Teens, Video Games, and Civics

Analyzes survey findings on trends in teenagers' video gaming, the social context, the role of parents and monitoring, and the link between specific gaming experiences and civic activities. Explores gaming's potential as civic learning opportunities

DNA methylation as a potential mediator of environmental risks in the development of childhood acute lymphoblastic leukemia

5-year survival rate for childhood acute lymphoblastic leukemia (ALL) has risen to approximately 90%, yet the causal disease pathway is still poorly understood. Evidence suggests multiple 'hits' are required for disease progression; an initial genetic abnormality followed by additional secondary 'hits'. It is plausible that environmental influences may trigger these secondary hits, and with the peak incidence of diagnosis between 2 and 5 years of age, early life exposures are likely to be key. DNA methylation can be modified by many environmental exposures and is dramatically altered in cancers, including childhood ALL. Here we explore the potential that DNA methylation may be involved in the causal pathway toward disease by acting as a mediator between established environmental factors and childhood ALL development

Identifying Priority and “Bright-Spot” Counties for Diabetes Preventive Care in Appalachia: An Exploratory Analysis

Introduction: Type 2 diabetes mellitus (T2DM) prevalence and mortality in Appalachian counties is substantially higher when compared to non-Appalachian counties, although there is significant variation within Appalachia. Purpose: The objectives of this research were to identify low-performing (priority) and high-performing (bright spot) counties with respect to improving T2DM preventive care. Methods: Using data from the Centers for Medicare and Medicaid (CMS), the Dartmouth Atlas of Health Care, and the Appalachia Regional Commission, conditional maps were created using county-level estimates for T2DM prevalence, mortality, and annual hemoglobin A1c (HbA1c) testing rates. Priority counties were identified using the following criteria: top 33rd percentile for T2DM mortality; top 33rd percentile for T2DM prevalence; bottom 50th percentile for A1c testing rates. Bright spot counties were identified as counties in the bottom 33rd percentile for T2DM mortality, the top 33rd percentile for T2DM prevalence; and the top 50th percentile for HbA1c testing rates. Results: Forty-one priority counties were identified (those with high T2DM mortality, high T2DM prevalence, and low HbA1c testing rates), which were located primarily in Central and North Central Appalachia; and 17 bright spot counties were identified (high T2DM prevalence, low T2DM mortality, and high HbA1c testing rates), which were scattered throughout Appalachia. Eight of the 17 bright spot counties were adjacent to priority counties. Implications: By employing conditional mapping to T2DM, multiple variables can be summarized into a single, easily interpretable map. This could be valuable for T2DM-prevention programs seeking to prioritize diagnostic and intervention resources for the management of T2DM in Appalachia

Improving Access to Treatment for Opioid Use Disorder in High-Need Areas: The Role of HRSA Health Centers

Introduction: Despite the opioid epidemic adversely affecting areas across the U.S. for more than two decades and increasing evidence that medication-assisted treatment (MAT) is effective for patients with opioid use disorder (OUD), access to treatment is still limited. The limited access to treatment holds true in the Appalachia region despite being disproportionately affected by the crisis, particularly in rural, central Appalachia. Purpose: This research identifies opportunities for health centers located in high-need areas based on drug poisoning mortality to better meet MAT care gaps. We also provide an in-depth look at health center MAT capacity relative to need in the Appalachia region. Methods: The analysis included county-level drug poisoning mortality data (2013–2015) from the National Center for Health Statistics (NCHS)and Health Center Program Awardee and Look-Alike data (2017) on the number of providers with a DATA waiver to provide medication-assisted treatment (MAT) and the number of patients receiving MAT for the U.S. Several geospatial methods were used including an Empirical Bayes approach to estimate drug poisoning mortality, excess risk maps to identify outliers, and the Local Moran’s I tool to identify clusters of high drug poisoning mortality counties. Results: High-need counties were disproportionately located in the Appalachia region. More than 6 in 10 health centers in high-need counties have the potential to expand MAT delivery to patients. Implications: The results indicate an opportunity to increase health center capacity for providing treatment for opioid use disorder in high-need areas, particularly in central and northern Appalachia

Pericytes contribute to airway remodeling in a mouse model of chronic allergic asthma

Myofibroblast accumulation, subepithelial fibrosis, and vascular remodeling are complicating features of chronic asthma, but the mechanisms are not clear. Platelet-derived growth factors (PDGFs) regulate the fate and function of various mesenchymal cells and have been implicated as mediators of lung fibrosis. However, it is not known whether PDGF-BB signaling via PDGFRβ, which is critical for the recruitment of pericytes to blood vessels, plays a role in airway remodeling in chronic asthma. In the present study, we used a selective PDGFRβ inhibitor (CP-673451) to investigate the role of PDGFRβ signaling in the development of airway remodeling and lung dysfunction in an established mouse model of house dust mite-induced chronic allergic asthma. Unexpectedly, we found that pharmacological inhibition of PDGFRβ signaling in the context of chronic aeroallergen exposure led to exacerbated lung dysfunction and airway smooth muscle thickening. Further studies revealed that the inflammatory response to aeroallergen challenge in mice was associated with decreased PDGF-BB expression and the loss of pericytes from the airway microvasculature. In parallel, cells positive for pericyte markers accumulated in the subepithelial region of chronically inflamed airways. This process was exacerbated in animals treated with CP-673451. The results indicate that perturbed PDGF-BB/PDGFRβ signaling and pericyte accumulation in the airway wall may contribute to airway remodeling in chronic allergic asthma

Sharpening the mesowear tool: geometric morphometric analysis of cusp shape and diet in ruminants

Mesowear is a dietary proxy that relates attritive wear and abrasive wear to the shape of worn tooth cusps of ungulates. Traditional mesowear methods categorize cusps according to relief and sharpness. A geometric morphometric approach has the potential to measure shape with higher precision and to discover unrecognized aspects of cusp shape, possibly improving the efficacy of mesowear. We quantified mesowear in extant Ruminantia, using a 2-D semilandmark outline technique on upper second molar metacones generated from photographs. Among the 91 species sampled, 65 were preassigned to dietary categories, browser, grazer, mixed feeder, and frugivore based on substantiated documentation of diet in the wildlife literature. Metacone cusp shape and metacone mesowear score were found to be independent of size. Principal component and discriminant function analyses of Procrustes transformed semilandmark coordinates revealed two diet-related components of cusp shape. The primary component is related to the traditional mesowear variables of cusp height and side steepness. The secondary shape component reveals variation in the mesiodistal symmetry of the metacone and may relate to a proal vector during the power stroke phase or the relative orientation of the cusps with respect to the chewing stroke vector. Discriminant function analysis of semilandmark data accurately classified the diets of species more frequently (67.2%) than the traditional mesowear method (56.1%). The semilandmark data successfully recognized the diets of grazing and browsing species with correct classification rates ranging from 69% to 95%. The diets of frugivorous and mixed feeding species were less frequently correctly recognized (33%–53%). Mixed feeding diets may be more difficult to recognize due to more heterogeneous diets when compared to browsers and grazers. Frugivores are more difficult to recognize because their rounded cusp apices resemble those of mixed feeders and grazers. We conclude that quantitative shape analysis improves the potential of mesowear. When used as a dietary proxy, we anticipate that mesowear analysis will correctly categorize the diets of most species. When misclassifications are made, they may most often be misclassifications of generalist mixed feeders and frugivores as either browsers or grazers

Effects of leucine-enriched essential amino acid and whey protein bolus dosing upon skeletal muscle protein synthesis at rest and after exercise in older women

Background & aims: Impaired anabolic responses to nutrition and exercise contribute to loss of skeletal muscle mass with ageing (sarcopenia). Here, we tested responses of muscle protein synthesis (MPS), in the under represented group of older women, to leucine-enriched essential amino acids (EAA) in comparison to a large bolus of whey protein (WP). Methods: Twenty-four older women (65 ± 1 y) received (N ¼ 8/group) 1.5 g leucine-enriched EAA supplements (LEAA_1.5), 6 g LEAA (LEAA_6) in comparison to 40 g WP. A primed constant I.V infusion of 13C6-phenylalanine was used to determine MPS at baseline and in response to feeding (FED) and feeding-plus-exercise (FED-EX; 6 x 8 unilateral leg extensions; 75%1-RM). We quantified plasma insulin/AA concentrations, leg femoral blood flow (LBF)/muscle microvascular blood flow (MBF), and anabolic signalling via immunoblotting. Results: Plasma insulineamia and EAAemia were greater and more prolonged with WP than LEAA, although LEAA_6 peaked at similar levels to WP. Neither LEAA or WP modified LBF or MBF. FED increased MPS similarly in the LEAA_1.5, LEAA_6 and WP (P < 0.05) groups over 0e2 h, with MPS significantly higher than basal in the LEAA_6 and WP groups only over 0e4 h. However, FED-EX increased MPS similarly across all the groups from 0 to 4 h (P < 0.05). Only p-p70S6K1 increased with WP at 2 h in FED (P < 0.05), and at 2/4 h in FED-EX (P < 0.05). Conclusions: In conclusion, LEAA_1.5, despite only providing 0.6 g of leucine, robustly (perhaps maximally) stimulated MPS, with negligible trophic advantage of greater doses of LEAA or even to 40 g WP. Highlighting that composition of EAA, in particular the presence of leucine rather than amount is most crucial for anabolism

Lithospheric geometry of the Wopmay orogen from a Slave craton to Bear Province magnetotelluric transect

Two‐dimensional inversions of lithospheric‐probing magnetotelluric (MT) data at a total of 20 sites acquired along an approximately east–west 300‐km‐long profile across the Wopmay orogen in the Northwest Territories, Canada, provide electrical resistivity models of the boundary between the Archean Slave craton and the adjacent Proterozoic Bear Province. An analysis of distortion effects and structural dimensionality indicates that the MT responses are primarily one‐dimensional or only weakly two‐dimensional with a depth‐independent geoelectric strike angle of N32°E, consistent with regional structural geology. The regional‐scale model, generated from the longer period responses from all of the sites along the profile, reveals significant lateral variations in the lithospheric mantle. Resistive cratonic roots are imaged to depths of ∼200 km beneath both the Slave craton and the Hottah terrane of the Bear Province. These are separated by a less resistive region beneath the Great Bear magmatic zone, which is speculatively interpreted as a consequence of a decrease in the grain size of olivine in the Wopmay mantle, caused by localized shearing, compared to its neighboring cratonic roots. Focused two‐dimensional models, from higher frequency responses at sites on specific sections of the profile, reveal the resistivity structure at crustal depths beneath the region. These suggest that the root of the Slave craton crosses beneath the Wopmay orogen, and that the Wopmay fault zone does not penetrate into the lower crust. A comparison of these results with those obtained during the Lithoprobe project farther south shows striking along strike variations in the conductivity structure associated with the Wopmay orogen

CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.CAG was supported by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number P50 HD103525. This work was funded by PID2020-112831GB-I00 AEI /10.13039/501100011033 (MN). SS was supported by a grant from the NIH/NINDS (K23NS119666). SWS is supported by the Hospital for Sick Children Foundation, Autism Speaks, and the University of Toronto McLaughlin Center. EM-G was supported by a grant from MICIU FPU18/06240. EVS. was supported by a grant from the NIH (EY025718). CRF was supported by the fund to support clinical research careers in the Region of Southern Denmark (Region Syddanmarks pulje for kliniske forskerkarriereforløb).Peer reviewe

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes