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Alternative splicing impacts most multi-exonic human genes. Inaccuracies during this process may have an important role in ageing and disease. Here, we investigate splicing accuracy using RNA-sequencing data from >14k control samples and 40 human body sites, focusing on split reads partially mapping to known transcripts in annotation. We show that splicing inaccuracies occur at different rates across introns and tissues and are affected by the abundance of core components of the spliceosome assembly and its regulators. We find that age is positively correlated with a global decline in splicing fidelity, mostly affecting genes implicated in neurodegenerative diseases. We find support for the latter by observing a genome-wide increase in splicing inaccuracies in samples affected with Alzheimers disease as compared to neurologically normal individuals. In this work, we provide an in-depth characterisation of splicing accuracy, with implications for our understanding of the role of inaccuracies in ageing and neurodegenerative disorders.

The pre-mRNA life cycle requires intron processing; yet, how intron-processing defects influence splicing and gene expression is unclear. Here, we find that TTDN1/MPLKIP, which is encoded by a gene implicated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to spliceosomal function. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, whereas its N-terminal intrinsically disordered region (IDR) binds the intron-binding complex (IBC). TTDN1 loss, or a mutated IDR, causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. A Ttdn1-deficient mouse model recapitulates intron-processing defects and certain neurodevelopmental phenotypes seen in NP-TTD. Fusing DBR1 to the TTDN1 IDR is sufficient to recruit DBR1 to the IBC and circumvents the functional requirement for TTDN1. Collectively, our findings link RNA lariat processing with splicing outcomes by revealing the molecular function of TTDN1.

BackgroundDNA sequencing is increasingly incorporated into the routine care of cancer patients, many of whom also carry inherited, moderate/high-penetrance variants associated with other diseases. Yet, the prevalence and consequence of such variants remain unclear.MethodsWe analyzed the germline genomes of 10,389 adult cancer cases in the TCGA cohort, identifying pathogenic/likely pathogenic variants in autosomal-dominant genes, autosomal-recessive genes, and 59 medically actionable genes curated by the American College of Molecular Genetics (i.e., the ACMG 59 genes). We also analyzed variant- and gene-level expression consequences in carriers.ResultsThe affected genes exhibited varying pan-ancestry and population-specific patterns, and overall, the European population showed the highest frequency of pathogenic/likely pathogenic variants. We further identified genes showing expression consequence supporting variant functionality, including altered gene expression, allelic specific expression, and mis-splicing determined by a massively parallel splicing assay.ConclusionsOur results demonstrate that expression-altering variants are found in a substantial fraction of cases and illustrate the yield of genomic risk assessments for a wide range of diseases across diverse populations.

Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer's disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease.

Introduction: Physician finances are linked to wellness and burnout. However, few physicians receive financial management education. We sought to determine the financial literacy and educational need of attending and resident physician at an academic emergency medicine (EM) residency.  Methods: We performed a cross-sectional, survey study at an academic EM residency. We devised a 49-question survey with four major domains: demographics (16 questions); Likert-scale questions evaluating value placed on personal finances (3 questions); Likert-scale questions evaluating perceived financial literacy (11 questions); and a financial literacy test based on previously developed and widely used financial literacy questions (19 questions). We administered the survey to EM attendings and residents. We analyzed the data using descriptive statistics and compared attending and resident test question responses.  Results: A total of 44 residents and 24 attendings responded to the survey. Few (9.0% of residents, 12.5% of attendings) reported prior formal financial education. However, most respondents (70.5% of residents and 79.2% of attendings) participated in financial self-learning. On a five-point Likert scale (not at all important: very important), respondents felt that financial independence (4.7 ± 0.8) and their finances (4.7±0.8) were important for their well-being. Additionally, they valued being prepared for retirement (4.7±0.9). Regarding perceived financial literacy (very uncomfortable: very comfortable), respondents had the lowest comfort level with investing in the stock market (2.7±1.5), applying for a mortgage (2.8±1.6), and managing their retirement (3.0±1.4). Residents scored significantly lower than attendings on the financial literacy test (70.8% vs 79.6%, P

Purpose: The use of online focus groups to explore children and young people's (CYP) perspectives of inequalities in health and associated "sensitive" topics raises important ethical and methodological issues to consider. The purpose of the paper is to discuss lessons learnt from navigating the authors' way through some of the key challenges the authors encountered when researching inequalities in health with CYP through online focus groups. Design/methodology/approach: In the paper, the authors draw on reflections and notes from the fieldwork design, public involvement and engagement (PIE) activities and data collection for their research project. Findings: Collecting data online influenced the authors' ability to develop rapport and relationships with CYP and to provide effective support when discussing sensitive topics. The authors note that building activities to develop rapport with participants during recruitment and data collection and establishing clear support and safeguarding protocols helped navigate challenges of online approaches around effective and supportive participant engagement. Originality/value: The paper highlights that despite ethical and methodological challenges of conducting online focus groups with CYP on potentially sensitive topics, the adoption of practical steps and strategies before, during and following data collection can facilitate the safe participation of CYP and generate useful and valid data in meaningful and appropriate ways.

Adults (N = 54, 80.78 ± 6.08 years) who reported falling during the previous 12 months participated in a 12-week wobble board training program with internal focus or external focus (EF) instructions. Verbal manipulation checks were performed after training sessions as a self-report of the attentional foci used. The percentage of sessions in which participants reported using an EF (EF[subscript SR]) was subsequently calculated. Mean velocity and mean power frequency in the anterior-posterior (MVELO[subscript AP] and MPF[subscript AP]) and medial-lateral (MVELO[subscript ML] and MPF[subscript ML]) direction were assessed during a 35-s wobble board task at Weeks 0, 6, 12, 13, 16, and 20, with the latter three as retention tests. Piecewise linear growth models estimated treatment effects on individual growth trajectories of MVELO[subscript AP] and [subscript ML] and MPF[subscript AP] and [subscript ML] during intervention and retention periods. Regardless of condition, MVELOML significantly decreased ([pi] = -0.0019, p = 0.005) and MPF[subscript ML] increased ([pi] = 0.025, p < 0.02) during the intervention period. In analyses including interaction terms, participants in the EF group who reported greater EF[subscript SR] had superior progression of MPF[subscript AP] during the intervention ([pi] = 0.0013, p = 0.025). Verbal manipulation checks suggest a preference for and advantage of EF for facilitating postural control performance and automaticity.

This study examined whether associations exist between PA intensity, self-regulation, and indicators of school readiness, a proxy for academic achievement, in young children. Thirty young children completed assessments of physical activity, school readiness indicators, and self-regulation. Physical activity intensity was classified as light, moderate or vigorous. School readiness indicators were assessed using expressive and receptive subtests. There were no associations between light and moderate physical activity, school readiness indicators, and self-regulation. Additionally, there was no association between vigorous activity and the receptive subtest of the school readiness indicators. Correlations were significant between vigorous activity, self-regulation, and expressive subtest. School indicator expressive scores and self-regulation were significantly predicted by the level of vigorous activity. Results suggest the existence of an intensity threshold influencing the PA, self-regulation, and school readiness association.

Objective: This article reports on a qualitative evaluation of the Love Life, "Smokefree Sports" primary school pilot intervention. This 8-week programme used sports and physical activity sessions to convey Smokefree messages to 120 children aged 10 and 11 in two primary schools in Sheffield in 2018. The study aimed to understand children's experiences of participating in the programme. Its objectives were to explore children's recall of the health promotion messages associated with each of the learning sessions; explore children's perceptions of the meaningfulness of those messages in the context of their everyday lives; and identify and understand any contextual factors that might impact upon children's recall and/or the meaningfulness of the Smokefree messages. Method: Qualitative data were generated with 25 children through focus groups after the programme concluded. Data were analysed thematically using cross-sectional, categorical indexing. Results: Learning from the programme was particularly likely to be described as meaningful by children when they could interact with material and visual representations of complex ideas and when sessions involved strongly embodied experiences. However, children did not always find it easy to relate learning to their everyday lives and sometimes struggled to reconcile pre-existing, contextualised understandings with intervention messages. We mobilise the concept of critical health literacy as a theoretical lens through which to interpret these findings. Conclusion: Health education should be meaningful in the context of children's everyday lives. Starting from the premise that children are active critical health literacy practitioners and working with them to design and evaluate health education initiatives can promote this.

This paper reports on a trial of a new model of clinical education designed to increase student clinical placement availability and address workforce constraints on supervision. The University of Sydney deployed the Capacity Development Facilitators (CDF) in selected Sydney hospitals to work with staff to expand student clinical placement opportunities by identifying enablers, barriers and stressors of clinical placements and collaboratively developing solutions, provide organizational and learning support and foster opportunities for interprofessional learning. A mixed methods study was undertaken collecting data from physiotherapy students and their clinical educators (CE). At completion of placement students and CEs completed a survey. This was analyzed for themes about placement structure, productivity, barriers, enablers, stressors and support. Preliminary findings suggest the CDF model increases capacity, provides robust learning experiences and satisfaction with placements from the hospital, university staff and students' perspectives.

Bottom-up synthesized graphene nanoribbons and graphene nanoribbon heterostructures have promising electronic properties for high-performance field-effect transistors and ultra-low power devices such as tunneling field-effect transistors. However, the short length and wide band gap of these graphene nanoribbons have prevented the fabrication of devices with the desired performance and switching behavior. Here, by fabricating short channel (L ch ~ 20 nm) devices with a thin, high-κ gate dielectric and a 9-atom wide (0.95 nm) armchair graphene nanoribbon as the channel material, we demonstrate field-effect transistors with high on-current (I on > 1 μA at V d = -1 V) and high I on /I off ~ 105 at room temperature. We find that the performance of these devices is limited by tunneling through the Schottky barrier at the contacts and we observe an increase in the transparency of the barrier by increasing the gate field near the contacts. Our results thus demonstrate successful fabrication of high-performance short-channel field-effect transistors with bottom-up synthesized armchair graphene nanoribbons.Graphene nanoribbons show promise for high-performance field-effect transistors, however they often suffer from short lengths and wide band gaps. Here, the authors use a bottom-up synthesis approach to fabricate 9- and 13-atom wide ribbons, enabling short-channel transistors with 105 on-off current ratio.

Through a collaborative university-hospital partnership, a student-led service model (SLS-model) was implemented to increase student placement capacity within a physiotherapy department of a 150 bed Sydney hospital. This study investigates the perceived barriers and enablers to increasing student placement capacity through student-led services (SLS) and the outcomes for hospital stakeholders and the university. Using mixed methods design, investigators interviewed nine clinical educators and surveyed thirty-four students over a ten month period to identify perceived barriers and enablers, clinical supervision models, experiences, support, and strategic innovations to increase student placement capacity. Content analysis of the interviews and quantitative visual analogue scores were statistically analyzed. Results demonstrate that student placement capacity increased by 212.5% at this hospital. Barriers and enablers included: student and clinical educator characteristics; placement support; workload and SLS-model context. Despite the perceived barriers challenging SLS implementation, enablers facilitated the SLS-model to increase healthcare service provision and increase student placement capacity for physiotherapy students at this hospital.