Autism genes converge on asynchronous development of shared neuron classes.

Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions1-6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals7,8. Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes-SUV420H1 (also known as KMT5B), ARID1B and CHD8-in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages-γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons-but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology.

Application of a Web-based Tool for Quantitative Bias Analysis: The Example of Misclassification Due to Self-reported Body Mass Index.

BACKGROUND: We describe the use of Apisensr, a web-based application that can be used to implement quantitative bias analysis for misclassification, selection bias, and unmeasured confounding. We apply Apisensr using an example of exposure misclassification bias due to use of self-reported body mass index (BMI) to define obesity status in an analysis of the relationship between obesity and diabetes. METHODS: We used publicly available data from the National Health and Nutrition Examination Survey. The analysis consisted of: (1) estimating bias parameter values (sensitivity, specificity, negative predictive value, and positive predictive value) for self-reported obesity by sex, age, and race-ethnicity compared to obesity defined by measured BMI, and (2) using Apisensr to adjust for exposure misclassification. RESULTS: The discrepancy between self-reported and measured obesity varied by demographic group (sensitivity range: 75%-89%; specificity range: 91%-99%). Using Apisensr for quantitative bias analysis, there was a clear pattern in the results: the relationship between obesity and diabetes was underestimated using self-report in all age, sex, and race-ethnicity categories compared to measured obesity. For example, in non-Hispanic White men aged 40-59 years, prevalence odds ratios for diabetes were 3.06 (95% confidence inerval = 1.78, 5.30) using self-reported BMI and 4.11 (95% confidence interval = 2.56, 6.75) after bias analysis adjusting for misclassification. CONCLUSION: Apisensr is an easy-to-use, web-based Shiny app designed to facilitate quantitative bias analysis. Our results also provide estimates of bias parameter values that can be used by other researchers interested in examining obesity defined by self-reported BMI.

Snakes and ladders: An integrative literature review of refugee doctors' workforce integration needs.

INTRODUCTION: Healthcare systems worldwide are facing a workforce crisis; meanwhile, refugee doctors throughout the world face difficulties in accessing work. The aims of this review were to explore the integration needs of refugee doctors into host healthcare systems from the refugee perspective, synthesise the literature to construct a theory of refugee doctor integration needs and explore how these needs are met or challenged on the pathway to full integration. METHODS: In this integrative literature review, 11 databases and eight grey literature sources were searched by combining terms for refugee doctor and social integration and limiting to research published in or after 2003. Data were extracted, and quality scoring was completed independently by two researchers. This study utilised template analysis to perform a qualitative synthesis of the data. The multidimensional template included a pre-defined template based on a theoretical framework and a concurrent fully inductive template. RESULTS: Twenty-two papers were included, incorporating the views of 339 doctors from 30 different home countries and 10 different host countries. The resultant theory included 'foundations' (rights and responsibilities) and three pillars. The 'learning' pillar included required knowledge and skills acquisition. The 'being' pillar encompassed necessary identity work. The 'connecting' pillar comprised social connections, which impacted all other domains. The random and non-linear path to integration faced by refugee doctors was also presented as a serious game. DISCUSSION: This study produced a theory exploring refugee doctors' integration needs and how these are met or challenged. Medical educators developing courses for refugee doctors should attend not only to knowledge and skills acquisition but also social connections, identity work and rights and responsibilities. The theory highlights the central importance of social connections. Medical educators can therefore have a transformative impact on refugee doctors' integration. This may also contribute to society by helping to alleviate the workforce crisis.

Opposing functions of the plant TOPLESS gene family during SNC1-mediated autoimmunity.

Regulation of the plant immune system is important for controlling the specificity and amplitude of responses to pathogens and in preventing growth-inhibiting autoimmunity that leads to reductions in plant fitness. In previous work, we reported that SRFR1, a negative regulator of effector-triggered immunity, interacts with SNC1 and EDS1. When SRFR1 is non-functional in the Arabidopsis accession Col-0, SNC1 levels increase, causing a cascade of events that lead to autoimmunity phenotypes. Previous work showed that some members of the transcriptional co-repressor family TOPLESS interact with SNC1 to repress negative regulators of immunity. Therefore, to explore potential connections between SRFR1 and TOPLESS family members, we took a genetic approach that examined the effect of each TOPLESS member in the srfr1 mutant background. The data indicated that an additive genetic interaction exists between SRFR1 and two members of the TOPLESS family, TPR2 and TPR3, as demonstrated by increased stunting and elevated PR2 expression in srfr1 tpr2 and srfr1 tpr2 tpr3 mutants. Furthermore, the tpr2 mutation intensifies autoimmunity in the auto-active snc1-1 mutant, indicating a novel role of these TOPLESS family members in negatively regulating SNC1-dependent phenotypes. This negative regulation can also be reversed by overexpressing TPR2 in the srfr1 tpr2 background. Similar to TPR1 that positively regulates snc1-1 phenotypes by interacting with SNC1, we show here that TPR2 directly binds the N-terminal domain of SNC1. In addition, TPR2 interacts with TPR1 in vivo, suggesting that the opposite functions of TPR2 and TPR1 are based on titration of SNC1-TPR1 complexes by TPR2 or altered functions of a SNC1-TPR1-TPR2 complex. Thus, this work uncovers diverse functions of individual members of the TOPLESS family in Arabidopsis and provides evidence for the additive effect of transcriptional and post-transcriptional regulation of SNC1.

From corners to community: exploring medical students' sense of belonging through co-creation in clinical learning.

BACKGROUND: Belonging is critical for the development and wellbeing of medical students. Belonging, particularly within a 'relational being' paradigm, presents a significant challenge for students, especially within clinical learning environments. Co-creation is a learning relationship in which students are actively involved in the education process. It is inherently relational and promotes belonging within higher education environments. Little is known about utilising co-creation in the curriculum, within medical education. The aim of this study was to explore medical students' experience of co-creation of learning resources within the clinical learning environment. METHODS: Following ethical approval, medical students were invited to become co-creators of a learning bulletin resource, within the paediatric acute receiving unit, at a paediatric teaching hospital. Interpretative phenomenological analysis (IPA) was used to enable an in-depth exploration of how medical students experienced co-creation within the clinical learning environment. Medical students participated in semi-structured interviews about their experience, which were transcribed verbatim and analysed using IPA. The analysis integrated individual lived experiences into an analytic summary. RESULTS: Nine medical students participated. Three group experiential themes were identified: identity maturation; learning community and workplace integration. The support found within this co-created learning community, along with maturation of their identity, allowed the participants to experience a challenge to their existing worldview. This shift in perspective resulted in them responding and behaving in the workplace in new ways, which enabled them to belong as themselves in the clinical learning environment. These findings were situated within the developmental concept of self-authorship, as well as contributing to a new understanding of how co-creation promoted social integration. CONCLUSIONS: Co-creation enabled students to learn in a meaningful way. The relational power of co-creation, can be harnessed to deliver participatory learning experiences, within our increasingly complex healthcare environment, to support the learning, development and integration of doctors of the future.

Exploring the role of palliative care occupational therapists in supporting compassionate communities in end-of-life care.

INTRODUCTION: The compassionate communities' movement is a public health approach to end-of-life care that emphasises the integral role of communities in supporting and caring for dying persons and their informal carers. Although occupational therapists have well-established roles in palliative care teams, little is known about their potential in assisting in the formation and maintenance of compassionate communities. METHOD: Data were gathered via semi-structured interviews with nine Australian occupational therapists with experience in specialist palliative care. Interview questions were based around the British Columbia Compassionate Community Ideal framework. Key themes were derived through qualitative descriptive analysis, blending deductive, and inductive reasoning. FINDINGS: Interviewees indicated that occupational therapists have a role in supporting compassionate communities that centres on the facilitation of networks and connections between palliative care professionals and in the promotion of informal care networks. The importance of education and awareness raising were also discussed as valuable to the development of community capacity. It was also suggested that occupational therapists have important skills to support dying persons and their caregivers to remain engaged and safe in their homes and communities, in a meaningful and sustainable way. However, many interviewees maintained a profession-centric view on control within compassionate communities, as opposed to approaches that are community led. CONCLUSION: Findings offer early insights into the promise and potential of occupational therapists in supporting the compassionate communities' movement. However, education regarding the ethos of the compassionate communities' movement so as to facilitate a shift away from professionally oriented modes of practice may be needed to maximise success.

De novo assembly and annotation of the singing mouse genome.

BACKGROUND: Developing genomic resources for a diverse range of species is an important step towards understanding the mechanisms underlying complex traits. Specifically, organisms that exhibit unique and accessible phenotypes-of-interest allow researchers to address questions that may be ill-suited to traditional model organisms. We sequenced the genome and transcriptome of Alston's singing mouse (Scotinomys teguina), an emerging model for social cognition and vocal communication. In addition to producing advertisement songs used for mate attraction and male-male competition, these rodents are diurnal, live at high-altitudes, and are obligate insectivores, providing opportunities to explore diverse physiological, ecological, and evolutionary questions. RESULTS: Using PromethION, Illumina, and PacBio sequencing, we produced an annotated genome and transcriptome, which were validated using gene expression and functional enrichment analyses. To assess the usefulness of our assemblies, we performed single nuclei sequencing on cells of the orofacial motor cortex, a brain region implicated in song coordination, identifying 12 cell types. CONCLUSIONS: These resources will provide the opportunity to identify the molecular basis of complex traits in singing mice as well as to contribute data that can be used for large-scale comparative analyses.

Real-World Evidence Comparing Vedolizumab and Ustekinumab in Antitumor Necrosis Factor-Experienced Patients With Crohn's Disease.

INTRODUCTION: Many patients with Crohn's disease (CD) lose response or become intolerant to antitumor necrosis factor (TNF) therapy and subsequently switch out of class. We compared the effectiveness and safety of ustekinumab to vedolizumab in a large, geographically diverse US population of TNF-experienced patients with CD. METHODS: We conducted a retrospective cohort study using longitudinal claims data from a large US insurer (Anthem, Inc.). We identified patients with CD initiating vedolizumab or ustekinumab with anti-TNF treatment in the prior 6 months. Our primary outcome was treatment persistence for >52 weeks. Secondary outcomes included (i) all-cause hospitalization, (ii) hospitalization for CD with surgery, (iii) hospitalization for CD without surgery, and (iv) hospitalization for infection. Propensity score fine stratification was used to control for demographic and baseline clinical characteristics and prior treatments. RESULTS: Among 885 new users of ustekinumab and 490 new users of vedolizumab, we observed no difference in treatment persistence (adjusted risk ratio 1.09 [95% confidence interval 0.95-1.25]). Ustekinumab was associated with a lower rate of all-cause hospitalization (adjusted hazard ratio 0.73 [0.59-0.91]), nonsurgical CD hospitalization (adjusted hazard ratio 0.58 [0.40-0.83]), and hospitalization for infection (adjusted hazard ratio 0.56 [0.34-0.92]). DISCUSSION: This real-world comparative effectiveness study of anti-TNF-experienced patients with CD initiating vedolizumab or ustekinumab showed similar treatment persistence rates beyond 52 weeks, although secondary outcomes such as all-cause hospitalizations, nonsurgical CD hospitalizations, and hospitalizations for infection favored ustekinumab initiation. We, therefore, advocate for individualized decision making in this medically refractory population, considering patient preference and other factors such as cost and route of administration.

Pre-treatment calprotectin (MRP8/14) provides no added value to testing CRP alone in terms of predicting response to TNF inhibitors in rheumatoid arthritis in a post hoc analysis.

OBJECTIVES: The inflammatory protein calprotectin (MRP8/14) has been identified as a promising biomarker of treatment response in rheumatoid arthritis (RA). Our aim was to test MRP8/14 as a biomarker of response to tumour necrosis factor (TNF)-inhibitors in the largest RA cohort to date and to compare with C-reactive protein (CRP). METHODS: Serum MRP8/14 was measured in 470 patients with RA about to commence treatment with adalimumab (n=196) or etanercept (n=274). Additionally, MRP8/14 was measured in the 3-month sera of 179 adalimumab-treated patients. Response was determined using European League against Rheumatism (EULAR) response criteria calculated using the traditional 4-component (4C) DAS28-CRP and alternate validated versions using 3-component (3C) and 2-component (2C), clinical disease activity index (CDAI) improvement criteria and change in individual outcome measures. Logistic/linear regression models were fitted for response outcome. RESULTS: In the 3C and 2C models, patients with RA were 1.92 (CI: 1.04 to 3.54) and 2.03 (CI: 1.09 to 3.78) times more likely to be classified as EULAR responders if they had high (75th quartile) pre-treatment levels of MRP8/14 compared with low (25th quartile). No significant associations were observed for the 4C model. When only using CRP as a predictor, in the 3C and 2C analyses, patients above the 75th quartile were 3.79 (CI: 1.81 to 7.93) and 3.58 (CI: 1.74 to 7.35) times more likely to be EULAR responders and addition of MRP8/14 did not significantly improve model fit (p values=0.62 and 0.80, respectively). No significant associations were observed in the 4C analysis. Exclusion of CRP from the outcome measure (CDAI) did not result in any significant associations with MRP8/14 (OR 1.00 (CI: 0.99 to 1.01), suggesting that the associations were due to the correlation with CRP and that there is no additional utility of MRP8/14 beyond use of CRP in patients with RA starting TNFi therapy. CONCLUSION: Beyond correlation with CRP, we found no evidence to suggest that MRP8/14 explains additional variability in response to TNFi in patients with RA over and above CRP alone.

Functional Neural Correlates of a Useful Field of View (UFOV)-Based fMRI Task in Older Adults.

Declines in processing speed performance occur in aging and are a critical marker of functional independence in older adults. Studies suggest that Useful Field of View (UFOV) training may ameliorate cognitive decline. Despite its efficacy, little is known about the neural correlates of this task. Within the current study, 233 healthy older adults completed a UFOV-based task while undergoing functional magnetic resonance imaging (fMRI). During the "stimulus" portion of this task, participants must identify a target in the center of the screen and the location of a target in the periphery, among distractors. During the "probe" portion, participants must decide if the object in the center and the location of the target in the periphery were identical to the "stimulus" screen. Widespread bilateral whole-brain activation was observed when activation patterns of the "probe" contrast were subtracted from the "stimulus" contrast. Conversely, the subtraction of "stimulus" from "probe" was associated with discrete activation patterns consisting of 13 clusters. Additionally, when evaluating the variance associated with task accuracy, specific subregions were identified that may be critical for task performance. Our data elucidate the functional neural correlates of a UFOV-based task, a task used in both cognitive training paradigms and assessment of function.

'Just pretending': Narratives of professional identity transitions in internal medicine.

INTRODUCTION: Health professional identity transitions involve a dynamic period of liminality prompting a time of considerable uncertainty and self-doubt. For postgraduate trainees in the United Kingdom, the transition to medical registrar can be a significant deterrent to recruitment and retention. Narrative analysis offers insight into identity work during transitions with potential to inform strategies for developing professional identities. This study aimed to use narrative analysis to explore trainees' experiences and their sense of agency during the liminal phase of this transition. METHODS: Following ethical approval, internal medicine (IM) trainees in their second year of IM training were interviewed. Transcripts were audio recorded, transcribed verbatim and analysed to identify narratives describing liminality during the transition to the role of medical registrar, including examples of rejecting and claiming identity grants. Narrative analysis, as described by Riessman and influenced by James Gee's units of discourse, was undertaken, with an agentive lens applied to the data. RESULTS: Between January 2021 and February 2022, 19 IM trainees were interviewed. Given the in-depth analysis, four narratives were purposively selected to present, including trainees rejecting and claiming the medical registrar role. Trainees tended to describe negative experiences, but those with a higher sense of agency demonstrated positive reflection and identity construction through narrative. There was often identity dissonance between how trainees defined their stage in the transition to medical registrar and how their narrative illustrated their identity work. CONCLUSION: This study exemplifies narrative analysis' linguistic and agentive lenses in exploring the experience of the liminal identity transitional period. The findings reflect the identity dissonance experienced by trainees during this time and sheds light on their sense of agency throughout. It heralds a need to acknowledge the significant liminality experienced during transitions throughout medical training and to empower a sense of agency to support identity work.

'There's no straight line ' a consumer-informed intervention for FTD family care partners: the STELLA-FTD pilot study.

OBJECTIVES: Behavioral symptoms and communication challenges are particularly apparent in frontotemporal degenerative (FTD) dementias. There is a paucity of psychoeducation programming specifically tailored to the needs of families with FTD. We revised an existing intervention to meet the needs of these families. METHODS: We used a quasi-experimental approach. In Phase 1, we sought consumer input about an existing intervention. In Phase 2, we modified the intervention based on the qualitative findings from Phase 1 and tested the revised intervention (STELLA-FTD) for feasibility, acceptability and early-stage efficacy. Outcome for Phase 2 included feasibility data and care partner reactivity to upsetting behaviors. Secondary outcomes included data from unobtrusive sleep monitoring. An inductive analysis of transcripts from the Phase 2 STELLA-FTD focus group provides guidance for future revisions. RESULTS: Fifteen family care partners participated in the Phase 1 focus groups; sixteen care partners enrolled in Phase 2. Testing in Phase 2 revealed that the care partners found our consumer-informed revised intervention both feasible and acceptable. The post-intervention findings suggest STELLA-FTD has the potential to reduce care partner reactivity to upsetting behaviors and to decrease care partner burden. Sleep did not change over the 8-week intervention. CONCLUSIONS: The revised STELLA-FTD intervention was found to be feasible and acceptable, and has potential to improve care partner burden for families living with FTD. Providing the intervention via telehealth maximized access and engaged rehabilitation specialists in providing disease management content. Future revisions will include examination of efficacy and mechanism of action (OHSU IRB # 00022721, ClinicalTrials.gov NCT05338710).

Frontline experiences of delivering remote mental health supports during the COVID-19 pandemic in Scotland: innovations, insights and lessons learned from mental health workers.

COVID-19 restrictions drove rapid adaptations to service delivery and new ways of working within Scotland's mental health sector. This study explores mental health workers' (MHWs') experiences of delivering their services remotely. Twenty participants, who had worked in mental health professions in the National Health Service (NHS) in Scotland throughout the COVID-19 pandemic, took part in online semi-structured interviews. Data was transcribed then analysed using an inductive thematic analysis. Two major themes are reported: (1) 'Improved Flexibility for both MHWs and Service Users' and (2) 'Teletherapies Challenge Therapeutic Boundaries'. In relation to (1) virtual platforms were seen as vital in maintaining patient care throughout the COVID-19 pandemic and a valuable resource for service users (SUs) who had previously struggled with mobility or social anxieties when accessing face-to-face services. Some MHWs' also noted benefits for their productivity and comfort. Regarding (2) MHWs highlighted that whilst conducting teletherapies from home, work-life boundaries became blurred and, in some instances, typically comforting spaces became associated with the traumatic content discussed by SUs. These stressors seemed to be compounded by MHWs' isolation, as they were less able to draw upon their colleagues for support. Further, confidentiality could not be assured, as MHWs and SUs alike had to accommodate their family members. These findings highlight important insights from MHWs in adapting to rapid changes in mental health working practices, particularly in relation to the challenges of delivering quality, safe and equitable services and the increased use of teletherapies. Such insights are vital in informing service developments and supporting future pandemic preparedness across a range of healthcare contexts and countries seeking to adopt hybrid models of mental health service delivery.

Performance, Hemodynamics, and Stress in a Two-Day Vigilance Task: Practical and Theoretical Implications.

OBJECTIVE: To explore vigilance task performance, cerebral blood flow velocity (CBFV), workload, and stress in a within-subjects, two-session experiment. BACKGROUND: Vigilance, or sustained attention, tasks are often characterized by a decline in operator performance and CBFV with time on task, and high workload and stress. Though performance is known to improve with practice, past research has not included measures of CBFV, stress, and workload in a within-subjects multi-session design, which may also provide insight into ongoing theoretical debate. METHOD: Participants performed a vigilance task on two separate occasions. Performance, CBFV, workload, and self-reported stress were measured. RESULTS: Within each session, results were consistent with the vigilance profile found in prior research. Across sessions, performance improved but the time on task decrement remained. Mean CBFV and workload ratings did not differ between sessions, but participants reported significantly less distress, worry, and engagement after session two compared to one. CONCLUSION: Though practice may not disrupt the standard vigilance profile, it may serve to improve overall performance and reduce stress. However, repeated exposure may have negative implications for engagement and mind-wandering. APPLICATION: It is important to better understand the relationship between experience, performance, physiological response, and self-reported stress and workload in vigilance because real-world environments often require operators to do the same task over many occasions. While performance improvement and reduced distress is an encouraging result, the decline in engagement requires further research. Results across sessions fail to provide support to the mind-wandering theory of vigilance.

Gene expression underlying variation in the survival skills of red drum larvae (Sciaenops ocellatus).

Mortality rates of marine fish larvae are incredibly high and can determine year-class strength. The major causes of larval mortality are predation and starvation, and the performance of larvae in survival skills that can mitigate this mortality (predator evasion, foraging) varies among individuals and cohorts, but the causes of the variation are not known. Transcriptomics can link gene expression variation to phenotypic variation at the whole-system level to investigate the molecular basis of behavioural variation. We used tag-based RNA-sequencing to examine the molecular basis of variation in predator evasion and routine swimming (trait related to foraging efficiency) in the larval red drum, Sciaenops ocellatus. We looked for functional gene networks in which interindividual variation would explain variation in larval behavioural performance. We identified co-expressed gene groups ("modules") associated with predator evasion traits and found enrichment of motor, neural and energy metabolism pathways. These functional associations and pattern of correlations between modules and traits suggest that energy availability and allocation were responsible for the magnitude of startle responses, while differential neural and motor activation were associated with differences in response latency.

Micro-computed tomography as a platform for exploring Drosophila development.

Understanding how events at the molecular and cellular scales contribute to tissue form and function is key to uncovering the mechanisms driving animal development, physiology and disease. Elucidating these mechanisms has been enhanced through the study of model organisms and the use of sophisticated genetic, biochemical and imaging tools. Here, we present an accessible method for non-invasive imaging of Drosophila melanogaster at high resolution using micro-computed tomography (µ-CT). We show how rapid processing of intact animals, at any developmental stage, provides precise quantitative assessment of tissue size and morphology, and permits analysis of inter-organ relationships. We then use µ-CT imaging to study growth defects in the Drosophila brain through the characterization of abnormal spindle (asp) and WD repeat domain 62 (Wdr62), orthologs of the two most commonly mutated genes in human microcephaly patients. Our work demonstrates the power of combining µ-CT with traditional genetic, cellular and developmental biology tools available in model organisms to address novel biological mechanisms that control animal development and disease.

No evidence that genetic predictors of susceptibility predict changes in core outcomes in JIA.

OBJECTIVES: The clinical progression of JIA is unpredictable. Knowing who will develop severe disease could facilitate rapid intensification of therapies. We use genetic variants conferring susceptibility to JIA to predict disease outcome measures. METHODS: A total of 713 JIA patients with genotype data and core outcome variables (COVs) at diagnosis (baseline) and 1 year follow-up were identified from the Childhood Arthritis Prospective Study (CAPS). A weighted genetic risk score (GRS) was generated, including all single nucleotide polymorphisms (SNPs) previously associated with JIA susceptibility (P-value < 5×10-08). We used multivariable linear regression to test the GRS for association with COVS (limited joint count, active joint count, physician global assessment, parent/patient general evaluation, childhood HAQ and ESR) at baseline and change in COVS from baseline to 1 year, adjusting for baseline COV and International League of Associations of Rheumatology (ILAR) category. The GRS was split into quintiles to identify high (quintile 5) and low (quintile 1) risk groups. RESULTS: Patients in the high-risk group for the GRS had a younger age at presentation (median low risk 7.79, median high risk 3.51). No association was observed between the GRS and any outcome measures at 1 year follow-up or baseline. CONCLUSION: For the first time we have used all known JIA genetic susceptibility loci (P=<5×10-08) in a GRS to predict changes in disease outcome measured over time. Genetic susceptibility variants are poor predictors of changes in core outcome measures, it is likely that genetic factors predicting disease outcome are independent to those predicting susceptibility. The next step will be to conduct a genome-wide association analysis of JIA outcome.

Independent Contributions of Dorsolateral Prefrontal Structure and Function to Working Memory in Healthy Older Adults.

Age-related differences in dorsolateral prefrontal cortex (DLPFC) structure and function have each been linked to working memory. However, few studies have integrated multimodal imaging to simultaneously investigate relationships among structure, function, and cognition. We aimed to clarify how specifically DLPFC structure and function contribute to working memory in healthy older adults. In total, 138 participants aged 65-88 underwent 3 T neuroimaging and were divided into higher and lower groups based on a median split of in-scanner n-back task performance. Three a priori spherical DLPFC regions of interest (ROIs) were used to quantify blood-oxygen-level-dependent (BOLD) signal and FreeSurfer-derived surface area, cortical thickness, and white matter volume. Binary logistic regressions adjusting for age, sex, education, and scanner type revealed that greater left and right DLPFC BOLD signal predicted the probability of higher performing group membership (P values<.05). Binary logistic regressions also adjusting for total intracranial volume revealed left DLPFC surface area that significantly predicted the probability of being in the higher performing group (P = 0.017). The left DLPFC BOLD signal and surface area were not significantly associated and did not significantly interact to predict group membership (P values>.05). Importantly, this suggests BOLD signal and surface area may independently contribute to working memory performance in healthy older adults.

The impact of simulation-based mastery learning, booster session timing and clinical exposure on confidence in intercostal drain insertion: a survey of internal medicine trainees in Scotland.

BACKGROUND: Intercostal chest drain (ICD) insertion is a skill that medical trainees lack confidence in performing. This study explores the impact of a national programme of Simulation-Based Mastery Learning (SBML) on procedural confidence, including the impact of time intervals between booster sessions and interim clinical experience. METHODS: Internal Medicine Trainees in Scotland were surveyed about confidence and clinical experience with ICD insertion before and immediately after SBML and booster session. Data were matched and analysed using paired sample t-tests. Short interval and long interval groups were compared using Student's unpaired t-test. The impact of interim clinical experience was assessed using Analysis of Variance. RESULTS: Mean confidence in ICD insertion rose following SBML, fell between initial and booster session, and increased again following booster session (P = < 0.001). 33 of 74 trainees had successfully inserted an ICD between sessions. Fall in confidence was unaffected by the time interval between training sessions, but was mitigated by interim clinical experience. CONCLUSIONS: SBML boosts trainee confidence in ICD insertion. However, there is evidence of confidence decay, possibly due to a lack of clinical experience between sessions. More research is needed to explore barriers to transfer of skills from simulated to real-world environments.

Combined genetic analysis of juvenile idiopathic arthritis clinical subtypes identifies novel risk loci, target genes and key regulatory mechanisms.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is the most prevalent form of juvenile rheumatic disease. Our understanding of the genetic risk factors for this disease is limited due to low disease prevalence and extensive clinical heterogeneity. The objective of this research is to identify novel JIA susceptibility variants and link these variants to target genes, which is essential to facilitate the translation of genetic discoveries to clinical benefit. METHODS: We performed a genome-wide association study (GWAS) in 3305 patients and 9196 healthy controls, and used a Bayesian model selection approach to systematically investigate specificity and sharing of associated loci across JIA clinical subtypes. Suggestive signals were followed-up for meta-analysis with a previous GWAS (2751 cases/15 886 controls). We tested for enrichment of association signals in a broad range of functional annotations, and integrated statistical fine-mapping and experimental data to identify target genes. RESULTS: Our analysis provides evidence to support joint analysis of all JIA subtypes with the identification of five novel significant loci. Fine-mapping nominated causal single nucleotide polymorphisms with posterior inclusion probabilities ≥50% in five JIA loci. Enrichment analysis identified RELA and EBF1 as key transcription factors contributing to disease risk. Our integrative approach provided compelling evidence to prioritise target genes at six loci, highlighting mechanistic insights for the disease biology and IL6ST as a potential drug target. CONCLUSIONS: In a large JIA GWAS, we identify five novel risk loci and describe potential function of JIA association signals that will be informative for future experimental works and therapeutic strategies.