Context Matters: A Community-Based Study of Urban Minority Parents’ Views on Child Health

Background: Among children, there are substantial ethno-racial minority disparities across a broad range of health-related behaviors, experiences, and outcomes. Addressing these disparities is important, as childhood and adolescence establish health trajectories that extend throughout life. Methods: The current study employed a community-based participatory research approach to gain community insight on child health priorities and to frame an intervention aimed at improving the health of minority children. Eight focus groups were conducted among seventy-five African American parents in a Southeastern city. The current study was guided by an ecological theoretical framework. Results: Although the focus of this investigation was on community identification of child health priorities, participants cited, as root determinants, contextual factors, which included lack of healthy food options, lack of spaces for physical activity, and community violence. These co-occurring factors were related to limited engagement in outdoor activities and physical activity, increased obesity, and poor mental health and coping. Poor parenting was cited as the most substantial barrier to improving child health outcomes, and quality parenting was identified as the most important issue to address for community programs focused on promoting the health and success of children. For improving health outcomes for children in their neighborhoods, establishment of positive social capital and constructive activities were also cited. Conclusions: These results reinforce social determinants of health as influences on child health outcomes and describe how community engagement can address potential solutions through interventions that resonate with program participants

Utilization of a Community-based Participatory Approach to Design and Implement a Peer-led Parenting Pilot Intervention to Influence Child Nutritional and Physical Activity Behaviors

Parents and primary child guardians within the household play critical roles in shaping their children’s nutritional and physical activity behaviors, which are among the individual-level determinants of childhood obesity and other chronic conditions. There are well-established correlations between race, socioeconomic status and the risk for obesity calling for both contextually- and individual-centered interventions that are community-driven. The Using Quality Parenting (UQP) pilot intervention was a peer-led, parenting education intervention developed in collaboration with community residents in Atlanta, Georgia to influence child nutritional and physical activity behaviors in African American low socioeconomic status communities. A community-based participatory research (CBPR) framework was used to conduct a mixed-methods needs assessment designed to the UQP curriculum. The UQP program targeted parents of children ages 6-14. The overarching aim was to increase quality parenting and address community identified child obesity disparities and inequities in early and middle childhood. The topics pertaining to parenting to children’s health/well-being addressed by the UQP included nutrition, physical activity, socio-emotional development, positive parenting, coping skills, child advocacy, and community development. Analyses were conducted using PSAW 18 statistical software. Descriptive statistics, including frequencies, means, standard deviations, and ranges for the individual survey items were conducted. A t-test was performed comparing pre- and post-program participation. A repeated measure analysis of variance was conducted on the items that demonstrated a significant t-test. The analytic sample was composed of 46 African American parents, with over 50% of the sample earning an annual household income of $25,000 or less. Participating parents reported significantly higher levels of water consumption for their children post-program in comparison to pre-test reports (p = .010). Additionally, based on t-test analyses, parents reported that their children consumed significantly higher levels of proteins, grains, fruits and vegetables at each meal, post-program (p=0.03). These findings highlight the potential efficacy of community-informed, parent-led interventions in improving health disparities and related outcomes for children

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing

More than 50 neurological and neuromuscular diseases are caused by short tandem repeat (STR) expansions, with 37 different genes implicated to date. We describe the use of programmable targeted long-read sequencing with Oxford Nanopore's ReadUntil function for parallel genotyping of all known neuropathogenic STRs in a single assay. Our approach enables accurate, haplotype-resolved assembly and DNA methylation profiling of STR sites, from a list of predetermined candidates. This correctly diagnoses all individuals in a small cohort (n = 37) including patients with various neurogenetic diseases (n = 25). Targeted long-read sequencing solves large and complex STR expansions that confound established molecular tests and short-read sequencing and identifies noncanonical STR motif conformations and internal sequence interruptions. We observe a diversity of STR alleles of known and unknown pathogenicity, suggesting that long-read sequencing will redefine the genetic landscape of repeat disorders. Last, we show how the inclusion of pharmacogenomic genes as secondary ReadUntil targets can further inform patient care

Loss of Gnas Imprinting Differentially Affects REM/NREM Sleep and Cognition in Mice

It has been suggested that imprinted genes are important in the regulation of sleep. However, the fundamental question of whether genomic imprinting has a role in sleep has remained elusive up to now. In this work we show that REM and NREM sleep states are differentially modulated by the maternally expressed imprinted gene Gnas. In particular, in mice with loss of imprinting of Gnas, NREM and complex cognitive processes are enhanced while REM and REM–linked behaviors are inhibited. This is the first demonstration that a specific overexpression of an imprinted gene affects sleep states and related complex behavioral traits. Furthermore, in parallel to the Gnas overexpression, we have observed an overexpression of Ucp1 in interscapular brown adipose tissue (BAT) and a significant increase in thermoregulation that may account for the REM/NREM sleep phenotypes. We conclude that there must be significant evolutionary advantages in the monoallelic expression of Gnas for REM sleep and for the consolidation of REM–dependent memories. Conversely, biallelic expression of Gnas reinforces slow wave activity in NREM sleep, and this results in a reduction of uncertainty in temporal decision-making processes

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Phenotypic plasticity masks range-wide genetic differentiation for vegetative but not reproductive traits in a short-lived plant

Genetic differentiation and phenotypic plasticity jointly shape intraspecific trait variation, but their roles differ among traits. In short-lived plants, reproductive traits may be more genetically determined due to their impact on fitness, whereas vegetative traits may show higher plasticity to buffer short-term perturbations. Combining a multi-treatment greenhouse experiment with observational field data throughout the range of a widespread short-lived herb, Plantago lanceolata, we (1) disentangled genetic and plastic responses of functional traits to a set of environmental drivers and (2) assessed how genetic differentiation and plasticity shape observational trait-environment relationships. Reproductive traits showed distinct genetic differentiation that largely determined observational patterns, but only when correcting traits for differences in biomass. Vegetative traits showed higher plasticity and opposite genetic and plastic responses, masking the genetic component underlying field-observed trait variation. Our study suggests that genetic differentiation may be inferred from observational data only for the traits most closely related to fitness

Phenotypic plasticity masks range-wide genetic differentiation for vegetative but not reproductive traits in a short-lived plant

Publication history: Accepted - 19 May 2021; Published - 5 August 2021.Genetic differentiation and phenotypic plasticity jointly shape intraspecific trait variation, but their roles differ among traits. In short-lived plants, reproductive traits may be more genetically determined due to their impact on fitness, whereas vegetative traits may show higher plasticity to buffer short-term perturbations. Combining a multi-treatment greenhouse experiment with observational field data throughout the range of a widespread short-lived herb, Plantago lanceolata, we (1) disentangled genetic and plastic responses of functional traits to a set of environmental drivers and (2) assessed how genetic differentiation and plasticity shape observational trait–environment relationships. Reproductive traits showed distinct genetic differentiation that largely determined observational patterns, but only when correcting traits for differences in biomass. Vegetative traits showed higher plasticity and opposite genetic and plastic responses, masking the genetic component underlying field-observed trait variation. Our study suggests that genetic differentiation may be inferred from observational data only for the traits most closely related to fitness.Eesti Teadusagentuur, Grant/Award Number: PRG609 and PUT1409; Academy of Finland; Natural Sciences and Engineering Research Council of Canada; Science Foundation Ireland, Grant/Award Number: 15/ERCD/2803; Spanish Ministry of Science, Innovation and Universities, Grant/Award Number: IJCI-2017- 32039; European Regional Development Fun

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570