Concordant B and T Cell Heterogeneity Inferred from the Multiomic Landscape of Peripheral Blood Mononuclear Cells in a Crohn's Disease Cohort.

BACKGROUND AND AIMS: Crohn's disease is characterized by inflammation in the gastrointestinal tract due to a combination of genetic, immune, and environmental factors. Transcriptomic and epigenomic profiling of intestinal tissue of Crohn's disease patients have revealed valuable insights into pathology, however have not been conducted jointly on less invasive peripheral blood mononuclear cells (PBMCs). Furthermore, the heterogeneous responses to treatments among individuals with Crohn's disease imply hidden diversity of pathological mechanisms. METHODS: We employed single nucleus multiomic analysis, integrating both snRNA-seq and snATAC-seq of PBMCs with a variety of open source bioinformatics applications. RESULTS: Our findings reveal a diverse range of transcriptional signatures among individuals, highlighting the heterogeneity in PBMC profiles. Nevertheless, striking concordance between three heterogeneous groups was observed across B cells and T cells. Differential gene regulatory mechanisms partially explain these profiles, notably including a signature involving TGFß signaling in two individuals with Crohn's disease. A mutation mapped to a transcription factor binding site within a differentially accessible peak associated with the expression of this pathway, with implications for a personalized approach to understanding disease pathology. CONCLUSIONS: This study highlights how multiomic analysis can reveal common regulatory mechanisms that underlie heterogeneity of PBMC profiles, one of which may be specific to inflammatory disease.

Annual Research Review: 'There, the dance is - at the still point of the turning world' - dynamic systems perspectives on coregulation and dysregulation during early development.

During development we transition from coregulation (where regulatory processes are shared between child and caregiver) to self-regulation. Most early coregulatory interactions aim to manage fluctuations in the infant's arousal and alertness; but over time, coregulatory processes become progressively elaborated to encompass other functions such as sociocommunicative development, attention and executive control. The fundamental aim of coregulation is to help maintain an optimal 'critical state' between hypo- and hyperactivity. Here, we present a dynamic framework for understanding child-caregiver coregulatory interactions in the context of psychopathology. Early coregulatory processes involve both passive entrainment, through which a child's state entrains to the caregiver's, and active contingent responsiveness, through which the caregiver changes their behaviour in response to behaviours from the child. Similar principles, of interactive but asymmetric contingency, drive joint attention and the maintenance of epistemic states as well as arousal/alertness, emotion regulation and sociocommunicative development. We describe three ways in which active child-caregiver regulation can develop atypically, in conditions such as Autism, ADHD, anxiety and depression. The most well-known of these is insufficient contingent responsiveness, leading to reduced synchrony, which has been shown across a range of modalities in different disorders, and which is the target of most current interventions. We also present evidence that excessive contingent responsiveness and excessive synchrony can develop in some circumstances. And we show that positive feedback interactions can develop, which are contingent but mutually amplificatory child-caregiver interactions that drive the child further from their critical state. We discuss implications of these findings for future intervention research, and directions for future work.

Alliance for Innovation on Maternal Health: Consensus Bundle on Cardiac Conditions in Obstetric Care.

Cardiac conditions are the leading cause of pregnancy-related deaths and disproportionately affect non-Hispanic Black people. Multidisciplinary maternal mortality review committees have found that most people who died from cardiac conditions during pregnancy or postpartum were not diagnosed with a cardiovascular disease before death and that more than 80% of all pregnancy-related deaths, regardless of cause, were preventable. In addition, other obstetric complications, such as preeclampsia and gestational diabetes, are associated with future cardiovascular disease risk. Those with cardiac risk factors and those with congenital and acquired heart disease require specialized care during pregnancy and postpartum to minimize risk of preventable morbidity and mortality. This bundle provides guidance for health care teams to develop coordinated, multidisciplinary care for pregnant and postpartum people with cardiac conditions and to respond to cardio-obstetric emergencies. This bundle is one of several core patient safety bundles developed by the Alliance for Innovation on Maternal Health that provide condition- or event-specific clinical practices for implementation in appropriate care settings. The Cardiac Conditions in Obstetric Care bundle is organized into five domains: 1) Readiness , 2) Recognition and Prevention , 3) Response , 4) Reporting and Systems Learning , and 5) Respectful Care . This bundle is the first by the Alliance to be developed with the fifth domain of Respectful Care . The Respectful Care domain provides essential best practices to support respectful, equitable, and supportive care to all patients. Further health equity considerations are integrated into elements in each domain.

Effect of all-but-one conditional analysis for eQTL isolation in peripheral blood.

Expression quantitative trait locus detection has become increasingly important for understanding how noncoding variants contribute to disease susceptibility and complex traits. The major challenges in expression quantitative trait locus fine-mapping and causal variant discovery relate to the impact of linkage disequilibrium on signals due to one or multiple functional variants that lie within a credible set. We perform expression quantitative trait locus fine-mapping using the all-but-one approach, conditioning each signal on all others detected in an interval, on the Consortium for the Architecture of Gene Expression cohorts of microarray-based peripheral blood gene expression in 2,138 European-ancestry human adults. We contrast these results with traditional forward stepwise conditional analysis and a Bayesian localization method. All-but-one conditioning significantly modifies effect-size estimates for 51% of 2,351 expression quantitative trait locus peaks, but only modestly affects credible set size and location. On the other hand, both conditioning approaches result in unexpectedly low overlap with Bayesian credible sets, with just 57% peak concordance and between 50% and 70% SNP sharing, leading us to caution against the assumption that any one localization method is superior to another. We also cross reference our results with ATAC-seq data, cell-type-specific expression quantitative trait locus, and activity-by-contact-enhancers, leading to the proposal of a 5-tier approach to further reduce credible set sizes and prioritize likely causal variants for all known inflammatory bowel disease risk loci active in immune cells.

Occurrence of male-specific and somatic coliphages and relationship with rainfall in privately-owned wells from peri­urban and rural households.

Privately-owned drinking water wells serving fewer than 25 people (private wells) are prevalent and understudied across most of the US. Private wells primarily serve rural households located outside of municipal drinking water and sewerage service coverage areas. These wells are not regulated by United States Environmental Protection Agency (EPA) under the Safe Drinking Water Act, are not regularly monitored by any public agency or utility, and generally do not undergo disinfection treatment. Coliphages are a group of viruses that infect coliform bacteria and are useful viral surrogates for fecal contamination in water systems in much the same way that fecal indicator bacteria (FIB), such as E. coli and to a lesser extent total coliforms, are used to quantify fecal contamination. Coliphages are approved by the EPA for regulatory monitoring in groundwater wells in the USA, but are not routinely used for this purpose. The present study characterizes the occurrence of male-specific and somatic coliphages, along with FIB, in private wells (n = 122) across two different counties in North Carolina. While occurrences of E. coli were rare and frequency of total coliform was generally low (~20%), male-specific and somatic coliphages were detectable in 66% and 54% of samples, respectively. Concentrations of male-specific coliphages were higher than somatics at each county and on a monthly basis. Rainfall appears to be partly influencing higher coliphage concentrations in December, January and February. This research underscores the need for increased surveillance in private wells and consideration of using coliphages in order to better characterize occurrence of fecal contamination at the time of sampling, especially during rainier months.

Effective therapeutic interventions for Australian adolescents using alcohol and/or other drugs: a scoping review.

BACKGROUND: There are a variety of residential and community service models of therapeutic interventions for people using substances. The focus of much of the currently available research is on adult populations with relatively little known about effective therapeutic interventions for adolescents. The aim of this paper is to identify the most effective therapeutic interventions for Australian adolescents using substances by conducting a systematic scoping literature review. METHODS: We followed the PRISMA guidelines to conduct a systematic scoping review that included searches of nine electronic databases (EMBASE, MEDLINE, EBSCO Host, APA PsycNet, SocIndex, Social Science Abstracts, Proquest Central Informit) and grey literature searches of government department and alcohol and other drugs peak body and service provider websites, Google Scholar and the Cochrane library. RESULTS: A total of 21 studies were identified. These studies included biological, psychological, social and technological therapeutic interventions targeted at different population groups and different substances. The review findings are limited and should considered with caution due to the inability to disaggregate the combinations of interventions provided and the low quality of most of the studies included. CONCLUSIONS: This scoping review highlights the paucity of quality research on effective therapeutic interventions for Australian adolescents using substances. This is primarily due to the available studies not controlling for all of the therapeutic interventions provided. While there is an evidence-base for some of these interventions, others such as encounter groups and journaling require further and more substantive research for use with adolescents. This is necessary to enable informed service design and delivery decision-making and fiscal accountability.

An assessment of schoolyard renovation strategies to encourage children's physical activity.

BACKGROUND: Children in poor and minority neighborhoods often lack adequate environmental support for healthy physical development and community interventions designed to improve physical activity resources serve as an important approach to addressing obesity. In Denver, the Learning Landscapes (LL) program has constructed over 98 culturally-tailored schoolyard play spaces at elementary schools with the goal to encourage utilization of play spaces and physical activity. In spite of enthusiasm about such projects to improve urban environments, little work has evaluated their impact or success in achieving their stated objectives. This study evaluates the impacts of LL construction and recency of renovation on schoolyard utilization and the physical activity rates of children, both during and outside of school, using an observational study design. METHODS: This study employs a quantitative method for evaluating levels of physical activity of individuals and associated environmental characteristics in play and leisure environments. Schools were selected on the basis of their participation in the LL program, the recency of schoolyard renovation, the size of the school, and the social and demographic characteristics of the school population. Activity in the schoolyards was measured using the System for Observing Play and Leisure Activity (SOPLAY), a validated quantitative method for evaluating levels of physical activity of individuals in play and leisure environments. Trained observers collected measurements before school, during school recess, after school, and on weekends. Overall utilization (the total number of children observed on the grounds) and the rate of activity (the percentage of children observed who were physically active) were analyzed. Observations were compared using t-tests and the data were stratified by gender for further analysis. In order to assess the impacts of LL renovation, recently-constructed LL schoolyards were compared to LL schoolyards with older construction, as well as un-renovated schoolyards. RESULTS: Overall utilization was significantly higher at LL schools than at un-renovated schools for most observation periods. Notably, LL renovation had no impact on girl's utilization on the weekends, although differences were observed for all other periods. There were no differences in rates of activity for any comparison. With the exception of the number of boys observed, there was no statistically significant difference in activity when recently-constructed LL schools are compared to LL schools with older construction dates and there was no difference observed in comparisons of older LL with unrenovated sites. CONCLUSIONS: While we observed greater utilization and physical activity in schools with LL, the impact of specific features of LL renovation is not clear. However, schoolyard renovation and programs to encourage schoolyard use before and after school may offer a means to encourage greater physical activity among children, and girls in particular. Additional study of schoolyard renovation may shed light on the specific reasons for these findings or suggest effective policies to improve the physical activity resources of poor and minority neighborhoods.