Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Testing Processability Theory in L2 Spanish: Can readiness or markedness predict development?

The goal of this dissertation is to test the five stages of Processability Theory (PT) for second language (L2) learners of Spanish and investigate how instruction can facilitate the development through the stages. PT details five fixed stages in the acquisition of L2 morphosyntax based on principles of speech processing (Levelt, 1989) and modeled on Lexical- Functional Grammar (LFG) (Kaplan & Bresnan, 1982; Bresnan, 2001). In addition, two models that predict how instruction can affect staged language development are tested: the Teachability Hypothesis (Pienemann, 1984, 1989), which says that instruction will only be effective if aimed at the next developmental stage and Projection Model (Zobl, 1983, 1985), which claims that instruction on more marked items can project to less marked, related items. In Study 1, the specific stages for L2 Spanish morphology and syntax were proposed and tested on a cross-sectional corpus of conversational data by learners (n=21) with L1 English. Implicational scaling confirmed the five stages for the syntax and morphology with 100% scalability. Syntax was also found to emerge before morphology at all five stages. Studies 2 and 3 tested the effect of instruction aimed at Stages 3, 4 and 5 for beginning (first and second semester) learners of Spanish ( N=57). Learners' oral production and stage gains were measured between a pre-test, a post-test two days after instruction, and a delayed post-test three weeks later. Learners' production of the target structures increased after instruction on the next, next + 1 or next + 2 stages, while the control groups made no significant changes. These results present counter-evidence to the prediction of the Teachability Hypothesis that instruction only on the next stage can aid learners to advance to subsequent developmental stages. Overall, the results offer further cross-linguistic support for the PT hierarchy, while refuting one of its corollaries, the Teachability Hypothesis

Utilización de corpus de español L1 en el aula de LE/L2/LH : ¿por qué y para qué?

For more than three decades, researchers have encouraged using corpora in the second language (L2) classroom. Still, despite the support many researchers express for this idea, it seems the use of corpora in Spanish as an L2, foreign language (FL), and heritage language (HL) classrooms remains rare. This article aims to elucidate how successful integration of corpus tools depends on a clear link between tools and classroom needs. In order to do so, common pedagogical trends in the L2 Spanish classroom will be reviewed along with empirical studies and didactic proposals that demonstrate how first language (L1) Spanish corpora can be used, while keeping in mind the application of corpora both from the perspective of students and instructors. The authors’ experiences, as instructors and researchers, will also guide part of this conversation. At the same time, this article aims to highlight the importance of conducting research informed by the perspectives and needs of instructors. From this angle, it is easier to discover how corpus tools can contribute to the classroom by pursuing a broader vision of multiple possibilities for corpus use

Electronic devices as correlates of sedentary behavior and screen time among diverse low-income adolescents during the school year and summer time

Excessive screen time among adolescents increases risk for overweight/obesity. Having electronic devices in the adolescent’s bedroom is associated with more screen time. The present study expanded on previous studies by also examining portable personal electronic devices and social media membership as correlates of screen time use and total sedentary time in the school year and summer among diverse low-income adolescents. Adolescents aged 10-17 years were recruited from lower-income areas, and n=150 completed surveys and wore accelerometers in both the school year and summer: 34 African Americans, 23 American Indians, 16 Asian/Pacific Islanders, 39 Latinos, and 38 White/non-Hispanics. Total sedentary time was computed from accelerometers. Recreational screen time was assessed with a 3-item validated scale. Adolescents reported the presence of 6 electronic devices in their bedrooms, ownership of 4 portable devices, and social media membership. General linear modeling was conducted for both time periods, with demographic covariates and interactions with sex and race-ethnicity. More electronic devices in bedrooms were related to more screen time during the school year and summer, and to more total sedentary time in summer. Personal electronics were only related to more screen time in the school year. Social media membership was related to more total sedentary time in summer, but only among African Americans, American Indians, and non-Hispanic Whites. Electronic devices in bedrooms was confirmed as a risk factor for sedentary behavior among low-income adolescents of color. Social media membership and use should be further studied with diverse adolescents

Race/ethnic variations in school-year versus summer differences in adolescent physical activity

Children and adolescents gain more weight in the summer than the school year, and there are race/ethnic differences in this pattern. Youth physical activity is lower in the summer, and the main aim of the present study was to examine race/ethnic and sex differences in adolescent physical activity, sedentary behavior, and related variables, comparing the school-year and summer. Adolescents aged 11–17 years were recruited from lowerincome areas of five states in 2017–2018, and n=207 completed surveys in both the school-year and summer: 56 African Americans, 30 American Indians, 21 Asian/Pacific Islanders, 49 Latinos, and 51 White, non- Hispanics. Of these, n=150 also had accelerometer data. Objectively-measured physical activity was lower in the summer, especially among American Indian, Asian/Pacific Islander, and Latino subgroups. Reported screen time was substantially higher in the summer (p < .04), with the biggest increase among African Americans. Reported enjoyment of physical activity was generally lower in the summer (p < .02), which could help explain reduced physical activity. Which race/ethnic groups were at higher risk in the summer varied for physical activity and screen time, so interventions should be tailored for each group. Improved strategies to increase physical activity in the summer, especially among higher-risk groups, could contribute to youth obesity control

Contextual factors related to implementation of classroom physical activity breaks

Brief structured physical activity in the classroom is effective for increasing student physical activity. The present study investigated the association between implementation-related contextual factors and intervention implementation after adoption of a structured classroom physical activity intervention. Six elementary-school districts adopted structured classroom physical activity programs in 2013-2014. Implementation contextual factors and intervention implementation (structured physical activity provided in past week or month, yes/no) were assessed using surveys of 337 classroom teachers from 24 schools. Mixed-effects models accounted for the nested design. Availability of resources (yes/no, ORs = 1.91-2.93) and implementation climate z-scores (ORs = 1.36-1.47) were consistently associated with implementation. Teacher-perceived classroom behavior benefits (OR = 1.29) but not student enjoyment or health benefits, and time (OR = 2.32) and academic (OR = 1.63) barriers but not student cooperation barriers were associated with implementation (all z-scores). Four implementation contextual factor composites had an additive association with implementation (OR = 1.64 for each additional favorable composite). Training and technical assistance alone may not support a large proportion of teachers to implement structured classroom physical activity. In addition to lack of time and interference with academic lessons, school climate related to whether administrators and other teachers were supportive of the intervention were key factors explaining whether teachers implemented the intervention. Evidence-based implementation strategies are needed for effectively communicating the benefits of classroom physical activity on student behavior and improving teacher and administrator climate/attitudes around classroom physical activity

Implementing classroom physical activity breaks: Associations with student physical activity and classroom behavior

Objective: To investigate the relation of classroom physical activity breaks to students' physical activity and classroom behavior. Methods: Six elementary-school districts in California implemented classroom physical activity interventions in 2013–2014. Students' (N = 1322) accelerometer-measured moderate-to-vigorous physical activity (MVPA) during school and teachers' (N = 397) reports of implementation and classroom behavior were assessed in 24 schools at two time points (both post-intervention). Mixed-effects models accounted for nested data. Results: Minutes/day of activity breaks was positively associated with students' MVPA (βs = .07–.14; ps = .012–.016). Students in classrooms with activity breaks were more likely to obtain 30 min/day of MVPA during school (OR = 1.75; p = .002). Implementation was negatively associated with students having a lack of effort in class (β = − .17; p = .042), and student MVPA was negatively associated with students being off task or inattentive in the classroom (β = − .17; p = .042). Students provided with 3–4 physical activity opportunities (classroom breaks, recess, PE, dedicated PE teacher) had ≈ 5 more min/day of school MVPA than students with no opportunities (B = 1.53 min/opportunity; p = .002). Conclusions: Implementing classroom physical activity breaks can improve student physical activity during school and behavior in the classroom. Comprehensive school physical activity programs that include classroom-based activity are likely needed to meet the 30 min/day school physical activity guideline

Linking Parent Confidence and Hospitalization through Mobile Health: A&nbsp;Multisite Pilot Study

ObjectiveTo evaluate the associations between parent confidence in avoiding hospitalization and subsequent hospitalization in children with medical complexity (CMC); and feasibility/acceptability of a texting platform, Assessing Confidence at Times of Increased Vulnerability (ACTIV), to collect repeated measures of parent confidence.Study designThis prospective cohort study purposively sampled parent-child dyads (n&nbsp;=&nbsp;75) in 1 of 3 complex care programs for demographic diversity to pilot test ACTIV for 3&nbsp;months. At random days/times every 2&nbsp;weeks, parents received text messages asking them to rate confidence in their child avoiding hospitalization in the next month, from 1 (not confident) to 10 (fully confident). Unadjusted and adjusted generalized estimating equations with repeated measures evaluated associations between confidence and hospitalization in the next 14&nbsp;days. Post-study questionnaires and focus groups assessed ACTIV's feasibility/acceptability.ResultsParents were 77.3% mothers and 20% Spanish-speaking. Texting response rate was 95.6%. Eighteen hospitalizations occurred within 14&nbsp;days after texting, median (IQR) 8 (2-10) days. When confidence was &lt;5 vs&nbsp;≥5, adjusted odds (95% CI) of hospitalization within 2&nbsp;weeks were 4.02 (1.20-13.51) times greater. Almost all (96.8%) reported no burden texting, one-third desired more frequent texts, and 93.7% were very likely to continue texting. Focus groups explored the meaning of responses and suggested ACTIV improvements.ConclusionsIn this demographically diverse multicenter pilot, low parent confidence predicted impending CMC hospitalization. Text messaging was feasible and acceptable. Future work will test efficacy of real-time interventions triggered by parent-reported low confidence