Right-hook crashes in right-hand traffic where cyclists going straight are struck by right-turning vehicles pose a major safety concern. This study aims to establish to which extent such conflicts may stem from non-driving-related tasks (NDRT), low saliency of cyclists (covertness), or drivers' insufficient knowledge of applicable rules. Forty-four drivers participated in a fixed-base driving simulator study using an extended reality (XR) setup with integrated eye tracking. Participants were stratified by urban cycling experience (cyclist-drivers vs. drivers) and self-reported driving style (cautious vs. assertive). Each drove an urban route including 12 right-turn-on-yield scenarios, with and without NDRT. Observed visual sampling was combined with a questionnaire-based rule knowledge assessment to examine whether scanning failures were due to workload or lack of rule knowledge. NDRT engagement primarily reduced default glances while glances to relevant areas (Left, Right, Over Shoulder) were preserved. Over-the-shoulder checks were rare overall. In 85 % of right-turns, no such glance occurred before turning, regardless of NDRT status. Rule knowledge mirrored these patterns, with drivers being more likely to correctly indicate the requirement to yield to salient crossing traffic streams of cars (96 % correct) or cyclists and pedestrians (81 % correct) than non-salient crossing bicycle or pedestrian traffic (46 % correct). Drivers with cycling experience scored slightly better overall but still missed nearly half of the non-salient yielding requirements. The findings indicate that gaps in rule knowledge contribute to failures to check for cyclists. Countermeasures should prioritise systemic interventions, complemented by education, rather than solely relying on behaviour-focused measures.
Cyanobacterial harmful algal blooms (cHABs) represent an escalating global threat due to their ability to produce a wide range of potent cyanotoxins that threaten aquatic ecosystems, drinking water safety and public health. While eutrophication has long been recognized as a primary driver of bloom formation, increasing evidence suggests that climate change acts as a critical catalyst influencing not only bloom frequency and intensity but also toxin diversity and regulation. However, the mechanistic pathways through which climate-associated abiotic stressors regulate cyanotoxin biosynthesis remain insufficiently resolved. This review critically synthesizes current knowledge on how key environmental drivers, including rising temperatures, elevated CO₂ concentrations, nutrient enrichment, ultraviolet (UV) radiation, and hydrological variability regulate toxin production at physiological and molecular levels. Evidence supports that temperature influences toxin biosynthesis through complex regulation of gene expression, while elevated CO₂ has been proposed to alter intracellular carbon allocation and may shift toxin composition towards more bioactive variants. Nutrient availability, particularly nitrogen, modulates toxin synthesis through global regulatory networks such as NtcA in Microcystis, whereas UV radiation induces oxidative stress responses have been hypothesized to be linked to toxin release through programmed cell death pathways. Importantly, this review emphasizes that these stressors rarely act in isolation; instead, their interaction can produce synergetic or antagonistic effects that fundamentally reshape bloom toxicity. A key contribution of this review is the identification of persistent inconsistencies across studies, particularly regarding per-cell toxin quota responses under different environmental conditions. By integrating molecular mechanisms with ecological observations, this review provides a more nuanced framework for understanding how climate change drives cyanotoxin dynamics. Such mechanistic understanding is essential for improving predictive models of bloom risk and developing adaptive management strategies to mitigate the growing threats posed by cHABs under future climate scenarios.
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Exposure to blast overpressures in the line of duty causes many service members and veterans to suffer inner ear injuries and the resulting hearing disabilities. The response to blast waves within the cochlea, particularly by the sensory hair cells within the organ of Corti (OC), is challenging to measure experimentally. Recently, 3D finite element (FE) models of the human ear at macroscale and OC models at microscale have been established to examine the blast transmission throughout the ear and the OC response at the middle turn of the basilar membrane (BM). This multiscale model was lacking OC models at other locations along the BM, which would allow the investigation of OC behavior and distribution of injury throughout the cochlea. Microscale FE models of the OC were developed representing the basal, middle, and apical turns of cochlea, located 4.25, 16.8, and 29.3 mm from the base of the BM. Each model contained the comprehensive biostructures of membranes, sensory hair cells, and supporting cells, with changes in their dimensions and localized material properties. BM displacements caused by transmission of a 30 kPa blast overpressure were derived from the macroscale ear model and applied as input to the BM in each OC model. The simulations were run for 2 ms with a 1 μs time step. The displacements, stresses, and strains on each component were tracked. The stress on the sensory outer hair cells (OHCs) and the strain at the connection between the tectorial membrane (TcM) and stereociliary hair bundles (HBs) were used as the primary metrics that could indicate injury to the OC. The basal turn OC model reported the highest stress on the OHCs, with a maximum von Mises stress of 0.84 kPa. OHC stress is associated with hair cell apoptosis, and documented hair cell loss because of blast exposure is concentrated in the basal turn of the cochlea. The model-derived results align with these observations. The strain on the TcM was most severe on its connections to HBs, with the highest maximum strain reported occurring in the middle turn OC model. This strain may indicate the decoupling of stereocilia from the TcM without hair cell death, which is an inner ear injury unique to blast-damaged cochleae. Three microscale FE models of the OC were developed and provided detailed information about the blast-induced inner ear biomechanical behavior. The stress on the OHCs and strain at the connection between the TcM and HBs were used to predict the likelihood of injury, which appeared most likely in the basal and middle turns of the cochlea. This study represents an important step towards a comprehensive and accurate model of the human ear.
To evaluate the measurement properties of the functional index for hand osteoarthritis (FIHOA) in subjects with rhizarthrosis using classical and modern psychometric methods. 164 individuals with rhizarthrosis were included in this retrospective study. We conducted a Confirmatory Factor Analysis (CFA) for unidimensionality, Cronbach's alpha (α) for internal consistency, and Rasch analysis (RA) for internal construct validity (stochastic invariance, monotonicity, local independence, unidimensionality, measurement invariance), reliability, and targeting. The FIHOA demonstrated sufficient internal consistency (α = 0.87). The final CFA partially fit to a unidimensional model (RMSEA = 0.08; SRMR = 0.06; CFI = 0.98; TLI = 0.97). Base RA revealed a fit to the model (χ2df = 26.2820; p = 0.16), satisfied the requirement of monotonicity (no disordered thresholds), unidimensionality (percentage of significant tests = 4.3%, lower bound confidence interval = 1.3%), but not the local independence and measurement invariance. After creating three clinically coherent subtests to account for the local dependence, the final Rasch analysis fit to the model (χ2df = 11.1924; p = 0.34), satisfying the requirements of the local independence, monotonicity, and measurement invariance (a non-significant DIF for age). Reliability indexes for the fit estimates were suitable for individual-level measurements (Distribution-Independent Person Separation Index = 0.96). After statistical modifications through Rasch analysis, the FIHOA turns out to be a unidimensional, valid, reliable, and invariant measure of activity limitation in patients with rhizarthrosis. The functional index for hand osteoarthritis (FIHOA) provides a thumb-relevant patient-reported outcome measure for people with rhizarthrosis, capturing disability in everyday grasping, pinching and manipulation tasks that are central to hand function.Rasch-based validation in a rhizarthrosis-only sample supports the FIHOA as a unidimensional and invariant measure of activity limitation, allowing clinicians and researchers to use its total score confidently for monitoring disability and evaluating rehabilitation outcomes.The Rasch raw-score conversion table enables more precise use of the FIHOA in clinical trials and rehabilitation programs, including a more sensitive detection of change over time in patients with mild to moderate thumb osteoarthritis.Given its feasibility and psychometric robustness, the FIHOA can be integrated into routine hand rehabilitation to support goal setting, stratification of patients with rhizarthrosis, and evaluation of both conservative and surgical interventions.
Mutations in transmembrane channel-like protein 1 (TMC1), the pore-forming component of the mechano-electrical transducer (MET) channel in auditory hair cells, cause cell death and deafness in 3-wk old mice. We studied mice with mutations Tmc1 p.T416K, p.M412K, p.D528N, and p.D569N, which possessed functional MET channels at postnatal day (P)6 but became deaf before P21. These Tmc1 mutants had channels with reduced Ca2+ permeability and lower expression of the PMCA2 calcium pump in outer hair cell (OHC) stereocilia. The reduction in PMCA2 density was directly correlated with reduced Ca2+ entry via the MET channel. Over the first postnatal week, PMCA2 expression decreased in cochlear cultures containing lowered extracellular Ca2+, but after P11, PMCA2 density was insensitive to Ca2+ changes. The lower PMCA2 density in mutants was maintained into adulthood and may contribute to hair cell death. Before the onset of hearing, PMCA2 continuously turns over, and its insertion into stereocilia from an identified vesicular compartment is regulated by cytoplasmic [Ca2+]. PMCA2 turnover was strongly inhibited by the endocytosis blocker, Pitstop2, and by PtdIns(4,5)P2 blockers like phenylarsine oxide (PAO), which was shown to elevate stereociliary [Ca2+]. We argue the effects of PAO on mechanotransduction may be partly due to this Ca2+ increase. OHC bundles also expressed Neuroplastin (NPTN), a PMCA2 accessory protein, whose development paralleled PMCA2, and we propose it stabilizes the pump complex in stereocilia. NPTN expression was delayed about 2 d relative to PMCA2 and was less Ca2+ sensitive, implying it originates from a different internal pool of vesicles.
Humans recreating in wilderness areas face a risk of encountering and being harmed by fearsome large wild carnivores. Yet, the risk is exceedingly low, because, it turns out, these fearsome predators become quite fearful when encountering humans.
Spinal cord injury often causes permanent disability because the body's own repair mechanisms are limited, and the molecules that control damage and healing are not fully understood. One such molecule, FK506-binding protein 5 (FKBP5), is known to rise sharply after injury, but whether it only drives harmful inflammation or also participates in later recovery has been unclear. In this study, we investigated how FKBP5 affects microglia-the brain's immune cells-at different stages after spinal cord injury in mice. We found that FKBP5 plays a dual role. In the first few days, it works together with another protein, GPR84, to boost the production of an inflammatory signal called interleukin-1β. This signal pushes microglia into a destructive state and triggers a coordinated form of neuronal cell death that involves multiple death pathways. However, as FKBP5 levels continue to rise over time, it switches its function. It binds to and modifies an enzyme called LDHA, changing how microglia process lactate. This lactate then acts as a signal to add chemical tags (lactylation) onto histones, which turns on a protective gene, Fxyd5, and its partner Lgals1. These changes convert microglia from a harmful to a healing state, reduce neuronal death, and improve the local environment for tissue repair. Our results reveal that FKBP5 is a double-edged sword-first worsening damage, then promoting repair. This discovery suggests that precisely timing therapies that target FKBP5 could offer a new way to improve recovery after spinal cord injury.
It is only through the advent of extended release/long-acting opioids that the concept of breakthrough pain emerged. The concept suggests that if pain emerges through satisfactory analgesia achieved by an extended release/long-acting opioid, then additional dosing with a short-acting opioid is needed. The concept therefore suggests that breakthrough pain is due to inadequate dosing of opioid. A different explanation, that of drug opposite neuroadaptation or tolerance, turns this thinking on its head. Suppose inadequate analgesia while receiving opioids is not due to an inadequate dose, but rather due to the rebound pain of tolerance. As such, the need to increase the dose sets up further need for pain relief by increasing the dose, the hallmark of negative reinforcement. Negative reinforcement, continued use to avoid negative effects (in this case withdrawal pain), then drives the unhappy state of needing higher doses in a futile attempt to relieve the pain created by the drug itself. PERSPECTIVE: This article describes the neurobiological basis for tolerance to opioid analgesics and highlights the ultimate futility of dose increase as a means of overcoming tolerance. The article argues that so called breakthrough pain could equally be withdrawal hyperalgesia demanding a different response. SUMMARY: Could neuroadaptation explain breakthrough pain, and what would this mean in terms of optimizing opioid efficacy and reducing risk of dependence on opioids.
The catabolism of the priority environmental pollutant 2,4-xylenol requires bacteria to oxidize its ortho-methyl group. Its exact biochemical mechanism is uncharacterized until now. In this study, we resolve key metabolic bottlenecks in Pseudomonas putida NCIMB 9866. We demonstrate that functionally redundant Rieske oxygenase systems ensure the robust ortho-methyl oxidation of 2,4-xylenol. On the para-methyl oxidation branch, PchA2 acts as the main aldehyde dehydrogenase. It shows significantly higher catalytic efficiency than the previously reported PchA. Additionally, we characterized PmmA1B1, a newly identified three-component Rieske oxygenase system responsible for ortho-methyl oxidation, which is supported by two redundant isoenzymes (PmmA2B2 and PmmA3B3), by recruiting the shared endogenous ferredoxin Orf05169. The PmmA1B1-Orf05169 system catalyzes the successive oxidation of the ortho-methyl group of 4-hydroxy-3-methylbenzoate to a carboxyl group, yielding the high-value pharmaceutical precursor 4-hydroxyisophthalate. Structural and kinetic data revealed that the active site architecture of PmmA1 enables efficient successive oxidation, distinguishing it from isoenzymes PmmA2B2 and PmmA3B3 that, when coupled with Orf05169, catalyze only incomplete oxidation. Overall, these results complete the 2,4-xylenol catabolic pathway by defining the enzymes required for both para- and ortho-methyl oxidation. They also reveal functional redundancy as an adaptive feature of microbial aromatic degradation and establish Rieske oxygenases as biocatalysts for converting methylated aromatic pollutants into value-added chemicals.IMPORTANCEMethylated aromatics like 2,4-xylenol pose ongoing environmental risks and are primary targets for bioremediation. We know how bacteria break down many simple aromatics, but the precise ways that enzymes bypass the steric and electronic hurdles of hindered methyl groups remain unclear. In this study, we characterized a novel three-component Rieske oxygenase, PmmA1B1-Orf05169, capable of a rare successive oxidation that turns an ortho-methyl group directly into a carboxyl group. We also found parallel, redundant oxygenase pathways that protect the bacterium's ability to degrade 2,4-xylenol during environmental stress or genetic loss. This discovery not only completes the metabolic map of 2,4-xylenol but also provides a robust biocatalytic tool for the green synthesis of 4-hydroxyisophthalate, a high-value pharmaceutical precursor.
In most Bacillus thuringiensis strains, the cry genes are transcribed by RNA polymerases containing sporulation-sigma factors E or K, leading to the formation of an insecticidal crystal within the mother cell along spore development. The kurstaki HD1 strain, a parent of commercial strains, also releases the insecticidal proteins Cry1I and Vip3A in the extracellular medium. vip3A expression is activated by the transcriptional regulator VipR at the onset of the stationary phase. Here, we expanded the VipR regulon in strain HD1 by identifying the VipR-binding box upstream from the cry2Aa, cry2Ab, and cry1Ia genes, and conducting transcription assays. Unexpectedly, a VipR box was located in the promoter of a putative N-acetylmuramoyl-l-alanine amidase (ami) gene upstream from cry1Ac in strain kurstaki HD73, closely related to the HD1 but devoid of vipR. Introduction of vipR in this strain led to the expression of the ami-cry1Ac operon, resulting in an early and increased production of Cry1Ac. We demonstrated that Cry1Ac was also produced in a VipR-dependent manner in an HD73 ∆spo0A mutant. Similarly, an HD1 ∆spo0A strain produces all the insecticidal proteins encoded in its genome, including cry2Ab, previously considered unexpressed. A genomic analysis also revealed the presence of putative VipR-binding sequences in lepidopteran-active strains, upstream from cry genes such as cry1E, cry1F, cry9D, and cry9E. Overall, our results break the dogma on the regulation of cry1A and cry2A genes and provide evidence of sporulation-independent Cry toxin production in biopesticidal Bt strains.IMPORTANCEBacillus thuringiensis is a remarkably efficient entomopathogen due to its ability to produce various insecticidal proteins, such as Cry or Vip. This property has made it a highly effective biopesticide used worldwide. Our work modifies the paradigm of cry1 and cry2 genes being regulated solely by sporulation-specific sigma factors and thus exclusively expressed during this process. Indeed, we demonstrated that the VipR regulator controls the transcription of vip3Aa, cry2Aa, cry2Ab, cry1Ia, and the ami-cry1A operons encoded by a strain closely related to that of commercial biopesticides and specifically turns on their expression from the onset of the stationary phase, leading to the production of insecticidal crystals independently of sporulation. By providing new knowledge on the regulation of insecticidal protein genes, these findings bring new insight for the genetic improvement of Bt strains used as commercial biopesticides.
To evaluate the clinical impact of the DHACA® method on the development of social skills in children with Autism Spectrum Disorder (ASD). This longitudinal quantitative intervention study conducted with 23 children with ASD, aged 3 to 6 years, who were nonverbal or minimally verbal. Individual intervention sessions using the DHACA® method were held weekly for 20 weeks. Social skills were assessed before and after the intervention using the ACOTEA-R protocol. Data were statistically analyzed using the Wilcoxon test. There was a significant improvement (p < 0.05) in ten of the sixteen skills assessed, including "responds to name," "eye contact," "shared attention," and "symbolic play." Other skills, such as "responds to 'no'" and "takes turns," showed a tendency toward clinical improvement, although not statistically significant. Only three skills did not show relevant progress. The DHACA® method proved effective in promoting social skills in children with ASD, contributing to greater autonomy and social participation. The results reinforce its clinical potential as a therapeutic resource in both educational and healthcare settings. avaliar o impacto clínico do método DHACA® no desenvolvimento de habilidades sociais em crianças com TEA. Estudo de intervenção, longitudinal e quantitativo, realizado com 23 crianças com TEA, entre 3 e 6 anos, não-verbais ou minimamente verbais. As sessões individuais de intervenção com o DHACA® ocorreram semanalmente durante 20 semanas. A avaliação das habilidades sociais foi realizada antes e após a intervenção, por meio do protocolo ACOTEA-R. Os dados foram analisados estatisticamente com o teste de Wilcoxon. Houve melhora significativa (p < 0,05) em dez das 16 habilidades avaliadas, incluindo “responde pelo nome”, “contato visual”, “atenção compartilhada” e “brincar simbólico”. Outras habilidades, como “responde ao ‘não’” e “respeita turnos”, apresentaram tendência de melhora clínica, ainda que sem significância estatística. Apenas três habilidades não demonstraram evolução relevante. Os achados indicam melhorias nas habilidades sociais de crianças com TEA associadas ao uso do método DHACA®, contribuindo para maior autonomia e participação social. Os resultados reforçam seu potencial clínico como recurso terapêutico em contextos educacionais e de saúde. avaliar o impacto clínico do método DHACA® no desenvolvimento de habilidades sociais em crianças com TEA. Estudo de intervenção, longitudinal e quantitativo, realizado com 23 crianças com TEA, entre 3 e 6 anos, não-verbais ou minimamente verbais. As sessões individuais de intervenção com o DHACA® ocorreram semanalmente durante 20 semanas. A avaliação das habilidades sociais foi realizada antes e após a intervenção, por meio do protocolo ACOTEA-R. Os dados foram analisados estatisticamente com o teste de Wilcoxon. Houve melhora significativa (p < 0,05) em dez das 16 habilidades avaliadas, incluindo “responde pelo nome”, “contato visual”, “atenção compartilhada” e “brincar simbólico”. Outras habilidades, como “responde ao ‘não’” e “respeita turnos”, apresentaram tendência de melhora clínica, ainda que sem significância estatística. Apenas três habilidades não demonstraram evolução relevante. Os achados indicam melhorias nas habilidades sociais de crianças com TEA associadas ao uso do método DHACA®, contribuindo para maior autonomia e participação social. Os resultados reforçam seu potencial clínico como recurso terapêutico em contextos educacionais e de saúde.
Spatiotemporal control over supramolecular assemblies holds promise for precise theranostics, yet conventional designs often require an extensive modification of the backbone by introducing responsive motifs. Herein, with minimal interference of the molecular backbone, we report a chiral engineering strategy to enhance the pH sensitivity of a tripeptide-drug conjugate (PDC). Specifically, homochiral PDC forms supramolecular nanofibers with a low pH dependence, whereas the heterochiral isomer with alternating D/L residues exhibits a highly pH-dependent self-assembly. Importantly, in carbonic anhydrase IX (CAIX)-overexpressing tumor cells, fibrous assemblies of homochiral PDCs occur at the cell surface, while heterochiral PDCs form nanofibers within lysosomes via protonation. This process subsequently promoted lysosomal membrane permeabilization and enhanced CAIX inhibition, which turns into an efficient way of enhancing cellular Fenton reactions to evoke ferroptosis, thereby improving the antitumor efficacy in breast tumors. Overall, this work proposes a chiral engineering approach for enhancing the pH sensitivity of supramolecular assemblies, which establishes an efficient strategy for spatiotemporal control over supramolecular assemblies and offers alternative insights into the biological effects of heterochirality.
Heart failure (HF) palliative care communication is essential but difficult to train at scale because conventional role-play programmes require facilitators and standardized patients. Large language models (LLMs) have emerged as potential tools for scalable communication training. This pilot study aimed to evaluate the feasibility of a web-based LLM-driven communication training application and to explore its early educational signal on physicians' self-efficacy. This single-arm pilot study included physicians who completed one session using a Japanese-language web-based LLM application designed to simulate patients with advanced HF and provide automated framework-based feedback. The primary outcome was change in self-efficacy scores assessed by pre- and post-session questionnaires. Ten sessions were analysed. Physicians engaged in a mean of 7.6 ± 2.0 dialogue turns. Mean response time per model output and feedback generation were approximately 3 and 17 s, respectively. Significant improvements were observed in knowledge of palliative care communication (mean difference +1.7, adjusted P < 0.01) and confidence in HF palliative care communication (+1.2, adjusted P = 0.03). Other domains showed non-significant changes. This pilot study demonstrated the feasibility of a web-based LLM-simulated patient system and suggested an early educational signal in physicians' self-efficacy for HF palliative care communication. Our scalable LLM-driven communication training may complement traditional educational approaches with further evaluation in larger controlled studies. Trial registration number: UMIN000059988.
Millions of users turn to consumer artificial intelligence chatbots to discuss emotional, behavioral and mental-health concerns, creating an urgent need for rigorous and scalable safety evaluations. Here we introduce simulated (SIM) vulnerability-amplifying interaction loops (VAILs) (SIM-VAIL), a clinically validated framework for auditing chatbot behavior in mental-health contexts. SIM-VAIL simulates users with specific psychiatric vulnerabilities and conversational intents, engages them in multi-turn conversations with frontier artificial intelligence chatbots (including Claude, ChatGPT, Gemini, Grok and Llama models) and scores each exchange across 13 clinically grounded risk dimensions. Across 810 conversations, spanning 9 target chatbots and 30 simulated user profiles, concerning behavior in target chatbots was widespread, albeit reduced in newer models. Concerning behavior varied by user vulnerability and conversational intent, accumulated over turns, and could be reduced by interventions at early escalation points. Risk was highest when otherwise supportive chatbot behaviors reinforced the psychological mechanisms underlying the simulated user's vulnerability, a pattern we term a VAIL. SIM-VAIL provides a scalable framework for mapping mental-health risk across users, chatbots and conversational trajectories, offering a foundation for targeted safety improvements.
Sight loss will affect an estimated 2.7 million people in the UK by 2030 and is associated with substantial reductions in quality of life, mobility, independence, and poorer mental health. Our own research has demonstrated that depressive symptoms are highly prevalent among blind and partially sighted people yet often remain unrecognised and untreated. To effectively disseminate our research to healthcare professionals, we involved members of the public with lived experience of sight loss in an art installation. The aim of this project is to evaluate the feasibility and value of using such an arts-based approach as a method for involving blind and partially sighted individuals in dissemination, and here we reflect on what all stakeholders learnt from the process. We recruited eight blind and partially sighted storytellers to share themes from our research using narratives of their own lived experience, focusing on the emotional impact of sight loss and professional interactions. Audio-recorded stories and accompanying portraits were developed into Eight Voices in Darkness, a sound installation designed to reflect both the literal and metaphorical darkness associated with vision impairment and depression. The installation was exhibited publicly over three days alongside workshops for eyecare professionals and mental health practitioners. Visitor and participant feedback (n = 92) was analysed using Pendleton's reflective framework to explore what went well, what did not, and what was learned. Visitors consistently reported an enhanced understanding of the mental health consequences of sight loss, valuing the authenticity, emotional resonance, and individuality conveyed through the artistic format. Many indicated intentions to adopt more empathetic, patient centred practices, improve accessibility, and initiate conversations about mental health. Storytellers highlighted the value of being heard and connecting with others' experiences. Researchers and the artist reflected on the strengths of partnership with the charity, the power of the immersive format, and challenges relating to managing expectations. The process generated important insights into involving the public in dissemination through art, including ethical editing, audience preparation, and sustaining involvement. Involving people with lived experience in arts-based dissemination offers a powerful and engaging method for disseminating research findings to professionals to improve healthcare. Future work should refine practical elements and enhance coproduction. Many people in the UK live with sight loss, which can make every aspect of everyday life harder, including tasks like reading and mobility. Our research showed that sight loss can also impact mental health, and that many people with sight loss do not get the emotional support they need, partly because some eyecare professionals do not realise how common mental health problems are among this group. Our aim was to involve patients and the public, specifically blind and partially sighted people, in sharing our research effectively so that vision-related professionals and the public could learn how sight loss affects mental health. We created an art project called Eight Voices in Darkness. Eight individuals talked about the key topics noted in our previous body of research on sight loss and mental health: how their sight loss affects their feelings, challenges faced, and support required. Their stories were recorded, along with a portrait photo of each person. An artist turned these stories into an art installation. In a quiet, dark theatre, visitors could sit and listen to short parts of each person’s story. Over three days, almost 200 people visited. Many said the experience helped them understand sight loss in a new and powerful way and they would try to be more kind, patient, and willing to talk about mental health in the future. The storytellers also said it felt good to be listened to. This project showed that art is a valuable mechanism to involve individuals with lived experience in sharing research with professionals and the public to improve healthcare. Research teams must consider practical and ethical considerations when individuals’ stories are harnessed to share research findings and allow sufficient time and resources.
In the past, people with lung cancer received less public recognition and fewer organized support systems, compared with other cancer communities (such as pediatric or breast cancer). In the 1990s, limited benefit from systemic therapies discouraged support networks and advocacy. However, in the past two decades, transformative advances in targeted therapies, immunotherapy, molecular diagnostics, screening programs, and surgical and radiotherapy techniques have dramatically changed the patient experience. Advocacy organizations have played a crucial role in ensuring that these scientific gains translate into meaningful, equitable, patient-centered care. This article highlights lung cancer patient advocacy as an essential driver of progress in access to prevention, screening, treatment, and supportive care. Advocates have challenged stigma, underfunding, and neglect. Over time, organizations have expanded, professionalized, and formed national and international coalitions, amplifying their collective voice and coordinating policy efforts across countries. Beginning in the late 1990s, early organizations laid the groundwork for private research funding and public awareness. The 2010s marked a turning point, with social media enabling widespread patient connection, biomarker-driven communities emerging, and deepening collaboration between advocates and researchers. Today, advocacy groups serve as essential partners across the research continuum, shaping study concepts, reviewing protocols, co-designing patient-facing materials, and enhancing the dissemination of results. For example, across Europe, many lung patient advocacy organizations have been initiated by patients and their families, often starting as grassroots or online communities, or social networks, and later expanding into national or European networks. Examples include Lung Cancer Europe, ALK Positive Europe, and Women Against Lung Cancer in Europe, illustrating a decentralized yet strongly patient-led advocacy model. Advocates have also influenced public policy and societal perceptions. Their efforts have strengthened tobacco control measures and advanced anti-stigma work that centers dignity, respect, and person-first language. Despite meaningful progress, stigma continues to impede access to care and participation in research. Advocacy organizations work to change public perception because people with lung cancer deserve the same care and respect as people with other forms of cancer. Globally, advocacy in low- and middle-income countries is still developing but is increasingly recognized as vital. A major milestone was the first Pan-African Lung Cancer Conference in Accra in 2025, where advocates prioritized early detection, caregiver support, policy reform, and community education, while acknowledging the need for long-term infrastructure development. As lung cancer care becomes more complex, patient advocacy remains indispensable in promoting equitable access, harmonizing policy across regions, accelerating innovation, and expanding survivorship support. To sustain progress, advocates should be formally embedded in trial design, clinical guideline development, implementation of research projects, and dissemination of research findings and support the health care ecosystem so innovations in research and care are accessible, timely, and equitable. The field is entering an "Impact Era," where success is measured not only by survival but by how well people live. Advocacy will continue to drive systems toward more patient-centered and equitable lung cancer care locally, nationally, and globally.
Biliary tract cancers (BTC), including cholangiocarcinoma, gallbladder cancer, and ampullary cancer, remain poor-prognosis tumours. Chemo-immunotherapy is now established as the first-line standard of care. In parallel, precision medicine is now well established in the form of targeted therapies. These have transformed outcomes for defined subgroups, particularly intrahepatic cholangiocarcinoma with FGFR2 fusions/rearrangements, where pemigatinib and futibatinib provide meaningful response rates and durable disease control. On top of this, next-generation FGFR inhibitors aim to address secondary resistance. IDH1-mutant cholangiocarcinoma benefits from ivosidenib, with multiple combination strategies currently under investigation. HER2-directed therapies, including zanidatamab and trastuzumab deruxtecan, have shown promising efficacy in HER2-amplified or strongly overexpressing BTC, with ongoing clinical trials in the first-line setting. Tumour-agnostic targets (BRAF V600E, MSI-H/dMMR, RET/NTRK/NRG1 fusions) and other emerging therapies are further broadening therapeutic opportunities. However, key barriers to implementation include heterogeneous biomarker testing, limited tissue availability, the need for DNA/RNA hybrid-capture sequencing, and evolving resistance biology, underscoring the importance of optimised diagnostics and innovative trial designs to realise personalised care in BTC. This review provides detailed insights on these therapies, and most importantly a view to what the future may hold.
Gout development and progression are closely linked to inflammatory processes. Six novel systemic inflammation indices, including the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), inflammation score, systemic inflammation response index (SIRI), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) have shown significant value in assessing systemic inflammation severity and related comorbidities. This study aims to explore the relationship between these systemic inflammation indices and the risk of gout. Data from the 2015-2018 National Health and Nutrition Examination Survey (NHANES) were analyzed in this study to explore the link between systemic inflammation indices and gout risk. Demographic information of all participants was collected, and multivariable logistic regression was applied to evaluate the relationship between the inflammation indices and gout risk. Restricted cubic splines (RCS) were used to investigate the nonlinear association between inflammation scores and gout risk. Stratified and interaction analyses were also conducted to examine the relationships in different populations. A total of 7,681 participants were included in the analysis. After adjusting for all covariates in the multivariable logistic regression model, the inflammation score demonstrated the most significant association with gout risk. Further RCS analysis revealed a nonlinear relationship (P=0.0134) with a turning point at 1.641. When the inflammation score was below 1.641, an increase in the score was significantly associated with a higher risk of gout. Stratified analyses indicated that age, race, and smoking status interacted with the relationship between inflammation scores and gout risk. This study identified a significant association between the inflammation score and gout risk, particularly at low-to-moderate inflammation levels, suggesting that systemic inflammation may play an important role in the early stages of gout development. The inflammation score remained independently associated with gout after full adjustment, indicating its potential utility for early risk identification. The findings suggest that the inflammation score is a robust and independent predictor of gout risk, particularly at low-to-moderate levels, highlighting its potential for the early identification of high-risk individuals.
This perspectives article explores magical thinking (which is often dismissed as irrational or pathologized) as a potentially valuable personal orientation and resource for people living with chronic pain: as a way to make more sense of their complex and challenging life experience, psychologically as well as socially. Magical thinking entails a broader acceptance of connectivity between phenomena generally considered to be independent, and it includes symbolic meaning-making acts such as rituals. The authors explicitly exclude in their discussion magical superstitions which involve the conviction that magical acts can directly impact physical reality (such as enabling levitation or turning people into frogs). Drawing on a reflective, interpretive, and conversational methodology, a pain scientist, a nurse researcher, and a writer-practitioner of magical thinking explored how magical thinking functions as a personal orientation and resource that enables symbolic meaning-making and supports emotional regulation and relation with self, others and the wider world. As such, it may be potentially valuable for people living with chronic pain. The article shows that traces of magical thinking can be found within psychology and medicine and invites a broader conversation about how the symbolic and imaginative modes of magical thinking might be valuable in pain care.