Maternal smoking DNA methylation risk score associated with health outcomes in offspring of European and South Asian ancestry.

Background: Maternal smoking has been linked to adverse health outcomes in newborns but the extent to which it impacts newborn health has not been quantified through an aggregated cord blood DNA methylation (DNAm) score. Here, we examine the feasibility of using cord blood DNAm scores leveraging large external studies as discovery samples to capture the epigenetic signature of maternal smoking and its influence on newborns in White European and South Asian populations. Methods: We first examined the association between individual CpGs and cigarette smoking during pregnancy, and smoking exposure in two White European birth cohorts (n=744). Leveraging established CpGs for maternal smoking, we constructed a cord blood epigenetic score of maternal smoking that was validated in one of the European-origin cohorts (n=347). This score was then tested for association with smoking status, secondary smoking exposure during pregnancy, and health outcomes in offspring measured after birth in an independent White European (n=397) and a South Asian birth cohort (n=504). Results: Several previously reported genes for maternal smoking were supported, with the strongest and most consistent association signal from the GFI1 gene (6 CpGs with p<5 × 10-5). The epigenetic maternal smoking score was strongly associated with smoking status during pregnancy (OR = 1.09 [1.07, 1.10], p=5.5 × 10-33) and more hours of self-reported smoking exposure per week (1.93 [1.27, 2.58], p=7.8 × 10-9) in White Europeans. However, it was not associated with self-reported exposure (p>0.05) among South Asians, likely due to a lack of smoking in this group. The same score was consistently associated with a smaller birth size (-0.37±0.12 cm, p=0.0023) in the South Asian cohort and a lower birth weight (-0.043±0.013 kg, p=0.0011) in the combined cohorts. Conclusions: This cord blood epigenetic score can help identify babies exposed to maternal smoking and assess its long-term impact on growth. Notably, these results indicate a consistent association between the DNAm signature of maternal smoking and a small body size and low birth weight in newborns, in both White European mothers who exhibited some amount of smoking and in South Asian mothers who themselves were not active smokers. Funding: This study was funded by the Canadian Institutes of Health Research Metabolomics Team Grant: MWG-146332.

Consistent cord blood DNA methylation signatures of gestational age between South Asian and white European cohorts.

BACKGROUND: Epigenetic modifications, particularly DNA methylation (DNAm) in cord blood, are an important biological marker of how external exposures during gestation can influence the in-utero environment and subsequent offspring development. Despite the recognized importance of DNAm during gestation, comparative studies to determine the consistency of these epigenetic signals across different ethnic groups are largely absent. To address this gap, we first performed epigenome-wide association studies (EWAS) of gestational age (GA) using newborn cord blood DNAm comparatively in a white European (n = 342) and a South Asian (n = 490) birth cohort living in Canada. Then, we capitalized on established cord blood epigenetic GA clocks to examine the associations between maternal exposures, offspring characteristics and epigenetic GA, as well as GA acceleration, defined as the residual difference between epigenetic and chronological GA at birth. RESULTS: Individual EWASs confirmed 1,211 and 1,543 differentially methylated CpGs previously reported to be associated with GA, in white European and South Asian cohorts, respectively, with a similar distribution of effects. We confirmed that Bohlin's cord blood GA clock was robustly correlated with GA in white Europeans (r = 0.71; p = 6.0 × 10-54) and South Asians (r = 0.66; p = 6.9 × 10-64). In both cohorts, Bohlin's clock was positively associated with newborn weight and length and negatively associated with parity, newborn female sex, and gestational diabetes. Exclusive to South Asians, the GA clock was positively associated with the newborn ponderal index, while pre-pregnancy weight and gestational weight gain were strongly predictive of increased epigenetic GA in white Europeans. Important predictors of GA acceleration included gestational diabetes mellitus, newborn sex, and parity in both cohorts. CONCLUSIONS: These results demonstrate the consistent DNAm signatures of GA and the utility of Bohlin's GA clock across the two populations. Although the overall pattern of DNAm is similar, its connections with the mother's environment and the baby's anthropometrics can differ between the two groups. Further research is needed to understand these unique relationships.

Extracellular Vesicle Treatment Alleviates Neurodevelopmental and Neurodegenerative Pathology in Cortical Spheroid Model of Down Syndrome.

Down syndrome (DS), or trisomy 21, is manifested in a variety of anatomical and cellular abnormalities resulting in intellectual deficits and early onset of Alzheimer's disease (AD) with no effective treatments available to alleviate the pathologies associated with the disorder. The therapeutic potential of extracellular vesicles (EVs) has emerged recently in relation to various neurological conditions. We have previously demonstrated the therapeutic efficacy of mesenchymal stromal cell-derived EVs (MSC-EVs) in cellular and functional recovery in a rhesus monkey model of cortical injury. In the current study, we evaluated the therapeutic effect of MSC-EVs in a cortical spheroid (CS) model of DS generated from patient-derived induced pluripotent stem cells (iPSCs). Compared to euploid controls, trisomic CS display smaller size, deficient neurogenesis, and AD-related pathological features, such as enhanced cell death and depositions of amyloid beta (Aß) and hyperphosphorylated tau (p-tau). EV-treated trisomic CS demonstrated preserved size, partial rescue in the production of neurons, significantly decreased levels of Aß and p-tau, and a reduction in the extent of cell death as compared to the untreated trisomic CS. Together, these results show the efficacy of EVs in mitigating DS and AD-related cellular phenotypes and pathological depositions in human CS.

Asynchronous excitatory neuron development in an isogenic cortical spheroid model of Down syndrome.

The intellectual disability (ID) in Down syndrome (DS) is thought to result from a variety of developmental deficits such as alterations in neural progenitor division, neurogenesis, gliogenesis, cortical architecture, and reduced cortical volume. However, the molecular processes underlying these neurodevelopmental changes are still elusive, preventing an understanding of the mechanistic basis of ID in DS. In this study, we used a pair of isogenic (trisomic and euploid) induced pluripotent stem cell (iPSC) lines to generate cortical spheroids (CS) that model the impact of trisomy 21 on brain development. Cortical spheroids contain neurons, astrocytes, and oligodendrocytes and they are widely used to approximate early neurodevelopment. Using single cell RNA sequencing (scRNA-seq), we uncovered cell type-specific transcriptomic changes in the trisomic CS. In particular, we found that excitatory neuron populations were most affected and that a specific population of cells with a transcriptomic profile resembling layer IV cortical neurons displayed the most profound divergence in developmental trajectory between trisomic and euploid genotypes. We also identified candidate genes potentially driving the developmental asynchrony between trisomic and euploid excitatory neurons. Direct comparison between the current isogenic CS scRNA-seq data and previously published datasets revealed several recurring differentially expressed genes between DS and control samples. Altogether, our study highlights the power and importance of cell type-specific analyses within a defined genetic background, coupled with broader examination of mixed samples, to comprehensively evaluate cellular phenotypes in the context of DS.

Identification of novel prophage regions in Xenorhabdus nematophila genome and gene expression analysis during phage-like particle induction.

BACKGROUND: Entomopathogenic Xenorhabdus bacteria are endosymbionts of Steinernema nematodes and together they form an insecticidal mutualistic association that infects a wide range of insect species. Xenorhabdus produce an arsenal of toxins and secondary metabolites that kill the insect host. In addition, they can induce the production of diverse phage particles. A few studies have focused on one integrated phage responsible for producing a phage tail-like bacteriocin, associated with an antimicrobial activity against other Xenorhabdus species. However, very little is known about the diversity of prophage regions in Xenorhabdus species. METHODS: In the present study, we identified several prophage regions in the genome of Xenorhabdus nematophila AN6/1. We performed a preliminary study on the relative expression of genes in these prophage regions. We also investigated some genes (not contained in prophage region) known to be involved in SOS bacterial response (recA and lexA) associated with mitomycin C and UV exposure. RESULTS: We described two integrated prophage regions (designated Xnp3 and Xnp4) not previously described in the genome of Xenorhabdus nematophila AN6/1. The Xnp3 prophage region appears very similar to complete Mu-like bacteriophage. These prophages regions are not unique to X. nematophila species, although they appear less conserved among Xenorhabdus species when compared to the previously described p1 prophage region. Our results showed that mitomycin C exposure induced an up-regulation of recA and lexA suggesting activation of SOS response. In addition, mitomycin C and UV exposure seems to lead to up-regulation of genes in three of the four integrated prophages regions.

The Lived Experiences of Fathers in Mealtimes: A Thematic Synthesis of Qualitative Literature.

The paternal experience of family mealtimes is an emerging field within qualitative literature. Previous quantitative studies suggest that differences exist between fathers' and mothers' mealtime behaviours, particularly in response to fussy eating. However, qualitative research has not yet focused exclusively on fathers' fussy eating experiences. This metasynthesis aimed to provide insights into the general paternal experience, inclusive of their fussy eating responses. Thematic synthesis methodology was adopted to achieve this process and consisted of a systematic search resulting in the inclusion of 16 studies (18 papers). The direct quotations presented within each study were subjected to three stages of analysis to produce three analytical themes, supported by eight descriptive themes. The analytical themes presented were: (1) environmental influences on fathers' mealtime experiences; (2) attitudes and emotions of fathers during mealtimes; and (3) observable behaviours of fathers during mealtimes. These themes highlighted the complexity of the mealtime experience from a paternal perspective. Multidirectional relationships were identified between each mealtime component (i.e., the environment, attitudes, emotions and behaviours) as evidenced by the paternal commentary presented. The findings also provided insights into fathers' fussy eating experiences, recognising that fathers should be considered as individuals in the presence of mealtime intervention.

The effects of COVID-19 restrictions on physical activity and mental health of children and young adults with physical and/or intellectual disabilities.

BACKGROUND: COVID-19 has caused unprecedented restrictions, significantly affecting the most vulnerable groups in society, such as those with a disability. OBJECTIVE: The aim of the study was to investigate the effects of COVID-19 lockdown restrictions on physical activity and mental health of children and young adults with physical and/or intellectual disabilities. METHODS: The study was a cross-sectional design. Parents/carers completed an electronic survey in the UK between June-July 2020 on behalf of their child. Through Likert scales and free-text questions, the survey asked about physical activity levels and mental health during lockdown compared to before, access to specialist facilities and equipment to aid with physical activity, and the short- and long-term concerns around ongoing lockdown restrictions. RESULTS: Generally, respondents reported negative effects of lockdown restrictions, with 61% reporting a reduction in physical activity levels and over 90% reporting a negative impact on mental health (including poorer behaviour, mood, fitness and social and learning regression). Many respondents cited a lack of access to specialist facilities, therapies and equipment as reasons for this, and raised concerns about the long-term effects of this lack of access on their child's mental health and physical activity levels. CONCLUSIONS: The survey highlights the negative impact of the COVID-19 lockdown on the physical activity levels and mental health of children and young adults with disabilities and highlights the importance of addressing the needs of the disabled community as restrictions are eased.

The intellectual ableism of leisure research: Original considerations towards understanding well-being with and for people with intellectual disabilities.

People with intellectual disabilities (IDs) are considered to be one of the most marginalized, isolated and disenfranchised groups in society. However, recent social prescription intervention programmes are being introduced to enhance the physical and mental well-being of these individuals through participation in leisure activities, thus increasing academic interest in research within the area. This article introduces the theoretical and methodological tensions in applying mainstream scholarly thinking of leisure and well-being to people with IDs and argues that by failing to acknowledge and address such tensions scholars are at risk of demonstrating intellectual ableism. Layering Kleiber's components of leisure over Seligman's Positive Emotion, Engagement, Relationships, Meaning, and Accomplishment concept of well-being, this article poses critical questions of how each contributing element of well-being could be reconceptualized for people with neurological diversities. The intersection of leisure, well-being and ID is ripe for research development; however, many studies in the domain are falling short of suitable theoretical discussion and methodological rigour. This article concludes with suggestions on how scholars can reduce intellectual ableism through inclusive design, methodological reporting, acknowledging bias and grappling theoretical dissonance.

Partnerships between an At-Risk Youth CrossFit Program and Local Community Organizations: Focusing on the Antecedents to Partnership Development.

A large body of research has established that sport intervention programs can have social, emotional and health benefits for at-risk youth. While research has focused on the positive outcomes associated with these programs, little attention has been given to program inputs. It is recognized that community partnerships can help intervention programs achieve their goals. Yet, how are such partnerships formed and what can help to promote the successful formation of partnerships? This paper provides a detailed account of the partnership implementation process undertaken to develop and deliver a health promotion physical activity program for at-risk youth through the medium of CrossFit in a low socioeconomic area in a rural community in the southeastern United States. Developing successful partnerships serves as a valuable component to help organizations obtain resources and skills needed to initiate and continue programs for underserved populations. The scholars identify and explain how critical success factors such as personal contact, partnership complementarity and fit and the promotion of high levels of commitment and trust, serve as important starting points for developing and maintaining strong community partnerships.

Ethnic and diet-related differences in the healthy infant microbiome.

BACKGROUND: The infant gut is rapidly colonized by microorganisms soon after birth, and the composition of the microbiota is dynamic in the first year of life. Although a stable microbiome may not be established until 1 to 3 years after birth, the infant gut microbiota appears to be an important predictor of health outcomes in later life. METHODS: We obtained stool at one year of age from 173 white Caucasian and 182 South Asian infants from two Canadian birth cohorts to gain insight into how maternal and early infancy exposures influence the development of the gut microbiota. We investigated whether the infant gut microbiota differed by ethnicity (referring to groups of people who have certain racial, cultural, religious, or other traits in common) and by breastfeeding status, while accounting for variations in maternal and infant exposures (such as maternal antibiotic use, gestational diabetes, vegetarianism, infant milk diet, time of introduction of solid food, infant birth weight, and weight gain in the first year). RESULTS: We demonstrate that ethnicity and infant feeding practices independently influence the infant gut microbiome at 1 year, and that ethnic differences can be mapped to alpha diversity as well as a higher abundance of lactic acid bacteria in South Asians and a higher abundance of genera within the order Clostridiales in white Caucasians. CONCLUSIONS: The infant gut microbiome is influenced by ethnicity and breastfeeding in the first year of life. Ethnic differences in the gut microbiome may reflect maternal/infant dietary differences and whether these differences are associated with future cardiometabolic outcomes can only be determined after prospective follow-up.

Harmonization of Food-Frequency Questionnaires and Dietary Pattern Analysis in 4 Ethnically Diverse Birth Cohorts.

BACKGROUND: Canada is an ethnically diverse nation, which introduces challenges for health care providers tasked with providing evidence-based dietary advice. OBJECTIVES: We aimed to harmonize food-frequency questionnaires (FFQs) across 4 birth cohorts of ethnically diverse pregnant women to derive robust dietary patterns to investigate maternal and newborn outcomes. METHODS: The NutriGen Alliance comprises 4 prospective birth cohorts and includes 4880 Canadian mother-infant pairs of predominantly white European [CHILD (Canadian Healthy Infant Longitudinal Development) and FAMILY (Family Atherosclerosis Monitoring In earLY life)], South Asian [START (SouTh Asian birth cohoRT)-Canada], or Aboriginal [ABC (Aboriginal Birth Cohort)] origins. CHILD used a multiethnic FFQ based on a previously validated instrument designed by the Fred Hutchinson Cancer Research Center, whereas FAMILY, START, and ABC used questionnaires specifically designed for use in white European, South Asian, and Aboriginal people, respectively. The serving sizes and consumption frequencies of individual food items within the 4 FFQs were harmonized and aggregated into 36 common food groups. Principal components analysis was used to identify dietary patterns that were internally validated against self-reported vegetarian status and externally validated against a modified Alternative Healthy Eating Index (mAHEI). RESULTS: Three maternal dietary patterns were identified-"plant-based," "Western," and "health-conscious"-which collectively explained 29% of the total variability in eating habits observed in the NutriGen Alliance. These patterns were strongly associated with self-reported vegetarian status (OR: 3.85; 95% CI: 3.47, 4.29; r2 = 0.30, P < 0.001; for a plant-based diet), and average adherence to the plant-based diet was higher in participants in the fourth quartile of the mAHEI than in the first quartile (mean difference: 46.1%; r2 = 0.81, P < 0.001). CONCLUSION: Dietary data collected by using FFQs from ethnically diverse pregnant women can be harmonized to identify common dietary patterns to investigate associations between maternal dietary intake and health outcomes.

Electronic SSKIN pathway: reducing device-related pressure ulcers.

This article describes how an interprofessional project in a London NHS Foundation Trust was undertaken to develop an intranet-based medical device-related pressure ulcer prevention and management pathway for clinical staff working across an adult critical care directorate, where life-threatening events require interventions using medical devices. The aim of this project was to improve working policies and processes to define key prevention strategies and provide clinicians with a clear, standardised approach to risk and skin assessment, equipment use, documentation and reporting clinical data using the Trust's CareVue (electronic medical records), Datix (incident reporting and risk-management tool) and eTRACE (online clinical protocol ordering) systems. The process included the development, trial and local implementation of the pathway using collaborative teamwork and the SSKIN care bundle tool. The experience of identifying issues, overcoming challenges, defining best practice and cascading SSKIN awareness training is shared.

Taking knowledge for health the extra mile: participatory evaluation of a mobile phone intervention for community health workers in Malawi.

In Malawi, where the majority of the population resides in rural areas, community health workers (CHWs) are the first, and often only, providers of health services. An assessment of health information needs, however, found that these frontline workers often lacked essential health information. A pilot project, implemented in 2 rural districts of Malawi between 2010 and 2011, introduced a mobile phone system to strengthen knowledge exchange within networks of CHWs and district staff. To evaluate the mobile phone intervention, a participatory evaluation method called Net-Map was used, an approach built on traditional social network analysis. Together, CHWs and district personnel discussed information needs and gaps and the roles of different actors in their information networks. They then used drawings and 3-dimensional objects to create baseline and endline maps showing the linkages and levels of influence among members of the information network. Net-Map provided them with powerful evidence of differences before and after the mobile phone initiative. At baseline, CHWs were not mentioned as actors in the information network, while at endline they were seen to have significant connections with colleagues, beneficiaries, supervisors, and district health facilities, as both recipients and providers of information. Focus groups with CHWs complemented the Net-Map findings with reports of increased self-confidence and greater trust by their communities. These qualitative results were bolstered by surveys that showed decreases in stockouts of essential medicines, lower communication costs, wider service coverage, and more efficient referrals. As an innovative, participatory form of social network analysis, Net-Map yielded important visual, quantitative, and qualitative information at reasonable cost.

Single-electron/pericyclic cascade for the synthesis of dienes.

The highly efficient and diastereoselective synthesis of E dienes has been accomplished through radical cyclization of bromoallyl hydrazones. This methodology has been further extended to generate these products through a one-pot condensation/radical cyclization/cycloreversion cascade from simple aldehyde starting materials in high yields (>75%) and high diastereoselectivities (>95:5). Mechanistic investigations suggest that the cascade reaction proceeds through a cyclic diazene intermediate prior to the cycloreversion.

Construction of carbo- and heterocycles using radical relay cyclizations initiated by alkoxy radicals.

An efficient method for the rapid construction of carbo- and heterocycles has been developed using radical relay cyclizations initiated by alkoxy radicals. Linear substrates were cyclized to form a wide range of cyclopentane, pyrrolidine, tetrahydropyran, and tetrahydrofuran derivatives in excellent yields. This methodology was utilized as a key step in the synthesis of the tetrahydrofuran fragment in (-)-amphidinolide K.