The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells.

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.

Default mode network abnormalities in idiopathic generalized epilepsy.

Idiopathic generalized epilepsy (IGE) is associated with widespread cortical network abnormalities on electroencephalography. Resting state functional connectivity (RSFC), based on fMRI, can assess the brain's global functional organization and its disruption in clinical conditions. We compared RSFC associated with the 'default mode network' (DMN) between people with IGE and healthy controls. Strength of functional connectivity within the DMN associated with seeds in the posterior cingulate cortex (PCC) and medial prefrontal cortices (MPFC) was compared between people with IGE and healthy controls and was correlated with seizure duration, age of seizure onset and age at scan. Those with IGE showed markedly reduced functional network connectivity between anterior and posterior cortical seed regions. Seizure duration positively correlates with RSFC between parahippocampal gyri and the PCC but negatively correlates with connectivity between the PCC and frontal lobe. The observed pattern of disruption provides evidence for integration- and segregation-type network abnormalities and supports aberrant network organization among people with IGE.

Financial stress during COVID-19: implications for parenting behaviour and child well-being.

BACKGROUND: Family financial stress and parenting behaviours are each associated with child behaviours. We sought to explore the association between parent financial stress and child socioemotional and behavioural difficulties during the COVID-19 pandemic and examine parenting behaviour, including overreactive and lax parenting approaches, as a potential mediator to this relationship. METHODS: Cross-sectional sample of parent and child data pairings in Ontario, Canada between April and November of 2020. Linear models were used to describe the relationships between financial worry, child Strengths and Difficulties Questionnaire (SDQ) total difficulties and parenting behaviours measured by the Parenting Scale 8-item (PS-8), which includes measures of both overreactive and lax parenting tendencies. Formal mediation testing was performed to assess the potential mediating role of parenting behaviour. RESULTS: 528 parent and child pairs were enrolled from largely European ancestry (78%), female (93%) and varied household income levels. Analysis revealed increased financial worry during the COVID-19 pandemic was significantly associated with increased child SDQ total difficulties scores (ß=0.23, SE=0.10, p=0.03). This relationship was mediated by reported parenting behaviour, independent of parent education, household income, parent age, parent sex, parent anxiety and child sex (total effect: ß=0.69, p=0.02, average causal mediation effects: ß=0.50, p=0.02, average direct effects: ß=0.19, p=0.08). CONCLUSION: Financial stress during the COVID-19 pandemic was associated with poorer child social and emotional well-being. Parenting behaviours measured by the PS-8 significantly mediated these effects. This work supports the importance of policies aimed to alleviate family financial stresses and highlights the potential impact such policies have on child well-being.

Attachment insecurity and the biological embedding of reproductive strategies: Investigating the role of cellular aging.

Evolutionary-developmental psychologists have posited that individuals who grow up in stressful rearing circumstances follow faster life history strategies, thereby increasing their chances of reproduction. This preregistered study tested this stress-acceleration hypothesis in a low-risk longitudinal sample of 193 Dutch mother-child dyads, by investigating whether infant-mother attachment insecurity at 12 months of age predicted earlier pubertal onset and more callous-unemotional traits, aggression and risk-taking about a decade later. Also evaluated were the possible mediating roles of two biomarkers of accelerated aging (i.e., telomere length, epigenetic aging) at age 6. Structural equation modelling revealed no effects of attachment insecurity on biomarkers, pubertal timing or behavior. These null findings suggest that the explanatory value of evolutionary-developmental thinking might be restricted to high-risk samples, though unexplored variation in susceptibility to environmental influences might also explain the null findings.

Maternal Prenatal Anxiety and the Fetal Origins of Epigenetic Aging.

BACKGROUND: The fetal origins of mental health is a well-established framework that currently lacks a robust index of the biological embedding of prenatal adversity. The Pediatric-Buccal-Epigenetic (PedBE) clock is a novel epigenetic tool that associates with aspects of the prenatal environment, but additional validation in longitudinal datasets is required. Likewise, the relationship between prenatal maternal mental health and the PedBE clock has not been described. METHODS: Longitudinal cohorts from the Netherlands (Basal Influences on Baby Development [BIBO] n = 165) and Singapore (Growing Up in Singapore Towards Healthy Outcomes [GUSTO] n = 340) provided data on prenatal maternal anxiety and longitudinal assessments of buccal cell-derived genome-wide DNA methylation assessed at 6 and 10 years of age in BIBO, and at 3, 9, and 48 months of age in GUSTO. Measures of epigenetic age acceleration were calculated using the PedBE clock and benchmarked against an established multi-tissue epigenetic predictor. RESULTS: Prenatal maternal anxiety predicted child PedBE epigenetic age acceleration in both cohorts, with effects largely restricted to males and not females. These results were independent of obstetric, socioeconomic, and genetic risk factors, with a larger effect size for prenatal anxiety than depression. PedBE age acceleration predicted increased externalizing symptoms in males from mid- to late childhood in the BIBO cohort only. CONCLUSIONS: These findings point to the fetal origins of epigenetic age acceleration and reveal an increased sensitivity in males. Convergent evidence underscores the societal importance of providing timely and effective mental health support to pregnant individuals, which may have lasting consequences for both mother and child.

The effects of twenty-four nutrients and phytonutrients on immune system function and inflammation: A narrative review.

BACKGROUND AND AIM: Recently, optimal immune function has become a primary focus of worldwide attention not only in the prevention of chronic disease but also as one strategy to reduce the severity of acute illness. Inflammation, a process largely controlled by the immune system, has long been studied and recognized for its role in chronic disease. Optimizing immune function or managing inflammation using individual nutrients and phytonutrients is not well understood by the average person. Thus, this narrative literature review summarizes many of the more recent findings about how certain nutrients and phytonutrients affect immune function and inflammation, and how they may best be utilized considering the growing worldwide interest in this topic. METHODS: A comprehensive literature search of PubMed was performed to find clinical trials in humans that assessed the effect of nutrients and phytonutrients on immune function and inflammation, in individuals with acute and chronic health conditions, published in English between 2000 and 2020. Two independent reviewers evaluated the articles for their inclusion. RESULTS: Eighty-seven articles were summarized in this narrative review. In total 24 nutrients and phytonutrients were included in the study, that is, acetyl-L-carnitine, Aloe vera polysaccharides, beta-glucans, bilberry, black seed oil, coenzyme Q10, curcumin (turmeric), frankincense, garlic, ginger, hydrolyzed rice bran, isoflavones, lipoic acid, mistletoe, N-acetyl cysteine, omega-3 fatty acids, resveratrol, selenium, shiitake mushroom and its derivatives, Vitamin B12, Vitamin C, Vitamin D3 (cholecalciferol), Vitamin E (d-alpha- and gamma-tocopherol), and zinc. Some of the noteworthy immune function and anti-inflammatory responses to these interventions included modulation of nuclear factor-Kappa B, tumor necrosis factor-a, interferon-g, interleukin-6, and CD4+ T cells, among others. These findings are not completely consistent or ubiquitous across all patient populations or health status. CONCLUSIONS: Based on this review, many nutrients and phytonutrients are capable of significantly modulating immune function and reducing inflammation, according to multiple biomarkers in clinical trials in different populations of adults with varying health statuses. Thus, dietary supplementation may serve as an adjunct to conventional pharmaceutical or medical therapies, but evaluation of risks and benefits for each person and health status is necessary. Additional larger studies are also needed to investigate the safety and efficacy of nutritional compounds in various health conditions, with emphases on potential drug-supplement interactions and clinical endpoints. RELEVANCE FOR PATIENTS: As demonstrated in the reviewed clinical trials, patients of various health challenges with a wide range of severity may benefit from select nutrients and phytonutrients to improve their immune function and reduce inflammation.

Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts.

Cell fusion occurs when several cells combine to form a multinuclear aggregate (syncytium). In human placenta, a syncytialized trophoblast (syncytiotrophoblast) layer forms the primary interface between maternal and fetal tissue, facilitates nutrient and gas exchange, and produces hormones vital for pregnancy. Syncytiotrophoblast development occurs by differentiation of underlying progenitor cells called cytotrophoblasts, which then fuse into the syncytiotrophoblast layer. Differentiation is associated with chromatin remodeling and specific changes in gene expression mediated, at least in part, by histone acetylation. However, the epigenetic regulation of human cytotrophoblast differentiation and fusion is poorly understood. In this study, we found that human syncytiotrophoblast development was associated with deacetylation of multiple core histone residues. Chromatin immunoprecipitation sequencing revealed chromosomal regions that exhibit dynamic alterations in histone H3 acetylation during differentiation. These include regions containing genes classically associated with cytotrophoblast differentiation (TEAD4, TP63, OVOL1, CGB), as well as near genes with novel regulatory roles in trophoblast development and function, such as LHX4 and SYDE1. Prevention of histone deacetylation using both pharmacological and genetic approaches inhibited trophoblast fusion, supporting a critical role of this process for trophoblast differentiation. Finally, we identified the histone deacetylases (HDACs) HDAC1 and HDAC2 as the critical mediators driving cytotrophoblast differentiation. Collectively, these findings provide novel insights into the epigenetic mechanisms underlying trophoblast fusion during human placental development.

Semantic adaptation and competition during word comprehension.

Word comprehension engages the left ventrolateral prefrontal (lVLPFC) and posterior lateral-temporal cortices (PLTC). The contributions of these brain regions to comprehension remain controversial. We hypothesized that the PLTC activates meanings, whereas the lVLPFC resolves competition between representations. To test this hypothesis, we used functional magnetic resonance imaging (fMRI) to assess the independent effects of adaptation and competition on neural activity. Participants judged the relatedness of word pairs. Some consecutive pairs contained a common ambiguous word. The same or different meanings of this word were primed (e.g., SUMMER-FAN, CEILING-FAN; ADMIRER-FAN, CEILING-FAN). Based on the logic of fMRI adaptation, trials with more semantic overlap should produce more adaptation (less activation) in regions that activate meaning. In contrast, trials with more semantic ambiguity should produce more activation in regions that resolve competition. We observed a double dissociation between activity in the PLTC and lVLPFC. LPLTC activity depended on the amount of semantic overlap, irrespective of the amount of semantic ambiguity. In contrast, lVLPFC activity depended on the amount of semantic ambiguity. Moreover, across participants the size of the competition effect as measured by errors was correlated with the size of the competition effect in the lVLPFC. We conclude that the lVLPFC is an executive mechanism within language processing.

Scanning the Future of Medical Imaging.

The medical device industry is undergoing rapid change as innovation accelerates, new business models emerge, and artificial intelligence and the Internet of Things create disruptive possibilities in health care. On the innovation front, global annual patent applications related to medical devices have tripled in 10 years, and technology cycle times have halved in just 5 years. Connectivity has exploded-by 2021, the world will have more than three times as many smart connected devices as people-and more and more medical devices and processes contain integrated sensors. In this article, we report on recent McKinsey (McKinsey & Company, New York, New York) work to map start-ups and trends shaping the future of medical imaging. We identify technology clusters with prospects of future growth, look at some of their cutting-edge practices, and consider what the implications may be for our specialty.

Functional neuroimaging abnormalities in idiopathic generalized epilepsy.

Magnetic resonance imaging (MRI) techniques have been used to quantitatively assess focal and network abnormalities. Idiopathic generalized epilepsy (IGE) is characterized by bilateral synchronous spike-wave discharges on electroencephalography (EEG) but normal clinical MRI. Dysfunctions involving the neocortex, particularly the prefrontal cortex, and thalamus likely contribute to seizure activity. To identify possible morphometric and functional differences in the brains of IGE patients and normal controls, we employed measures of thalamic volumes, cortical thickness, gray-white blurring, fractional anisotropy (FA) measures from diffusion tensor imaging (DTI) and fractional amplitude of low frequency fluctuations (fALFF) in thalamic subregions from resting state functional MRI. Data from 27 patients with IGE and 27 age- and sex-matched controls showed similar thalamic volumes, cortical thickness and gray-white contrast. There were no differences in FA values on DTI in tracts connecting the thalamus and prefrontal cortex. Functional analysis revealed decreased fALFF in the prefrontal cortex (PFC) subregion of the thalamus in patients with IGE. We provide minimum detectable effect sizes for each measure used in the study. Our analysis indicates that fMRI-based methods are more sensitive than quantitative structural techniques for characterizing brain abnormalities in IGE.

Development of the jugular bulb: a radiologic study.

OBJECTIVE: Jugular bulb (JB) abnormalities such as JB diverticulum and high-riding JBs of the temporal bone can erode into the inner ear and present with hearing loss, vestibular disturbance, and pulsatile tinnitus. Their cause and potential to progress remain to be studied. This comprehensive radiologic study investigates the postnatal development of the venous system from transverse sinus to internal jugular vein (IJV). SETTING: Academic medical center. PATIENTS, INTERVENTION, MAIN OUTCOME MEASURE: Measurements of the transverse and sigmoid sinus, the JB, IJV, and carotid artery were made from computed tomographic scans of the neck with intravenous contrast in infants (n = 5), children (n = 13), adults (n = 35), and the elderly (n = 15). RESULTS: Jugular bulbs were not detected in patients younger than 2 years, enlarged in adulthood, and remained stable in the elderly. The venous system was larger in men than in women. From transverse sinus to IJV, the greatest variation in size was just proximal and distal to the JB with greater symmetry observed as blood returned to the heart. Right-sided venous dominance was most common occurring in 70% to 80% of cases. CONCLUSION: The JB is a dynamic structure that forms after 2 years, and its size stabilizes in adulthood. The determinants in its exact position and size are multifactorial and may be related to blood flow. Improved understanding of this structure's development may help to better understand the cause of the high-riding JB and JB diverticulum, both of which may cause clinical symptoms.