Child oral health and preventive dental service access among children with intellectual disabilities, autism and other educational additional support needs: a population-based record linkage cohort study

Objective: Inequalities in child oral health are a global challenge and the intersection of socioeconomic factors with educational additional support needs (ASN), including children with intellectual disabilities or autism, have thus far received limited attention in relatively small clinical studies. We aimed to address this evidence gap by investigating oral health and access to preventive dental services among children with ASN compared to the general child population. Methods: Cohort study linking data from six Scotland-wide health and education databases compared: dental caries experience and tooth extraction via general anaesthetic; receipt of school-based dental inspection; access to primary care and hospital dental services; and access to the Childsmile national oral health improvement programme between children with a range of ASN (intellectual disabilities, autism, social and other) and their peers for the school years 2016/17–2018/19 (n = 166 781). Results: Children with any ASN had higher rates of caries experience than those with no ASN, however, after adjustment for socioeconomic deprivation, sex, year, and school type only those with a social or other ASN remained at increased risk. Rates of tooth extraction under general anaesthesia in hospital were higher among children with intellectual disabilities (aRR = 1.67;95% CI = [1.16–2.37]). School-based dental inspection access improved for children with intellectual disability and/or autism from 2016/17 onwards, although higher rates of child refusal on the day were observed in these groups (no ASN refusal: 5.4%; intellectual disability: 35.8%; autism: 40.3%). Children with any ASN were less likely to attend primary dental-care regularly, and in those who attended, children with intellectual disability or autism were less likely than their peers to receive prevention (fluoride varnish, oral-hygiene instruction, or dietary advice). Childsmile nursery-supervised toothbrushing programme access among children with any ASN was similar to children with no ASN and children with intellectual disability (aRR = 1.27;95% CI = [1.12–1.45]) or autism (aRR = 1.32;95% CI = [1.19–1.45]) were more likely to receive support from Childsmile dental health support worker. Conclusions: We have identified inequalities in oral health and dental care for children with different ASN in Scotland with both a greater burden of disease among some groups and higher complexity of care; compounded by reduced and variable access to preventive dental services. Further efforts are needed to develop and improve preventive care pathways for children with ASN and integrate oral health to wider healthcare systems for these children to mitigate against oral health inequalities

p53 convergently activates Dux/DUX4 in embryonic stem cells and in facioscapulohumeral muscular dystrophy cell models

p53 activates Dux in mouse embryos and embryonic stem cells, as well as DUX4 in human facioscapulohumeral muscular dystrophy cell models.In mammalian embryos, proper zygotic genome activation (ZGA) underlies totipotent development. Double homeobox (DUX)-family factors participate in ZGA, and mouse Dux is required for forming cultured two-cell (2C)-like cells. Remarkably, in mouse embryonic stem cells, Dux is activated by the tumor suppressor p53, and Dux expression promotes differentiation into expanded-fate cell types. Long-read sequencing and assembly of the mouse Dux locus reveals its complex chromatin regulation including putative positive and negative feedback loops. We show that the p53-DUX/DUX4 regulatory axis is conserved in humans. Furthermore, we demonstrate that cells derived from patients with facioscapulohumeral muscular dystrophy (FSHD) activate human DUX4 during p53 signaling via a p53-binding site in a primate-specific subtelomeric long terminal repeat (LTR)10C element. In summary, our work shows that p53 activation convergently evolved to couple p53 to Dux/DUX4 activation in embryonic stem cells, embryos and cells from patients with FSHD, potentially uniting the developmental and disease regulation of DUX-family factors and identifying evidence-based therapeutic opportunities for FSHD.Molecular Technology and Informatics for Personalised Medicine and HealthFunctional Genomics of Muscle, Nerve and Brain Disorder

Narrative inquiry into (re)imagining alternative schools: a case study of Kevin Gonzales.

Although there are many alternative schools that strive for the successful education for their students, negative images of alternative schools persist. While some alternative schools are viewed as “idealistic havens,” many are viewed as “dumping grounds,” or “juvenile detention centers.” Employing narrative inquiry, this article interrogates how a student, Kevin Gonzales, experiences his alternative education and raises questions about the role of alternative schools. Kevin Gonzales’s story is presented in a literary form of biographical journal to provide a “metaphoric loft” that helps us imagine other students like Kevin. This, in turn, provokes us to examine our current educational practice, and to (re)imagine ways in which alternative education can provide the best possible educational experiences for disenfranchised students who are increasingly underserved by the public education system

Nucleosomes in gene regulation: theoretical approaches

This work reviews current theoretical approaches of biophysics and bioinformatics for the description of nucleosome arrangements in chromatin and transcription factor binding to nucleosomal organized DNA. The role of nucleosomes in gene regulation is discussed from molecular-mechanistic and biological point of view. In addition to classical problems of this field, actual questions of epigenetic regulation are discussed. The authors selected for discussion what seem to be the most interesting concepts and hypotheses. Mathematical approaches are described in a simplified language to attract attention to the most important directions of this field

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique\u2014Subtype and Stage Inference (SuStaIn)\u2014able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer\u2019s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 7 10 124 ) or temporal stage (p = 3.96 7 10 125 ). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine

Genes Responsible for Maintaining Embryonic Developmental Potential

A major question concerning early embryos involves how early cleavage-stage (two-cell) embryos establish unlimited developmental potential - termed totipotency. Cairns and colleagues identified the multicopy retrogene, DUX4 in humans or Dux in mice, as a transcription factor that is turned on in very early embryos and activates hundreds of genes and retroviral elements during cleavage stage. Remarkably, the expression of Dux efficiently converts mouse embryonic stem cells into 2-cell-embryo-like cells (2CLC) with expanded developmental potential. Interestingly, these 2CLC can contribute to either embryonic or extra-embryonic (trophectoderm/placenta) cell lineages. Thus, Dux-family proteins appear to play essential roles in determining developmental potential in early embryos. The improper expression of DUX4 underlies the common muscle disease facioscapulohumeral muscular dystrophy (FSHD), and the results from this work provide important and novel information on the typical role of DUX4 that can now be explored in the context of FSHD

Mechanisms of Epigenetic Inheritance

A central issue in epigenetics is whether and how epigenetic information in gametes (sperm and egg) is inherited. Cairns and colleagues discovered that "Placeholder" nucleosomes, containing histone variants, occupy DNA regions lacking methylation in both sperm and early embryos. Placeholder nucleosomes establish regions of the genome that lack DNA methylation, and their depletion leads to DNA methylation of promoters and enhancers, and transcriptional silencing. Placeholder nucleosomes reside at promoters of housekeeping genes and early embryonic transcription factors. Housekeeping genes with Placeholder become active when genome-wide transcription is activated, whereas developmental genes with Placeholder become ‘poised' by receiving two additional chromatin modifications, which are targeted by particular transcription factors. Taken together, the results defined a chromatin entity - Placeholder nucleosomes - that are inherited from the germline and remain at promoters and enhancers in embryos, where they help define both active and ‘poised' genes in the embryo