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We need to talk about resilience: The case for a pragmatic and holistic perspective
No full textThis essay offers a pragmatic and holistic perspective of resilience to assist careers and employability professionals in supporting university students and graduates. It examines the evolution of employability models from skills-based to capital-based frameworks, emphasising resilience as a key component of psychological capital. Drawing on the Employability Capital Growth Model (ECGM) and sustainable career theory, the essay critiques simplistic views of resilience grounded in positive psychology, advocating for a more nuanced understanding that considers personal, contextual, and temporal dimensions. Drawing parallels with physical strength-building through weight training, it underscores the importance of progressive challenges, mental fortitude, supportsystems, consistency, and recovery in developing resilience. These factors provide a practical framework for guiding university students and graduates toward sustainable careers, with an emphasis on health, well-being, and long-term productivity. Resilience, the essay argues, is not about unyielding strength but adaptability and recovery, accounting for external factors and systemic barriers. By integrating principles from weight training into career guidance, careers and employability professionals can offer a balanced view of resilience, equipping students and graduates to navigate contemporary career challenges. This approach bridges career development and employability theories, providing new insights for practice and research in higher education and beyond
Clinical and cost-effectiveness of a personalised guided consultation versus usual physiotherapy care in people presenting with shoulder pain: a protocol for the PANDA-S cluster randomised controlled trial and process evaluation
No full textIntroduction: musculoskeletal shoulder pain is a common reason for people to be treated in physiotherapy services, but diagnosis can be difficult and often does not guide treatment or predict outcome. People with shoulder pain cite a need for clear information, and timely, tailored consultations for their pain. This trial will evaluate the introduction of a personalised guided consultation to help physiotherapists manage care for individuals with shoulder pain.Methods and analysis: this is a cluster randomised controlled trial to evaluate the clinical and cost-effectiveness of introducing a personalised guided consultation compared to usual UK NHS physiotherapy care. Physiotherapy services (n=16) will be randomised in a 1:1 ratio to either intervention (physiotherapy training package and personalised guided consultation incorporating a new prognostic tool) or control (usual care). 832 participants (416 in each arm) identified from participating physiotherapy service waiting lists aged 18 years or over with shoulder pain will be enrolled. Follow-up will occur at 3-time points: 6 weeks, 6 months and 12 months. The primary outcome will be the Shoulder Pain and Disability Index (SPADI) score over 12 months. Secondary outcomes include global perceived change of the shoulder condition, sleep, work absence and the impact of shoulder pain on work performance, healthcare utilisation and health-related quality of life (using the EQ-5D-5L). A multi-method process evaluation will investigate views and experiences of participants and physiotherapists, assess uptake, facilitators and barriers to delivery, and changes in factors assumed to explain intervention outcomes. Primary analysis of effectiveness will be by intention-to-treat, and a health economic evaluation will assess cost-utility of introducing the personalised consultation.Ethics and dissemination: the trial received ethics approval from the Yorkshire & The Humber (South Yorkshire) Research Ethics Committee (REC reference: 23/YH/0070). Findings will be shared through journal publications, media outlets, and conference presentations. Supported by patient contributors and clinical advisors, we will communicate findings through a designated website, networks, newsletters, leaflets, and in the participating physiotherapy services.Trial registration: ISRCTN: 45377604<br/
Treatment considerations for severe osteoporosis in older adults
No full textOsteoporosis, a chronic metabolic bone disease, increases the predisposition to fragility fractures and is associated with considerable morbidity, high health care cost as well as mortality. An elevation in the rate of incident fragility fractures will be observed proportional with the increase in the number of older people worldwide. Severe osteoporosis is currently defined as having a bone density determined by dual-energy X-ray absorptiometry that is more than 2.5 standard deviations (SD) below the young adult mean with one or more past fractures due to osteoporosis. Nutrition, physical activity and adequate vitamin D are essential for optimal bone strength throughout life. Hormone (oestrogen/sex steroid) status is also a major determinant of bone health. This review explores mechanisms involved in bone homeostasis, followed by the assessment and management of severe osteoporosis, including an overview of several treatment options in older people that range from anti-resorptive to anabolic therapies
Psychological mechanisms underpinning change in intolerance of uncertainty across anxiety-related disorders: new insights for translational research
No full textIntolerance of uncertainty (IU), the tendency to find uncertainty negative, is a fundamental transdiagnostic dimension across anxiety-related disorders. Over the past two decades, there has been an increase in both clinical and experimental research on the role of IU in the maintenance and treatment of anxiety-related disorders. However, there has been a lack of integration of research findings from a mechanistic perspective, which has slowed progress in translational research. This review seeks to fill this gap by synthesising the clinical (e.g. randomised controlled trials) and experimental (e.g. lab-based) literature on the psychological mechanisms that drive change in IU across anxiety-related disorders. The review highlighted that: (1) cognitive restructuring, supported by mechanisms such as cognitive appraisal, modify IU-related cognitions, (2) behavioural exposures, supported by mechanisms such as inhibitory learning, alter IU-related cognitions and physiological arousal, and (3) mindfulness techniques underpinned by mechanisms such as attentional monitoring, decentering, and acceptance, change IU-related cognitions. Across the different therapeutic techniques reviewed, there was a lack of evidence for how different mechanisms change IU-related emotions and behaviours. Directions for further research include directly comparing the effectiveness of different mechanisms that produce change in IU across anxiety disorders and other mental health disorders, and examining the specificity of change in IU over other anxious traits. Overall, the findings provide a foundation for future translational research efforts to build upon maximising existing treatment interventions and/or to develop novel treatment interventions to target dispositional IU and situational uncertainty-related distress in anxiety-related disorders and beyond.</p
A Bayesian framework for crop model calibration: a case study in the US Corn Belt
No full textCrop models play a key role in simulating crop growth, predicting yield, and assessing interventions for improving production. Nevertheless, their reliability is often hindered by uncertainties in parameterization, soil properties, management practices, and meteorological inputs. These uncertainties can significantly affect model accuracy, especially when models are applied to different crops, cultivars, or fields. This study explores these concepts using the APSIM crop model under varying weather conditions, soil types, and management practices across multiple production years, but with a focus on a single location. Our analysis focuses on three research fields near Lincoln, Nebraska, growing different maize cultivars in either mono-cropping or rotational-crop configurations, and under both rain-fed and irrigated regimes. Initially, we perform a global sensitivity analysis to assess how variations in cultivar parameters affect key model outputs: leaf area index, biomass, and yield. We advance the analysis by conducting an intra-season sensitivity analysis to track the temporal impact of parameters over the growing cycle. Using an MCMC-based Bayesian inference approach, we estimate the most influential parameters. Results indicate that, for this specific location and agronomy, over 50 % (7 out of 13) of cultivar parameters have the greatest impact on model outputs, with the most sensitive parameters varying depending on the model output under investigation. Notably, parameters involved in the early capture of radiation were the most influential across all fields and outputs. The intra-season sensitivity analysis reveals that parameter sensitivity varies across different crop phenological stages, suggesting the potential for a targeted parameter calibration within specific windows of the season. The calibrated model using MCMC in a real-world case scenario delivers a strong agreement between predicted and observed outputs, with R2 values ranging from 0.84 to 0.98, and relative RMSE between 10 % and 34 %. Compared to its uncalibrated counterpart, the calibrated model exhibits improved performance, with at least a 30 % reduction in RMSE values and enhanced correlation with in situ measurements. These findings confirm the robustness of the Bayesian calibration approach and its ability to accurately predict crop development across multiple seasons and maize cultivars. As such, this approach provides a valuable tool for calibrating crop models while simultaneously quantifying the uncertainty associated with input parameters. Extension of this analysis and model to larger regional areas would test its suitability for more generalized application of models at scale
NALCN/Cch1 channelosome subunits originated in early eukaryotes and are fully conserved in animals, fungi, and apusomonads
No full textThe sodium leak channel NALCN, a key regulator of neuronal excitability, associates with three ancillary subunits that are critical for its function: an extracellular subunit called FAM155, and two cytoplasmic subunits called UNC79 and UNC80. Interestingly, NALCN and FAM155 have orthologous phylogenetic relationships with the fungal calcium channel Cch1 and its extracellular subunit Mid1, however, UNC79 and UNC80 have not been reported outside of animals. In this study, we leveraged expanded gene sequence data available for eukaryotes to re-examine the evolutionary origins of NALCN and Cch1 channel subunits. Our analysis corroborates the direct phylogenetic relationship between NALCN and Cch1 and identifies a larger clade of related channels in additional eukaryotic taxa. We also identify homologues of FAM155/Mid1 in Cryptista algae, and UNC79 and UNC80 homologues in numerous non-metazoan eukaryotes including basidiomycete and mucoromycete fungi, and the microbial eukaryotic taxa Apusomonadida, Malawimonadida, and Discoba. Furthermore, we find that most major animal lineages, except ctenophores, possess a full complement of NALCN subunits. Comparing structural predictions with the solved structure of the human NALCN complex supports orthologous relationships between metazoan and non-metazoan FAM155/Mid1, UNC79, and UNC80 homologues. Together, our analyses reveal unexpected diversity and ancient eukaryotic origins of NALCN/Cch1 channelosome subunits and raise interesting questions about the functional nature of this conserved channel complex within a broad, eukaryotic context
Global analysis of ligand-gated ion channel conservation across Platyhelminthes
No full textLigand-gated ion channels (LGICs) are critical for neurotransmission, mediating responses to neurotransmitters and hormones, and influencing diverse physiological processes. This study identifies and classifies LGICs across Platyhelminthes, with a particular focus on parasitic neodermatans, which impact human and animal health. Using bioinformatics tools, we analyzed LGICs from 41 neodermatan species and expanded our investigation to encompass vertebrates, other invertebrates, and non-bilaterians to trace LGIC evolutionary pathways across Metazoa. We identified 2,269 putative LGICs within neodermatan species, which we classified into the cys-loop, ASIC/Deg/ENaC, iGluR, and P2X families. Our phylogenetic and clustering analyses reveal lineage-specific patterns with distinct evolutionary trajectories for each LGIC family in neodermatans compared to free-living platyhelminths and other taxa. Notably, the ASIC/Deg/ENaC family displayed the greatest degree of neodermatan-specific divergence, while cys-loop and P2X families were more conserved across taxa. To provide insight into their potential physiological roles, we analyzed LGIC expression patterns in Schistosoma mansoni, revealing widespread expression across neuronal and muscle cell types. The distribution of acid-sensing ion channels (ASICs) in both neurons and muscles suggests a role in neuromuscular signalling, while the P2X receptor (Smp_333600) exhibited sex-specific expression, potentially indicating distinct functional roles in males and females. Additionally, several cys-loop acetylcholine and GABA receptors showed differential neuronal and muscle expression, highlighting their likely contributions to cholinergic and inhibitory neurotransmission. These findings underscore the relevance of LGICs in parasite physiology, particularly in neuromuscular and sensory processes, and suggest potential targets for antiparasitic interventions.</p
Accelerating drug development for neuroblastoma: consensus statement from the third neuroblastoma drug development strategy forum
No full textHigh-risk neuroblastoma is a poor prognosis cancer of the sympathetic nervous system that accounts for a disproportionate number of childhood cancer deaths. Many viable biological targets have been identified and the number of potential combinations is even larger. Several products have attained marketing authorization for treatment of patients with neuroblastoma. Patient outcomes remain poor, with approximately 50% of children with newly diagnosed high-risk neuroblastoma cured of their disease. International, multistakeholder Neuroblastoma Drug Development Strategy (NDDS) meetings were established more than a decade ago. This third NDDS meeting included academia, industry, regulatory, and patient advocacy representatives to prioritize agents and to address key challenges in drug development in this disease. Given the central role that anti-GD2 therapy plays, novel GD2-directed combinations were a key focus, including epigenetic enzymes such as EZH2 and immunologic targets such as IL15 and TIGIT as potential combination partners. GD2-directed chimeric antigen receptor (CAR)-T cells were a top priority, along with emerging CAR-T targets such as B7-H3 and GPC2. Recognizing that combination therapies are likely to be most impactful for patients and for advancing therapies to frontline, another key focus was on high priority combinations of targeted therapies, including Aurora A kinase plus BCL2 or ATR inhibitors. Additional targets and agents were prioritized or deprioritized based upon current data. Access to drugs for clinical trials was viewed as a major barrier to progress. Strategies to overcome this challenge focused on united efforts by the international scientific and advocacy community and early engagement by industry with regulatory authorities
The changing portrayal of neanderthals in the museum. separating them and us
No full textOver the last century our portrayal of Homo neanderthalensis has changed radically. They were initially conceptualised as primitive savages, dim-witted and brutish cavemen, understood either as a missing link in the evolution of our own species, Homo sapiens (modern humans), or an evolutionary dead-end (Moser 1992; Drell 2000; Madison 2021). Although Neanderthals have moved between animality and humanness (Corbey 2005), and in and out of the direct lineage of human origins, the prevailing view considered them as a primitive prototype of our own species. However, modern Neanderthals are visually reconstructed and recognised as essentially human (Peeters and Zwart 2020). This thesis highlights how technological innovations in ancient DNA (paleogenetics), and archaeological discoveries are providing new and exciting windows onto the past, but questions whether these new relationships and findings are reflected in the context of the museum and hyperrealism (Peeters and Zwart 2020). In this scientific journey of rediscovery, it has become abundantly clear that the assumed modern human-Neanderthal boundary so clear cut when evolutionary studies began, is breaking down (Finlayson 2019: xi). It is increasingly difficult to pinpoint what the difference between Neanderthals and AMHs is and yet there remains a persistent quest for a minimal difference which separates ‘them’ from ‘us’ (Peeters and Zwart 2020). The archaeology of Neanderthals therefore remains in a philosophical crisis, charged with creating a narrative that centres on the dualistic construction of ‘them’ and ‘us’, and slow modernity, which ultimately perpetuates the great divide at the centre of cartesian philosophy between nature and culture (Peeters and Zwart 2020). This thesis argues a dualistic style of thinking (modernity) and the progressive tendencies of the evolutionary museum are no longer tenable and can no longer encompass the complexity of new data, techniques and interpretations available to archaeologists and the museum (Crellin and Harris 2020).<br/
Ideas and perspectives: How sediment archives can improve model projections of marine ecosystem change
No full textGlobal warming is a major threat to marine biodiversity and ecosystem functioning, with consequences that are yet largely unknown. To frame these consequences, we need to understand how marine ecosystems respond to warming and related environmental changes. Ecosystem models have proven to be a valuable tool in this respect, but their projections vary considerably. A major limitation in current ecosystem models may be that they largely ignore evolutionary processes, which nonetheless can be relevant on the simulated timescales. In addition, ecosystem models are usually fit to contemporary data and used predictively afterwards, without further validation that they are equally applicable to past (and, by inference, future) scenarios. A promising approach to validate evolutionary ecosystem models is the use of biological archives such as natural sediments, which record long-term ecosystem changes. Since the ecosystem changes present in sediment records are affected by evolution, evolution needs to be represented in ecosystem models not only to realistically simulate the future, but also the sediment record itself. The sediment record, in turn, can provide the required constraints on long-term evolutionary changes, along with information on past environmental conditions, biodiversity, and relative abundances of taxa. Here, we present a framework to make use of such information to validate evolutionary ecosystem models and improve model projections of future ecosystem changes. Using the example of phytoplankton, key players in marine systems, we review the existing literature and discuss (I) which data can be derived from ancient sedimentary archives, (II) how we can integrate these data into evolutionary ecosystem models to improve their projections of climate-driven ecosystem changes, and (III) future perspectives and aspects that remain challenging
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