Search Results (11,594)

The 2025 approval of the selective NaV1.8 blocker suzetrigine for acute pain marked a pivotal advance in analgesic drug development. Yet the subsequent failure of Vertex’s next-generation NaV1.8 inhibitor VX993 to demonstrate clinical analgesia underscores enduring challenges in translating mechanistic promise into patient benefit. This review examines why promising targets and compounds, spanning NaV and TRP channels, often falter and outlines a path toward more reliable target selection and validation. I first summarize the pain pathway, from nociceptor transduction through spinal processing to cortical perception, emphasizing how inflammation and peripheral sensitization reshape excitability. Historically serendipitous, pain drug discovery now prioritizes molecular precision. Most approved chronic pain therapies act in the CNS and are limited by modest efficacy and adverse effects. Nociceptor-enriched targets (NaV1.7/1.8/1.9; TRP channels) remain attractive, yet redundancy among NaV subtypes and the necessity of blocking targets at the correct anatomical sites complicate translation. Human genetics and multi-omics provide a powerful, unbiased engine for target discovery. Rare high-impact variants offer strong causal hypotheses, while common polygenic contributions illuminate broader susceptibility. Large biobanks increasingly reveal a mismatch between legacy pain targets and genetically supported candidates across neuronal and non-neuronal cells. Human DRG transcriptomics highlight NaV channel redundancy. Human in vitro electrophysiology and PK/PD analyses show suzetrigine achieves ~90–95% NaV1.8 engagement, yet neurons can still fire unless additional channels are blocked. Species differences and drug distribution (including BBB/PNS penetration and P-gp efflux) critically influence efficacy; centrally accessible blockade (e.g., for NaV1.7 or TRPA1) may be necessary to achieve robust analgesia, challenging peripherally restricted strategies. Osteoarthritis illustrates how obesity-driven metabolic inflammation, synovial immune activation, subchondral bone remodeling, and specific nociceptor subtypes converge to drive mechanical pain. Multi-omic integration across diseased human tissues can pinpoint causal processes and cell types, enabling more selective and safer target choices. I propose a practical framework for target validation that integrates: (i) rigorous human genetic support; (ii) cell-type and site-of-action mapping; (iii) human-relevant electrophysiology and PK/PD with verified target engagement; (iv) species-appropriate models; (v) consideration of modality (small molecule, biologic, RNA, targeted protein degradation). Advancing genetically and anatomically aligned targets, tested at the right sites and exposures, offers the best path to genuinely effective, better-tolerated pain therapeutics. Full article

Background and Objectives: Functional decline and sarcopenia are major aging-related concerns. While protein intake is known to influence muscle health, its longitudinal impact on strength and physical function across age and gender remains underexplored. We assessed whether low protein intake correlate with future onset of low handgrip strength (HGS) and physical impairments in older adults using SHARE data. Methods: We analyzed 38,073 adults aged ≥50 years from 27 European countries using SHARE Waves 8 (2019/20) and 9 (2021/22). A protein intake index was derived from the frequency of consuming dairy, legumes/eggs, and meat/fish/poultry. Low intake was defined as the lowest decile. Logistic regression models, adjusted for age, gender, country, and baseline health, examined associations with low HGS and ten physical difficulties, stratified by age (50–65 vs. ≥66 years) and gender. Results: Low protein intake is associated with higher odds of low HGS in men (OR = 1.39 for 50–65; OR = 1.35 for ≥66) and older women (OR = 1.21). It was also associated with higher odds of mobility-related limitations, including walking 100 m (ORs = 1.25–1.53), stooping/kneeling (ORs = 1.20–1.19 in women), and reaching overhead (ORs = 1.19–1.33). Strength-related tasks, such as pushing/pulling large objects were more affected in men (ORs = 1.44 and 1.21). Notably, women aged 50–65 had over twice the odds of toileting difficulty (OR = 2.27) and significantly higher odds of difficulty shopping (OR = 1.65). These patterns highlight gender- and age-specific vulnerabilities. Conclusions: Low protein intake is associated with modest but consistent increases in the risk of reduced muscle strength and functional difficulties in older adults. Tailored nutritional strategies may mitigate age- and gender-specific risks to physical independence. Full article

Children gifted for music are often described as possessing heightened perceptual and sensory abilities, yet little is known about how these abilities are understood within different family contexts or how giftedness is experienced as an identity. This mixed-methods study examined alignment between gifted children’s and parents’ perceptions of children’s mental–perceptual abilities, the role of parental musical background, and how giftedness is explained and emotionally negotiated. Twenty-two children identified as gifted for music and 25 parents completed a survey based on Gagné’s Differentiated Model of Giftedness and Talent assessing six mental–perceptual abilities, followed by semi-structured interviews. Quantitative analyses revealed a strong positive association between child and parent ratings, alongside a consistent tendency for parents to provide higher evaluations. Parental professional musical background did not significantly moderate alignment but was associated with greater variability in both children’s and parents’ ratings. Qualitative findings indicated shared experiential understandings of ability across families, alongside systematic differences in evaluative frameworks: musician parents more frequently drew on technical, comparative, and training-based standards, whereas non-musician parents relied on affective and everyday observations. Children across contexts often expressed modesty or ambivalence toward being labeled gifted, while parents balanced pride with concern about pressure. Overall, perceptions of mental–perceptual ability emerged as relationally constructed within family environments that shape how musical giftedness is recognized and supported. Full article

Objectives. Our objective was to study the ecological relationship of many risk factors and personal characteristics with mean age at death (AD) after a 50-year follow-up of nearly extinct cohorts. Material and Methods. There were 16 cohorts totaling 12,763 middle-aged men enrolled in the Seven Countries Study (SCS), and 58 variables were measured, including traditional risk factors, dietary nutrition and anthropometric variables. A follow-up of 50 years allowed the use of AD as the end-point. Analysis included simple linear regression correlation and multivariate modelling using Principal Component Analysis and regression and Ridge regression. Results. Out of 58 variables, only 11 (10 nutrition-dietary items plus age) showed a significant linear correlation coefficient (R) ≥ 0.50 and a p value ≤ 0.05. Linear regression was computed by using as a predictor the dietary factor score derived from a Principal Component Analysis of the 11 significant variables, which were used as independent variables, whose coefficients were significantly related with AD, and the final R² was 0.52. The Principal Component regression and Ridge regression documented the direct relationship of food groups of vegetable origin (including olive oil) with the AD and the inverse relationship for food groups of animal origin. Conclusions. A few variables, all related to diet and nutrition, were able to statistically explain about 50% of the different AD in 16 cohorts of men followed up with nearly until death. Other variables, including traditional cardiovascular disease risk factors, did not contribute in a significant way for this purpose. Full article

The investigation aimed to determine if live feedback of team- and player-specific global positioning system (GPS) running performance data between bouts of hurling small-sided games (SSGs) altered the physical and physiological responses during subsequent bouts of SSGs during a 6-week hurling pre-season period. Twenty-four (n = 24) hurling players (age 25.5 ± 3.2 years; height 177.9 ± 3.2 cm; body mass 83.5 ± 4.5 kg) received either feedback or no feedback during hurling-specific SSGs across a 6-week pre-season period. Teams were assigned to two specific groups, a) GPS live feedback or b) no GPS live feedback (control) for each session, with feedback provided during the SSG rest interval. Running performance (10-Hz, STATSports, Apex, Northern Ireland), heart rate (Polar T31 coded, Polar Electro, Finland), and rating of perceived exertion (RPE) were measured. Data was analyzed using linear mixed-effect models with the effect size (Cohen’s d) used to determine the size of the effect between feedback and non-feedback conditions. Trivial-o-small differences at all time points were observed in heart rate and RPE measures during SSGs, respectively. Trivial-to-moderate effects were observed between feedback and non-feedback conditions for total distance (p = 0.04; ES = 0.25; small) high-speed running (p = 0.043; ES = 0.59; moderate), maximal speed (p = 0.345; ES = 0.11; trivial) and accelerations (p = 0.03; ES = 0.55; moderate). The current data suggests that coaches and applied practitioners may use live GPS feedback to alter the running and physiological performance within hurling-specific SSGs during a pre-season period. Full article

Hypoxia activates hypoxia-inducible factors (HIFs), which regulate genes involved in erythropoiesis, angiogenesis, and metabolism. HIF stability is controlled by oxygen-dependent HIF prolyl 4-hydroxylases (HIF-P4Hs). Pharmacological HIF-P4H inhibitors are approved for the treatment of anaemia in chronic kidney disease (CKD). Beyond erythropoiesis, these drugs have been linked to improved lipid profiles in CKD, and preclinical studies suggest benefits for glucose tolerance and cardiovascular protection. However, cardiometabolic effects of HIF-P4H inhibitors have not been systematically examined in healthy or non-anaemic individuals. This investigator-initiated, double-blind, placebo-controlled, randomised crossover trial evaluates the systemic effects of roxadustat, an orally administered pan-HIF-P4H inhibitor. The study consists of two 10-day study arms separated by a minimum 4-week washout. Participants receive 70 mg of roxadustat or a placebo thrice a week. The primary hypothesis is that roxadustat lowers plasma total cholesterol. Secondary outcomes include changes in LDL cholesterol, triglycerides, insulin sensitivity, glucose tolerance, body composition, 24 h blood pressure, exercise capacity, autonomic cardiovascular regulation, and skeletal muscle microcirculation. Healthy volunteers (n = 24) aged 18–40 years will be enrolled. This study will provide insights into the potential of HIF-P4H inhibitors for obesity, dyslipidaemia, insulin resistance, and hypertension, and may inform future therapeutic strategies for metabolic syndrome, type 2 diabetes, and cardiovascular disease. Full article

The raspberry (Rubus idaeus L.), an economically important crop, is affected by the crumbly fruit disorder, a malformation that leads to fruit disintegration at harvest due to poor drupelet cohesion. Despite previous efforts to identify genetic determinants of this phenotype, its complex inheritance and strong environmental component have limited the development of robust predictive markers. This study assessed the behavior and transferability of previously reported SSR and SNP markers associated with crumbly fruit across plants from a diverse panel of 34 R. idaeus cultivars, including in adjacent genomic regions not screened previously. Phenotyping was based on multi-season fruit performance and drupelet cohesion, and genetic variation was analysed using PCR-based genotyping within a multilocus approach. Consistent clustering patterns were observed across multiple SSR and SNP loci, suggesting a reproducible association between these genomic regions and the crumbly phenotype. Overall, the results support a multilocus genetic architecture underlying crumbly fruit, but also demonstrate that previously reported markers are not universally transferable across genetic backgrounds. These findings highlight the importance of integrated, population-aware marker validation to enable more reliable implementation of marker-assisted strategies in raspberry breeding programs. Full article

Epilepsy affects more than 50 million individuals worldwide, and approximately one-third of patients remain refractory to existing antiseizure medications. Advances in gene therapy and genome editing have opened new possibilities for disease-modifying interventions that directly target the molecular and circuit-level mechanisms underlying epileptogenesis. Recent progress in central nervous system tropic viral vectors, non-viral delivery systems, and programmable genome-editing technologies has enabled precise manipulation of neuronal and glial function in preclinical epilepsy models. Strategies range from restoration of haploinsufficient genes implicated in monogenic epilepsies, such as SCN1A in Dravet syndrome, to modulation of neuronal excitability through engineered ion channels, neuropeptides, and astrocyte-based approaches. In parallel, CRISPR-derived platforms, including transcriptional activation and repression systems, base editing, and prime editing, offer new avenues for regulating gene expression in post-mitotic neurons without introducing double-strand DNA breaks. Despite these advances, significant translational challenges remain, including efficient and cell-type-specific delivery, long-term safety, and the risk of network-level side effects in the epileptic brain. This review critically examines recent gene therapy and genome-editing approaches for epilepsy, highlights key technological and biological barriers to clinical translation, and discusses emerging strategies that may enable durable and targeted treatments for drug-resistant epilepsies. Full article

Research on Consumption-Based Carbon Footprints has recognised that lifestyles change significantly along the urban–rural continuum, with urban typically manifesting as an increase in the footprint of consumption while rural areas have a higher footprint for vehicle usage. However, there is limited research on the extent to which land-use patterns defined by urban plans influence these outcomes. To fill this lack, we controlled for household income and housing type and measured Spearman and Pearson partial correlations between the coverage of different zoning land-use types in the neighbourhoods and the footprints of different subdomains: Goods and services, Leisure travel, Vehicle, and Total footprint. These domains are central to both modern lifestyles and urban planning with related objectives. We found out that high Goods and Services and Leisure travel footprints do align with the urban land-use types, while Vehicle footprints show inverted results. However, the mirrored impact for higher Vehicle and Total footprint is not recognised in exurban areas, while the impact on Goods and services and Leisure travel is inverted. These findings diverge from the common per capita analysis of supply-side emissions used to analyse zoning impacts and call for more detailed research on the net climate impacts of the built environment designated with land-use plans. Full article

Current structural design codes use a stochastic approach (SC) in load combination and reliability calculation. This article presents a design model with a deterministic (DC) approach. Currently, design codes have variable load factors (γ_G ≠ γ_Q) and constant safety factors (γ_M) for all loads. This approach makes two significant approximations: It assumes a single material factor for all ratios of permanent to variable loads and across all types of variable loads. This research proposes the opposite strategy: instead of a single material factor, each load is assigned to its own material factor. Such a shift removes those approximations, simplifies codes, and reduces calculation effort. A central challenge in reliability assessment is combining loads. Existing SC methods differ in their reference time and target reliability. The fundamental fact of load–material interaction is that each load acts independently, without influencing others. This deduction results in the DC combination. Safety factors within the Eurocode framework are derived using today’s semi-probabilistic SC methods and a fully probabilistic DC approach. The proposed design model is straightforward, requires minimal computation, meets the target reliability, and yields significant savings in material use. Full article

Voice user interfaces (VUIs) have evolved from simple command-based systems to more advanced platforms capable of engaging in complex, multi-turn conversations. While current VUIs primarily perform routine tasks, their future trajectory is poised to be significantly shaped by advancements in large language models (LLMs), enhancing their language understanding and human-like interaction capabilities. This study explores user perceptions of next-generation VUIs using a design fiction approach. We crafted five plausible future scenarios, depicted in comic-style formats, showcasing diverse VUI use-cases. Results from the focus group discussions reveal valuable insights highlighting the potential and challenges of integrating advanced VUIs into everyday interactions. Our results highlight the importance of building trust, factors influencing trust, social aspects and implications of technology, preferences for interaction techniques, and various ethical considerations associated with technology. We conclude by providing design guidelines for future VUIs, emphasizing the need for designing to build trust, the importance of domain specificity, the importance of enabling social experiences mediated via VUIs, and more. Full article

Human health and well-being are dependent on natural environments, which is the core foundation of the growing discipline of outdoor therapies. However, as with psychotherapy research in general, the field of outdoor therapies lacks descriptive process-oriented theoretical frameworks that precisely reflect this multi-faceted practice. Therapeutic work, whether this takes place indoors or outdoors, comprises numerous implicit relational and environmental dimensions. Implicit aspects are largely sensed, embodied and intuitive, and therefore hard to pin down and describe accurately. In this exploratory study, a survey mapped implicit guiding frameworks amongst outdoor therapy practitioners (n = 68) representing 18 nations. A constructivist grounded theory analysis resulted in the proposition of a practice theory, called the implicit ecosystem of outdoor therapies, made up of eight interrelated components: (1) joint engagement and co-creating agendas; (2) a foundation of safety and trust; (3) being in parallel and not fix; (4) awareness and attunement here-now; (5) the dynamic of outer and inner landscapes; (6) a constantly moving and meaning-making endeavor; (7) creativity, play, and whole-body activation; and (8) working through natural barriers and rewriting narratives. This grounded theory offers a preliminary blueprint of a practice-guiding framework developed from within the outdoor therapy discipline intended to advance theory, training, and research. Full article

Current structural reliability calculations are typically based on combinations of load pairs. However, there is no consensus on key aspects such as the reference time, the target reliability, or the choice between a stochastic and independent (SC) versus a deterministic and dependent (DC) approach. This article shifts the focus from load–pair combinations to individual load–material pairs and evaluates structural reliability using both the existing Eurocode methodology and a new approach based on 50-year loads and 50-year target reliability as well as the DC framework. The aim is to provide a more consistent and transparent basis for reliability assessment in structural design. Full article

Via constructing an explicit Lagrangian for which the perturbation equations are analogs of a scalar field propagating in a planar black-hole space–time, it is found that all planar black holes conformal to a Painlevé–Gullstrand-type line element can be realized as analog metrics. We also introduce the concept of holographic entanglement entropy for planar black-hole space–times. This is valid for an arbitrary choice of conformal and blackening factor, thereby vastly extending the number of known examples of explicitly known analog metrics. Full article

Background: Blockchain and Multi-Agent System (MAS) are increasingly combined to support decentralized, secure, and autonomous peer-to-peer energy trading in microgrid environments. Objectives: This systematic review investigates how blockchain and MAS are integrated to support microgrid energy trading, identifies architectural and operational models, examines real-world implementations, and highlights technical, regulatory, and security challenges. Unlike prior reviews that focus on blockchain or MAS in isolation, this study provides a unified and comparative analysis of their joint integration. Methods: Following PRISMA 2020 guidelines, a systematic search was conducted in IEEE Xplore, ACM Digital Library, and ScienceDirect, with the last search performed on 10 January 2025. Eligible studies focused on blockchain–MAS integration in microgrid energy trading; non-energy and non-microgrid applications were excluded. Study selection was performed independently by two reviewers, and methodological quality was assessed using an adapted Joanna Briggs Institute (JBI) checklist. A narrative synthesis categorized integration levels, blockchain platforms, MAS roles, and implementation contexts. Results: A total of 104 studies were included. Three dominant integration levels were identified—basic, intermediate, and advanced—distinguished by how decision-making responsibilities are distributed between MAS and smart contracts. Ethereum and Hyperledger Fabric were the most commonly used platforms. MAS agents perform concrete operational functions such as bid and offer generation, price negotiation, matching, and local energy optimization, fundamentally transforming control and monitoring processes. By enabling distributed, intelligent agents to perform real-time sensing, analysis, and response, an MAS enhances system resilience and adaptability. This architecture allows for proactive fault detection, dynamic resource allocation, and coherent, large-scale operations without centralized bottlenecks. Blockchain ensured transparency, trust, and secure transaction execution. Major challenges include scalability constraints, interoperability limitations with legacy grids, regulatory uncertainty, and real-time performance issues. Limitations: Most included studies were simulation-based, with limited real-world deployment and substantial heterogeneity in evaluation metrics. Conclusions: Blockchain–MAS integration shows strong potential for secure, transparent, and decentralized microgrid energy trading. Addressing scalability, regulatory frameworks, and interoperability is essential for large-scale adoption. Future research should emphasize real-world validation, standardized integration architectures, and AI-enabled MAS optimization. Funding: No external funding. Registration: This systematic review was not registered. Full article