Variation between general practices in the rate of consultations for musculoskeletal pain conditions may signal important differences in access to primary care, perceived usefulness, or available alternative sources of care; however, it might also just reflect differences in underlying ‘need’ between practices’ registered populations. In a study of 30 general practices in Staffordshire, we calculated the proportion of adults consulting for a musculoskeletal pain condition, then examined this in relation to selected practice and population characteristics, including the estimated prevalence of self-reported musculoskeletal problems and chronic pain in each practices’ registered population. Between September 2021 and July 2022, 18,388 adults were consulted for a musculoskeletal pain condition. After controlling for length of recruitment, time of year, and age-sex structure, the proportion consulting varied up to two-fold between practices but was not strongly associated with the prevalence of self-reported long-term musculoskeletal problems, chronic pain, and high-impact chronic pain.

Psychologists and psychological research have shaped sleep and circadian science for over a century. Yet, psychology has not fully embraced sleep as a core area of inquiry, and sleep medicine has not distinctly acknowledged the foundational role psychology plays in understanding sleep and circadian rhythms. This Question Paper invites submissions exploring psychology’s profound impact on the study, measurement and intervention strategies in sleep and circadian science, as well as reciprocal influences. Manuscripts may include historiographies of key contributors, laboratory milestones, theoretical advancements and methodological innovations within a historical context. We aim to capture the full scope of sleep psychology from its origins to a vision of its future.

Sleep value is the relative worth individuals assign to sleep. We previously found that individual differences in several sleep value subfactors relate to demographic, health and sleep variables. Given the pivotal role values play in health behavior and the positive association between sleep value and sleep disturbance, individual differences in sleep value may influence vulnerability/resilience to sleep and circadian disturbance. This survey study (N = 455) aimed to establish the latent factor structure of sleep value and identify whether sleep value profiles relate to demographic and sleep characteristics. Factor analysis on the Sleep Valuation Item Bank 2.0 identified five factors (wanting, prioritizing, devaluing, appreciating and preferring). Latent profile analyses revealed five distinct sleep value profiles (unconcerned, appreciative, devalue, ambivalent priority and concerned). Depression, sleep disturbance and sleep-related impairment were highest among those who highly value sleep (concerned profile) and lowest among those who neither value nor devalue sleep (unconcerned profile). Findings suggest sleep value is a complex aspect of sleep health rather than a “more is better” construct and highlight that individual differences in sleep value profiles may be associated with vulnerability/resilience to sleep disturbance.

Civil wars are not only destructive: they can also generate new, long-lasting social, political, and economic structures and processes. To account for this productive potential and analyse post-conflict outcomes, I argue that we should analyse civil wars as critical junctures. Civil wars can relax structural constraints, opening opportunities for wartime processes to generate changes or to reinforce, rather than transform, the status quo. Changes or stasis may then be locked in by conflict outcomes, creating path dependencies. Studying civil wars as critical junctures allows for a clearer understanding of what variables mattered and interacted at different points in the conflict process, and the varying roles of structure and agency in producing institutional change or reinforcing pre-existing conditions. I explore the potential benefits of a critical juncture approach in the civil wars literature on different aspects of post-conflict politics and illustrate them in analysing the literature on women’s empowerment during and after civil wars. Applying the critical junctures framework to civil wars’ effects on institutions and socio-behavioural patterns can provide analytical clarity about complex processes and contexts, can facilitate comparison across cases and studies, and draws critical attention both to what civil wars change and to potential pathways not taken.

In the transitioning era towards the COVID-19 endemic, there is still a sizable population that has never been vaccinated against COVID-19 in the Netherlands. This study employs Bayesian spatio-temporal modelling to assess the relative chances of COVID-19 vaccination uptake – first, second, and booster doses – both at the municipal and regional (public health services) levels. Incorporating ecological regression modelling to consider socio-demographic factors, our study unveils a diverse spatio-temporal distribution of vaccination uptake. Notably, the areas located in or around the Dutch main urban area (Randstad) and regions that are more religiously conservative exhibit a below-average likelihood of vaccination. Analysis at the municipal level within public health service regions indicates internal heterogeneity. Additionally, areas with a higher proportion of non-Western migrants consistently show lower chances of vaccination across vaccination dose scenarios. These findings highlight the need for tailored national and local vaccination strategies. Particularly, more regional efforts are essential to address vaccination disparities, especially in regions with elevated proportions of marginalized populations. This insight informs ongoing COVID-19 campaigns, emphasizing the importance of targeted interventions for optimizing health outcomes during the second booster phase, especially in regions with a relatively higher proportion of marginalized populations.

This article examines the development, early operation and subsequent failure of the Tot-Kolowa Red Cross irrigation scheme in Kenya’s Kerio Valley. Initially conceived as a technical solution to address regional food insecurity, the scheme aimed to scale up food production through the implementation of a fixed pipe irrigation system and the provision of agricultural inputs for cash cropping. A series of unfolding circumstances, however, necessitated numerous modifications to the original design as the project became increasingly entangled with deep and complex histories of land use patterns, resource allocation and conflict. Failure to understand the complexity of these dynamics ultimately led to the project’s collapse as the region spiralled into a period of significant unrest. In tracing these events, we aim to foreground the lived realities of imposed development, including both positive and negative responses to the scheme’s participatory obligations and its wider impact on community resilience.

OBJECTIVES/GOALS: Vanishing White Matter Disease (VWM), is a childhood neurodegenerative leukodystrophy that presents with motor deficits, neurologic decline, and seizures leading to death.There are no treatments. Herein we investigate adeno-associated virus serotype 9 (AAV9) gene addition therapy for VWM. METHODS/STUDY POPULATION: To serve as a baseline for disease correction, we characterized the severe VWM Eif2b5I98M murine model with clinically relevant readouts including motor function, gait mapping and myelin loss through magnetic resonance imaging (MRI). Molecular characterization through the identification of biomarkers was also investigated. To provide targeted disease correction, we designed four gene replacement constructs to drive the rapeutic EIF2B5 expression in astrocytes—a critical cell type for VWM pathology. We are currently evaluating our AAV vectors in two murine VWM models, Eif2b5R191H and Eif2b5I98M, and are monitoring disease progression using traditional and clinically relevant readouts. RESULTS/ANTICIPATED RESULTS: The I98M mice display significant mobility loss, ataxic gait, and demyelination. Molecular characterization also indicates that the integrated stress response is significantly dysregulated, supporting the classic VWM phenotype. Our previous biodistribution study confirmed our ability to efficiently target astrocytes using varying iterations—including one novel—of the glial fibrillary acidic protein (GFAP) promoter. Our data suggests that targeting astrocytes with gene addition delays disease onset, partially rescues motor function, and attenuates myelin loss. Survival of the AAV9-gfaABC(1)D-EIF2B5 treated I98M mice is also significantly increased (p<0.0001), currently with a 2-fold extension in life expectancy. DISCUSSION/SIGNIFICANCE: Overall, we anticipate emergence of a lead astrocyte-targeted gene therapy candidate in which the data will be strengthened through the evaluation of clinically relevant measures in two murine models of disease, allowing fortimely translation to the clinic.

The influence of sleep and circadian rhythms on daytime functioning has long been noted. Psychologists and psychology-oriented researchers were among the first to investigate the role of sleep and circadian rhythms in motivation, emotion, cognition, and performance. At the dawn of modern sleep science, psychological fellow, F. B. Dresslar found that telegram tapping speed varied according to time of day providing the first clues to the role of circadian rhythms on performance (Dresslar 1892). Marie de Manacéïne was the first to experimentally demonstrate that sleep was critical to life and that the brain and behaviour were adversely impacted by sleep loss (de Manacéïne 1894) Patrick and Gilbert elaborated on the role of sleep on psychological functioning and were the first to experimentally study the impact of sleep loss in humans (Patrick and Gilbert 1896). The past century has seen an explosion of interest in understanding which aspects of sleep and circadian rhythms relate to which aspects of daytime psychological functioning.

A growing body of research suggests that contemporary law firms face challenges with the retention of legal talent—especially women and racialized lawyers. Yet, we know little about the conditions that prompt lawyers to leave law firms or where they go after leaving. This article builds on the scholarship of John Hagan, emphasizing the role of social capital in law firm culture, and work by Emmanuel Lazega, tracing dimensions of law firm collegiality—both with implications for lawyers’ careers within and beyond law firms. I draw on data from a twenty-seven-year longitudinal survey of Canadian lawyers. Using piecewise exponential survival models, I examine organizational, cultural, and individual factors that may encourage mobility from law firms. The study reveals a pervasive gender difference that is not explained by human capital, organizational characteristics, or individual traits. Results also demonstrate the importance of social capital and firm culture—specifically, the presence of workplace policies of flexible scheduling, lawyers’ sense of a good match with their firm, their satisfaction with status rewards, and finally, the role of mentors—in shaping the flow of legal talent from law firms to various job destinations.

Clinical sleep psychology is a branch of psychological science that aims to understand and harness psychological factors (i.e., affective, behavioral, cognitive, social, and environmental) that are involved in sleep and circadian disorders. Behavioral Sleep Medicine, a branch of sleep medicine, has a similar focus (https://www.behavioralsleep.org/). Collectively, these clinical branches of sleep psychology aim to effectively evaluate and treat sleep and circadian rhythm disorders to promote sleep health. Clinical sleep psychology has a long history, including early work in the areas of insomnia, behavioral treatment for pediatric sleep disorders, dream psychology, and hypnotic sleep (Jacobson 1934; McReynolds 1997; Mower and Mower 1938; Münsterberg 1915; Watson 1928). The past 100 years have seen considerable progress in identifying psychological factors involved in sleep and circadian rhythm disorders and their treatment, particularly in insomnia and pediatric sleep disorders. Barriers to advancement persist.

Based on the five-level model of emotions in the workplace (FLMEW), we present an analysis of emotion and mindfulness at work. The five levels of emotion are: (1) temporal variations in emotion at the within-person level of analysis, which relate to state mindfulness; (2) stable individual differences in experiencing and expressing emotions at the between-persons level, which correspond with trait mindfulness; (3) perceiving and communicating emotions in dyadic relationships at the inter-personal level, reflecting interpersonal mindfulness; (4) emotional processes and leadership at the group level, which are associated with team mindfulness; and (5) and emotional culture and climate at the organizational level, which relate to organizational mindfulness. We provide a definition of mindfulness at each level. We argue that mindfulness tends to be associated with more positive and less negative affective experience at each level. We highlight practical implications and suggest future research at each level.

OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.

OBJECTIVES/GOALS: The goal of this study was to develop a clinically applicable technique to increase the precision of in vivo dose monitoring during radiation therapy by mapping the dose deposition and resolving the temporal dose accumulation while the treatment is being delivered in real time. METHODS/STUDY POPULATION: Ironizing radiation acoustic imaging (iRAI) is a novel imaging concept with the potential to map the delivered radiation dose on anatomic structure in real time during external beam radiation therapy without interrupting the clinical workflow. The iRAI system consisted of a custom-designed two-dimensional (2D) matrix transducer array with integrated preamplifier array, driven by a clinic-ready ultrasound imaging platform. The feasibility of iRAI volumetric imaging in mapping dose delivery and real-time monitoring of temporal dose accumulation in a clinical treatment plan were investigated with a phantom, a rabbit model, and a cancer patient. RESULTS/ANTICIPATED RESULTS: The total dose deposition and temporal dose accumulation in 3D space of a clinical C-shape treatment plan in a targeted region were first imaged and optimized in a phantom. Then, semi-quantitative iRAI measurements were achieved in an in vivo rabbit model. Finally, for the first time, real-time visualization of radiation dose delivered deep in a patient with liver metastases was performed with a clinical linear accelerator. These studies demonstrate the potential of iRAI to monitor and quantify the radiation dose deposition during treatment. DISCUSSION/SIGNIFICANCE: Described here is the pioneering role of an iRAI system in mapping the 3D radiation dose deposition of a complex clinical radiotherapy treatment plan. iRAI offers a cost-effective and practical solution for real-time visualization of 3D radiation dose delivery, potentially leading to personalized radiotherapy with optimal efficacy and safety.