i.e., AMPH, NOTCH3, DNAJC5). Future studies that characterize the stability of these associations in larger samples, multiple cohorts, across tissues, and investigate the potential associations between these biomarkers and relevant health and neurodevelopmental outcomes are needed.

Clinical outcomes of first- and second-generation hydrogel coils compared with bare platinum coils: a systematic literature review.

Endovascular coiling has revolutionized intracranial aneurysm treatment; however, recurrence continues to represent a major limitation. The hydrogel coil was developed to increase packing density and improve neck healing and therefore decrease recurrence rates. In this paper, we review treatment outcomes of first- (1HCs) and second-generation (2HCs) hydrogel coils and compare them to those of bare platinum coils (BPC). A query of multiple databases was performed. Articles with at least 10 aneurysms treated with either 1HC or 2HC were selected for analysis. Collected data included aneurysm size, rupture status, initial occlusion, initial residual neck/aneurysm, packing density, mortality, morbidity, recurrence, and retreatment rates. The primary endpoint was recurrence at final follow-up. Secondary endpoints included residual neck and dome rates as well as procedure-related complications and functional dependence at final follow-up. Studies that compared 1HC to BPC showed significant lower recurrence (24% vs. 30.8%, p = 0.02) and higher packing density (58.5% vs. 24.1%, p < 0.001) in 1HC but no significant difference in initial occlusion rate (p = 0.08). Studies that compared 2HC to BPC showed lower recurrence (6.3% vs. 14.3%, p = 0.007) and retreatment rates (3.4% vs. 7.7%, p = 0.010) as well as higher packing density (36.4% vs. 29.2%, p = 0.002) in 2HC, with similar initial occlusion rate (p = 0.86). The rate of complications was not statistically different between HC (25.5%) and BPC (22.6%, p = 0.06). Based on our review, the 1HC and 2HC achieved higher packing density and lower recurrence rates compared to BPC. The safety profile was similar between both groups.

A Neural Circuit for Spirituality and Religiosity Derived From Patients With Brain Lesions.

BACKGROUND: Over 80% of the global population consider themselves religious, with even more identifying as spiritual, but the neural substrates of spirituality and religiosity remain unresolved. METHODS: In two independent brain lesion datasets (N1 = 88; N2 = 105), we applied lesion network mapping to test whether lesion locations associated with spiritual and religious belief map to a specific human brain circuit. RESULTS: We found that brain lesions associated with self-reported spirituality map to a brain circuit centered on the periaqueductal gray. Intersection of lesion locations with this same circuit aligned with self-reported religiosity in an independent dataset and previous reports of lesions associated with hyper-religiosity. Lesion locations causing delusions and alien limb syndrome also intersected this circuit. CONCLUSIONS: These findings suggest that spirituality and religiosity map to a common brain circuit centered on the periaqueductal gray, a brainstem region previously implicated in fear conditioning, pain modulation, and altruistic behavior.

Infant DNA methylation: an early indicator of intergenerational trauma?

Exposure to adverse childhood experiences (ACEs) increases risk for mental and physical health problems. Intergenerationally, mothers' ACEs predict children's health problems including neurodevelopmental and behavioural problems and poorer physical health. Theories of intergenerational trauma suggest that ACEs experienced in one generation negatively affect the health and well-being of future generations, with DNA methylation (DNAm) being one of several potential biological explanations. To begin exploring this hypothesis, we tested whether infant DNA methylation associated with intergenerational trauma. Secondary analysis employed data from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Subsample data were collected from mothers during pregnancy and postpartum on measures of distress, stress and ACEs and from infants at 3 months of age on DNAm from blood (n = 92) and buccal epithelial cells (BECs; n = 124; primarily nonoverlapping individuals between tissues). Blood and BECs were examined in separate analyses. Preliminary associations identified in blood and BECs suggest that infant DNAm patterns may relate to maternal ACEs. For the majority of ACE-related DNAm sites, neither maternal perinatal distress, nor maternal cortisol awakening response (CAR; a measure of hypothalamic-pituitary-adrenocortical axis function), substantially reduced associations between maternal ACEs and infant DNAm. However, accounting for maternal perinatal distress and cortisol substantially changed the effect of ACEs in a greater proportion of blood DNAm sites than BEC DNAm sites in the top ACEs-associated correlated methylated regions (CMRs), as well as across all CMRs and all remaining CpGs (that did not fall into CMRs). Possible DNAm patterns in infants, thus, might capture a signature of maternal intergenerational trauma, and this effect appears to be more dependent on maternal perinatal distress and CAR in blood relative to BECs.

Risk-focused differences in molecular processes implicated in SARS-CoV-2 infection: corollaries in DNA methylation and gene expression.

BACKGROUND: Understanding the molecular basis of susceptibility factors to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health imperative. It is well-established that males are more likely to acquire SARS-CoV-2 infection and exhibit more severe outcomes. Similarly, exposure to air pollutants and pre-existing respiratory chronic conditions, such as asthma and chronic obstructive respiratory disease (COPD) confer an increased risk to coronavirus disease 2019 (COVID-19). METHODS: We investigated molecular patterns associated with risk factors in 398 candidate genes relevant to COVID-19 biology. To accomplish this, we downloaded DNA methylation and gene expression data sets from publicly available repositories (GEO and GTEx Portal) and utilized data from an empirical controlled human exposure study conducted by our team. RESULTS: First, we observed sex-biased DNA methylation patterns in autosomal immune genes, such as NLRP2, TLE1, GPX1, and ARRB2 (FDR < 0.05, magnitude of DNA methylation difference Δß > 0.05). Second, our analysis on the X-linked genes identified sex associated DNA methylation profiles in genes, such as ACE2, CA5B, and HS6ST2 (FDR < 0.05, Δß > 0.05). These associations were observed across multiple respiratory tissues (lung, nasal epithelia, airway epithelia, and bronchoalveolar lavage) and in whole blood. Some of these genes, such as NLRP2 and CA5B, also exhibited sex-biased gene expression patterns. In addition, we found differential DNA methylation patterns by COVID-19 status for genes, such as NLRP2 and ACE2 in an exploratory analysis of an empirical data set reporting on human COVID-9 infections. Third, we identified modest DNA methylation changes in CpGs associated with PRIM2 and TATDN1 (FDR < 0.1, Δß > 0.05) in response to particle-depleted diesel exhaust in bronchoalveolar lavage. Finally, we captured a DNA methylation signature associated with COPD diagnosis in a gene involved in nicotine dependence (COMT) (FDR < 0.1, Δß > 0.05). CONCLUSION: Our findings on sex differences might be of clinical relevance given that they revealed molecular associations of sex-biased differences in COVID-19. Specifically, our results hinted at a potentially exaggerated immune response in males linked to autosomal genes, such as NLRP2. In contrast, our findings at X-linked loci such as ACE2 suggested a potentially distinct DNA methylation pattern in females that may interact with its mRNA expression and inactivation status. We also found tissue-specific DNA methylation differences in response to particulate exposure potentially capturing a nitrogen dioxide (NO2) effect-a contributor to COVID-19 susceptibility. While we identified a molecular signature associated with COPD, all COPD-affected individuals were smokers, which may either reflect an association with the disease, smoking, or may highlight a compounded effect of these two risk factors in COVID-19. Overall, our findings point towards a molecular basis of variation in susceptibility factors that may partly explain disparities in the risk for SARS-CoV-2 infection.

Glioblastoma as an age-related neurological disorder in adults.

BACKGROUND: Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDHwt GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDHwt GBM have a median age of diagnosis at 68-70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM. METHODS: The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship. RESULTS: Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve. CONCLUSIONS: Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDHwt GBM patient outcomes.

Paternal adverse childhood experiences: Associations with infant DNA methylation.

Adverse childhood experiences (ACEs), or cumulative childhood stress exposures, such as abuse, neglect, and household dysfunction, predict later health problems in both the exposed individuals and their offspring. One potential explanation suggests exposure to early adversity predicts epigenetic modification, especially DNA methylation (DNAm), linked to later health. Stress experienced preconception by mothers may associate with DNAm in the next generation. We hypothesized that fathers' exposure to ACEs also associates with their offspring DNAm, which, to our knowledge, has not been previously explored. An epigenome-wide association study (EWAS) of blood DNAm (n = 45) from 3-month-old infants was regressed onto fathers' retrospective ACEs at multiple Cytosine-phosphate-Guanosine (CpG) sites to discover associations. This accounted for infants' sex, age, ethnicity, cell type proportion, and genetic variability. Higher ACE scores associated with methylation values at eight CpGs. Post-hoc analysis found no contribution of paternal education, income, marital status, and parental postpartum depression, but did with paternal smoking and BMI along with infant sleep latency. These same CpGs also contributed to the association between paternal ACEs and offspring attention problems at 3 years. Collectively, these findings suggested there were biological associations with paternal early life adversity and offspring DNAm in infancy, potentially affecting offspring later childhood outcomes.

Current Parental Leave Policies for Medical Students at U.S. Medical Schools: A Comparative Study.

PURPOSE: Parental leave for new parents is essential as they adjust to the physical and psychological changes that accompany childbirth and caring for a newborn. This study sought to determine the current state of parental leave policies for medical students at medical schools in the United States. METHOD: From November to December 2019, 2 researchers independently reviewed the websites of 199 U.S. MD-granting and DO-granting medical schools (including in U.S. territories). Online student handbooks and school webpages were searched for the following keywords: "pregnant" OR "pregnancy" OR "maternity" OR "parent" OR "family" OR "child" OR "birth." Data were analyzed using descriptive statistics. Fisher's exact tests evaluated differences in proportion by group. RESULTS: Of 199 schools, 65 (32.66%) had parental leave policies available online or in the handbook: 39 of 155 (25.16%) MD-granting and 26 of 44 (59.09%) DO-granting schools. Of those policies, 59 (90.77%) were included in the student handbook. Most policies (28, 43.08%) were included as an option within the school's general leave of absence policy. Both parents were included in 38 (58.46%) policies; 23 (35.38%) policies mentioned only mothers; and 4 (6.15%) were unknown. An option to maintain original graduation date was offered in 21 (32.1%) schools' policies. Three schools (4.62%) included adoption as qualifying for parental leave. When comparing MD and DO programs, DO programs were statistically more likely to have a parental leave policy: 39 (25.16%) vs 26 (59.09%); P < .001. CONCLUSIONS: Balancing medical school with pregnancy and childbirth necessitates administrative support to address the inherent scheduling challenges. Currently, many schools lack parental leave policies for medical students that are easily accessible, are separate from formal leaves of absence, allow for at least 12 weeks, and are tailored to the student academic year to ensure on-time completion of medical education.