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Regulatory reliance pathways are increasingly being recognized as essential tools to accelerate patient access to medicines globally while building National Regulatory Authorities (NRA) capacity and capability. Although significant progress has been made in a number of international pilots for Chemistry, Manufacturing and Controls (CMC) post approval changes, there has been more limited application to labelling variations including indication extensions. This paper describes the first reliance pilot for an indication extension, which engaged 21 NRAs across multiple regions. The pilot leveraged the European Medicines Agency (EMA) as a reference agency and incorporated a digital platform, whose use was optional by the NRAs involved, for real-time sharing of questions and responses. The objectives were to reduce approval timelines, promote regulatory convergence, streamline health authority questions and enhance transparency among participating authorities. Results demonstrated significant reduction in approval timelines, with an average reduction of 3 months per country compared to standard timelines across participating countries. This article outlines the process of establishing the pilot, including planning and engagement with regulatory authorities, analysing success factors and challenges encountered including recommendations for optimising the process further. The findings suggest that regulatory reliance for indication extensions can substantially improve efficiency in regulatory processes, reducing approval timelines and ultimately benefiting a wider patient population to access medicines globally and timely.

Flat urothelial lesions represent a diagnostically challenging and clinically significant spectrum in bladder pathology. Distinguishing urothelial carcinoma in situ (CIS) from precursor lesions such as dysplasia remains problematic due to overlapping morphologic features, marked interobserver variability, and unresolved questions about biological behavior and progression risk. These challenges pose a substantial risk of underdiagnosis of neoplastic lesions-misclassified as reactive or benign-or overtreatment of precursors overcalled as CIS. As a result, intermediary lesions-particularly dysplasia-remain controversial and marginally addressed in major guidelines, including the 2022 WHO classification. Recent molecular studies, including next-generation sequencing and proteogenomics, have uncovered defining genomic alterations in flat lesions-such as prevalent TERT promoter mutations across the intraurothelial neoplasia spectrum, alongside variable TP53, FGFR3, and chromatin-remodeling gene changes-that help better define biological behavior and refine diagnostic categories. This review synthesizes recent molecular profiling data within the framework of established urothelial carcinogenesis pathways, offering insights into the biology and progression of flat lesions. It examines evolving classification systems, ongoing challenges in diagnostic reproducibility, and clinical implications. Ancillary modalities, including immunohistochemistry (e.g., CK20, p53, CD44) and emerging molecular tests, are appraised for their utility and constraints. Finally, the review highlights emerging computational tools-particularly artificial intelligence-based analysis of histopathology slides, which shows considerable promise in enhancing diagnostic accuracy-and concludes with evidence-based recommendations aimed to optimize the management of flat urothelial lesions.

Nuclear magnetic resonance (NMR) has a long history of addressing mechanistic questions in membrane biology. Its unique capabilities include the non-perturbing nature of isotope labels, the ability of NMR signals to provide atomic-level structural and dynamic information in complex samples, including living systems, and the ability to detect very weak binding through chemical shift changes. Solution and solid-state NMR methods are highly complementary and enable a wide range of biomolecular complexity and dynamic timescales to be analyzed. Here we describe recent advances that push the envelope of current technology and offer new opportunities for targeting membrane protein assemblies to gain fundamental human health insights.

Patients who are referred for genetic counseling and/or genetic testing may conduct web searches to try to gather more information prior to their appointment. However, little is known about the reading level of such resources or the suitability of the information they provide. This study aims to determine the readability and suitability of top-ranked webpages after general searches about genetic counseling and if there is a difference in these metrics depending on which type of organization (i.e., government, non-profit) authored the webpage. Twenty webpages were identified using Google. Searches of the questions "What is a genetic counselor?", "What is genetic testing?", "Why do I need genetic testing?", and "What happens at a genetic counseling appointment?" were completed and the top 5 pages were taken from each. These webpages were then analyzed using the readability tools of Flesch-Kincaid (FK) and Standardized Measure of Gobbledygook (SMOG). Both FK and SMOG provide an assessment of readability based on grade level with the goal of this study to find resources under grade level 8. Additionally, the webpages were analyzed using the Suitability Assessment of Materials (SAM) on 6 categories. To complete the SAM analysis, two reviewers completed the tool for each webpage. Sponsor type was determined based on the primary goal of the group that supported or published the webpage. When comparing between questions, the average FK scores for the webpages were between 8th and 12th grade and the average SMOG scores were between 11th and 14th grade. Most webpages rated as adequate on the SAM scale. The results of this study highlight the continued need for evaluation of patient resources, especially those on the internet, to ensure they are meeting the needs of the rising number of individuals being referred to genetic services.

Mycoplasmas are known for being fastidious, with scientists still struggling to propagate them in vitro. Improving their culture is vital for future research, despite limited metabolomics studies available. This study explored the chemical composition changes in four liquid media (A, B, C, D) inoculated with Mycoplasma gallisepticum (MG), aiming to uncover overlooked metabolic features. We used Direct Analysis in Real Time High-Resolution Mass Spectrometry (DART-HRMS) across five time points over 71 h. Integration of DART-HRMS data with statistical analysis showed that media A and D initially contained higher glucose levels, which declined over time. Lactic acid levels rose in all media, with signals reaching saturation at the latest time points. Subsequent pathway enrichment analysis revealed an unexpected overexpression of arginine metabolism. Spermidine accumulation in certain media suggests a potential link to inhibited biofilm formation, opening questions about polyamine function in MG. Histidinal accumulation indicated an unpredicted amino acid synthesis capability in a mycoplasma and MG's inability to convert arginine into glutamic acid. Additionally, MG was observed to utilize creatine when present. These findings highlight the importance of metabolomics in understanding enigmatic microorganisms like mycoplasmas, reaffirming that environmental factors drive alternative metabolic routes in MG and opening new research avenues.

Metformin demonstrates antiepileptogenic (primary prevention) and antiseizure (symptom control) properties in animal models of epilepsy. It is unclear whether these effects translate to humans, particularly outside diabetes, where metformin is increasingly prescribed for weight loss for example. We therefore addressed two questions in people without evidence of diabetes: (1) following an incident brain insult (ischaemic stroke, intracranial haemorrhage, head injury or brain tumour), is metformin associated with reduced risk of first recorded seizure, epilepsy diagnosis or antiseizure medication (ASM) initiation? (2) In established epilepsy treated with ASMs, is metformin add-on associated with reduced risk of potentially seizure-related morbidity (coded seizures, emergency department attendances, hospital admissions, falls, injuries, burns or a composite of these) and all-cause mortality? We undertook an international retrospective cohort study of real-world healthcare data in TriNetX. Propensity score matched cohorts compared metformin against licensed weight-management comparators. Cox proportional hazards models estimated HRs with 95% CIs for 10 year outcomes. 16 695 participants were included. Following brain insult, metformin was not associated with reduced risk of first recorded seizure, epilepsy diagnosis or ASM initiation. In established epilepsy, metformin add-on was associated with significantly lower hazards of coded seizures (HR 0.778, CI 0.624 to 0.971), emergency attendance or hospital admission (HR 0.696, CI 0.569 to 0.851), falls/injuries/burns (HR 0.677, CI 0.510 to 0.898) and a composite of these events (HR 0.729, CI 0.626 to 0.848; approximate number needed to treat ~6 at 10 years). Mortality did not differ (HR 1.039, CI 0.594 to 1.816). Metformin could have repurposed benefits in epilepsy. This warrants further investigation.

Persistent plastic micro- and nanoparticle (MNP) pollution poses a serious threat to global health. Yet they typically cannot be considered in conventional life cycle assessments (LCAs), which weakens decision-making. To avoid waiting for consensus on the MNPs' fate and impacts required by LCA, an innovative framework has been developed to conservatively estimate the plastic particle footprint (PPF), i.e., the total MNP emissions during the plastic's lifetime of an item, up to the very long-term fate. Reporting the PPF as an elementary flow alongside other indicators shows to improve the ability to weigh up the alternatives' benefits. Applying the calculation to four everyday items-kettles, crates, beverage containers, and T-shirts-radically changes the best material option for the three of them whose carbon footprints are close. This also raises trade-off questions such as: Are the 280 grams of greenhouse gas emissions saved by using a reusable plastic crate instead of a wood crate worth the 21 grams of additional MNP pollution?

Cardiothoracic transplantation is a lifesaving intervention for end-stage cardiopulmonary disease, however true recovery requires comprehensive social reintegration, including the opportunity for work participation. This systematic review (PROSPERO CRD42025634363) reports rates of work and characterises factors associated with working post-cardiothoracic transplant. Research questions were informed through consultation with the cardiothoracic transplant community and guided by a work and health perspective. Five databases (Ovid MEDLINE, Ovid Embase, CINAHL, Web of Science, PsycINFO) were searched for studies published 2000-2024. Quantitative and mixed-methods studies reporting post-transplant work outcomes were included. Screening, data extraction, and risk of bias assessment were conducted independently by two reviewers, with discrepancies resolved by consensus. Thirty-five manuscripts, representing 32 unique studies and 23,511 cardiothoracic transplant recipients (12,062 heart; 11,400 lung; 49 heart and lung), were included. Post-transplant employment rates at one year were 22-44% for heart and 28% for lung transplant recipients. At five years, 29.4-30% heart and 48% lung transplant recipients were employed. Return-to-work rates varied widely (heart 28-88%; lung 18-83%), with median time to return ranging from 5 to >31 months. Factors associated with higher work participation included pre-transplant employment, younger age, higher education, and male sex. Lower participation was associated with post-transplant complications, fatigue, and depression. Other work-related outcomes including work ability, absenteeism, and employer support were inconsistently reported. Methodological limitations were common, particularly reliance on self-reported, unvalidated work outcome measures and heterogeneous follow-up time points. Addressing modifiable determinants through targeted interventions is critical to improving work participation among cardiothoracic transplant recipients.

Many questions in plant pathology are of a causal nature. However, the formal framework of causal inference remains underutilized in the discipline. This review provides an accessible, higher-level introduction to causal concepts for agricultural researchers. The potential outcomes framework is introduced to define counterfactuals and directed acyclic graphs to visualize causal assumptions. We discuss the "gold standard" randomized controlled trial for estimating causal effects, with attention to agriculturally relevant contexts such as interplot interference and the estimation of heterogeneous treatment effects. The relevance and application of causal inference methods to observational data are also covered, in recognition of the growing role of this type of data. The limited but pioneering studies already applying these methods in plant pathology are highlighted.

Obesity is a global health challenge. An increasing number of patients with obesity are admitted to an intensive care unit. Airway management in these patients represents a unique challenge due to significant anatomical and physiological alterations. Increased adipose tissue in the face, cheeks, pharynx, hypopharynx, and neck narrows the upper airway, renders soft tissues more collapsible, and complicates airway management. In addition, the functional residual capacity is reduced, resulting in markedly shortened safe apnea time, contributing to severe hypoxemia during intubation. Non-invasive ventilation is effective in mitigating this risk and should be applied from pre-induction to laryngoscopy. Peri-intubation physiological optimization should include assessment of preload and cardiac contractility, with careful consideration of right ventricular strain. The transition from negative to positive intrathoracic pressure should be closely monitored, with cautious titration of positive end-expiratory pressure. Recognition of these anatomical and physiological challenges may prompt clinicians to consider awake intubation in selected patients. When rapid sequence induction is performed, both ketamine and etomidate are appropriate options; the choice between them should be guided by the clinical context, patient characteristics, local practice patterns and availability. Videolaryngoscopy increases the incidence of successful intubation on the first attempt and should be adopted routinely in the population with obesity. Several questions remain unanswered, including the safety and efficacy of pre-emptive vasopressor use to prevent post-intubation cardiovascular collapse and the optimal dosing of hypnotic agents to achieve ideal intubation conditions, while minimizing adverse events.

Obstructive sleep apnoea (OSA) is a common disorder associated with substantial morbidity. Although obesity is an important pathogenetic factor in OSA, the incorporation of weight loss into routine OSA care is currently limited. The development of glucagon-like peptide-1 (GLP-1) agonists has revolutionised obesity management and raises questions about the role of weight loss in OSA care. A debate was held at the 8th Sleep and Breathing Conference in April 2025 on whether weight loss should be first-line treatment for patients with OSA. Arguments in favour include the large and growing proportion of OSA attributable to excess weight, the effectiveness of modern weight-loss therapies in producing significant weight loss and the extent to which weight loss produces effects on clinical outcomes beyond OSA, such as the positive impact on cardiovascular and metabolic disease incidence and control. Conversely, arguments against include the fact that not all patients with OSA have obesity, the limited impact of weight loss on OSA resolution and the considerable data gap with obesity strategies in OSA including the lack of direct comparisons with CPAP on patient-centred outcomes and the impact on long-term health benefits in OSA patients specifically. Clearly, while more research is needed and treatment decisions should be personalised, clinicians need to gain competency with the use of novel weight-loss treatments as an essential part of OSA care.

Code-switching is common and effective among bilinguals. Studies have examined code-switching among undergraduate students, whereas code-switching among higher education students has been overlooked. Therefore, this study investigated classroom code-switching among postgraduate EFL students in Saudi Arabia. Quantitative data were collected using a questionnaire administered to 510 postgraduate students (men and women) majoring in literature, translation, theoretical linguistics, and applied linguistics. Questions examined cognitive and effectiveness attitudes toward, cognitive and social reasons for, and perceived benefits and challenges of code-switching. The results revealed that students had positive attitudes toward classroom code-switching and employed it for cognitive and social reasons. Although the students acknowledged the benefits of code-switching, some expressed concerns about its negative impact on English proficiency. Gender differences were observed, with men scoring significantly higher than women on both attitude and cognitive reasons. Academic majors significantly influenced all dimensions, with translation and theoretical linguistics students exhibiting higher positive perceptions than the other students. Code-switching served as a cognitive tool and social strategy. These results have implications for pedagogical practice, curriculum design, and language policies in higher education. This study contributes to the understanding of code-switching dynamics in advanced academic settings and highlights the need for further research across educational contexts.

To assess and compare the performance of four contemporary frontier large language models (LLMs)-GPT-5.2 (OpenAI), Gemini 3 Pro (Google DeepMind), Claude Sonnet 4.6 (Anthropic) and Grok 4.1 (xAI)-on a simulated Fellowship of The Royal College of Surgeons Urology (FRCS(Urol)) Part A examination, evaluating overall accuracy, subspecialty-level performance, output consistency and response time. Controlled comparative evaluation study using a standardised simulation framework with repeated independent testing runs per model. All models were accessed via their respective consumer-facing interfaces. No clinical setting or patient data were involved. Testing was conducted under uniform conditions with conversational memory disabled across all sessions. Four large language models were evaluated. No human participants were involved. Models were selected to represent the current frontier of publicly accessible LLMs from four distinct commercial developers. No models were excluded following selection. Each model was presented with 240 FRCS (Urol) Part A single best answer questions, mapped to the Joint Committee on Intercollegiate Examinations' Urology Syllabus Blueprint (2023). A standardised prompt was delivered at the start of each session. Each model completed five independent examination runs. No fine-tuning or system-level modification was applied to any model. The primary outcome was overall examination accuracy for each model, benchmarked against an indicative pass threshold for the FRCS (Urol) Part A examination. Secondary outcomes were performance across 18 individual urology subspecialty topics; response time reported as mean total and per-question elapsed time; and consistency of performance quantified by SD and 95% CIs derived from a sequential Monte Carlo sampling procedure. All outcomes were prospectively planned and fully measured as specified. Three of four models exceeded the indicative 74% pass threshold: Gemini 3 Pro (82.4%±0.9%; 95% CI 81.3 to 83.6%), Claude Sonnet 4.6 (79.3%±1.1%; 95% CI 77.9 to 80.6%) and GPT-5.2 (76.1%±2.4%; 95% CI 73.1 to 79.1%). Grok 4.1 failed (70.4%±0.6%; 95% CI 69.6 to 71.2%), with its entire CI below 74%. All models completed the assessment in under 3 min. Strong performance was observed in research methodology (90-98%) and andrology (92-98%), with the weakest results in paediatric urology (38.7-54.7%) and testicular cancer (48.2-67.3%). Substantial within-model output instability was identified across several domains, most notably GPT-5.2 in female urology (SD±22.8%) and anatomy (SD±14.2%). Three of four frontier LLMs achieved scores consistent with passing the FRCS (Urol) Part A examination, representing a substantial advance since ChatGPT-3.5. Aggregate accuracy alone, however, obscures important subspecialty weaknesses and output instability. LLMs should be regarded as adjunctive revision aids rather than authoritative knowledge sources and always used alongside expert-led teaching. Future work should evaluate performance on Part B and viva-style assessments.

Just over 125 years has passed since the 'filterable' agents of tobacco mosaic disease and foot-and-mouth disease were first described as infectious, replicating entities smaller than bacteria. Today, viruses are formally classified into more than 16,000 species ranked into genera, families and higher taxa. The development of an official virus taxonomy has been overseen by an International Committee, first constituted in 1966 and renamed as the International Committee on Taxonomy of Viruses (ICTV) in 1975. Despite the engagement of the ICTV in virus taxonomy over the last 60 years, many aspects of virus classification and nomenclature may seem odd or sometimes incomprehensible to virologists more familiar with the taxonomy of cellular organisms. Who runs the ICTV? What are virus species demarcation criteria? Why have all virus species names become binomial? How can a sequence in a metagenomic dataset be assigned to a virus species? This article attempts to answer several such questions and outlines how a large, inclusive and global community of virologists has developed new and responsive policies for virus taxonomy in a decade when the pace of virus discovery has dramatically accelerated.

Prostate cancer incidence in China is rising rapidly, yet health communication remains hindered by cultural stigma, low health literacy, and a lack of linguistically accessible materials. This study investigates how translation strategies prioritizing lay-friendliness and cultural relevance impact comprehension of prostate-specific antigen (PSA) screening benefits and risks among elderly Chinese males-a demographic underrepresented in health literacy research. We conducted a randomized controlled trial comparing two translated versions of PSA screening guidelines: a largely word-for-word translation (WWT, reflecting minimal adaptation for lay readers) and a lay-adapted translation (LAT) prioritizing readability, semantic clarity, and contextual adaptation for lay readers through systematic adaptation strategies. Participants (N = 82, aged 40-86) were stratified by age, education, and baseline prostate cancer knowledge (self-assessed). Validated comprehension questions assessed understanding of screening risks/benefits, with statistical analysis (Mann-Whitney U, Bonferroni correction) evaluating cohort-specific improvements. The LAT group showed significant improvements in comprehension versus WWT, particularly among males aged ≥ 57 (d = 1.035, p = 0.0027), those with education above Year 9 (d = 0.903, p = 0.0017), and participants with limited baseline knowledge (self-assessed) (d = 0.748, p = 0.0029). Key enhancements included familial risk narratives (e.g., "more relatives with cancer = earlier screening") and explicit clarifications (e.g., "false negative = misdiagnosis"). However, LAT had minimal impact on younger or highly educated cohorts, highlighting persistent health literacy disparities. Lay‑adapted translations that prioritize readability, terminological explicitation, and age‑appropriate examples significantly improve PSA screening comprehension for elderly, less‑educated Chinese males but require complementary strategies to address broader health‑literacy gaps. Rather than claiming full cultural adaptation, we treat these adaptations as purpose‑driven, text‑level strategies that modestly enhance comprehension for specific low‑literacy populations.

Marine bacteria display diverse lifestyles, many of which are shaped by close associations with microalgal partners. In the photic zone, where microalgae fix carbon through photosynthesis, bacteria consume algal-derived organic matter and often exhibit growth patterns that mirror algal activity and abundance. These interactions expose bacteria to strong fluctuations, with bursts of algal exudates during high productivity alternating with periods of scarcity. To cope, algal-associated bacteria have evolved strategies that balance rapid growth with the ability to endure starvation. This review highlights current knowledge and open questions in the physiology of algal-associated bacteria across three stages: the growth phase, supported by algal resources; the starvation phase, marked by storage strategies and a regulated decrease in cellular functions; and the transitions between these states, shaped by algal cues and corresponding bacterial responses. I hope this synthesis of our current understanding and the challenges ahead will inspire broader recognition of the importance and excitement of studying bacterial physiology in an environmental context.

Spatial cues and cell-cell interactions within in vivo tissue architecture generate physical signals that regulate cell behavior. These mechanical interactions drive processes such as morphogenesis, homeostasis, regeneration and disease progression. To recapitulate these spatial niches in vitro, lithographic micropatterning allows for precise control over the geometry, composition, topography and mechanics of cell-adhesive substrates. Micropatterned cultures have been essential in uncovering key mechanotransduction mechanisms, including YAP/TAZ-mediated signaling, mechanoregulation in cancer, aging and early embryonic development. However, accessible and adaptable micropatterning protocols for conventional cell biology laboratories remain limited. In this protocol, we present a comprehensive procedure for generating flexible, high-resolution micropatterns (down to 10 × 10 µm2), optimized for high-magnification confocal imaging, long-term cell culture, customizable functionalization (proteins, peptides or both) and extended shelf life. This versatile and convenient procedure can be performed by trained PhD students or postdoctoral researchers, does not require prior expertise in photolithography and can be completed within 2 d. In addition, we provide a step-by-step guide to study mechanotransduction using YAP/TAZ functional readouts that can be completed within 5 d. This protocol offers an affordable and scalable solution applicable to a wide range of biological questions, allowing for diverse experimental needs, and represents a valuable tool for advancing mechanobiology and other areas of cell biology.

Healthcare artificial intelligence (AI) has moved beyond answering medical questions. In early 2026, OpenAI, Anthropic, and Google launched agentic systems that retrieve evidence, use tools, and execute multi-step workflows. These systems can integrate information across multiple clinical knowledge domains within a single workflow, but the evidence base for evaluating their reliability in clinical practice has not kept pace with deployment. This perspective argues that healthcare is adopting a technology evolving faster than anyone can evaluate, and that a brief window exists to shape integration before the architecture becomes entrenched. These systems share common architectural principles, yet only 19 prospective trials exist among over 4,600 clinical large language model studies, none evaluating agentic pipelines. The architecture is locking in, professional roles are being redefined, and builders hold a structural information advantage. Transparency, adaptive governance, and broader participation are needed before these choices become irreversible, and to ensure that the boundary between human clinical judgment and automated capability is drawn in a way that strengthens both. Every stakeholder in healthcare must engage with this shift now.

Yersinopine, a nicotianamine-like metallophore, was recently identified through biochemical analyses, but its in vivo production and functional role remain uncharacterized. In Yersinia pseudotuberculosis and its recent descendant Yersinia pestis, the cnt operon (cntPQRLMI) putatively encodes the biosynthesis and transport of yersinopine. In Y. pestis, however, two frameshift mutations disrupt cntQ, which encodes the predicted permease for yersinopine-metal complexes. This pseudogenization raises critical questions about the functional relevance of yersinopine in these closely related species. Here, we show that cnt operon expression is repressed by the zinc uptake regulator Zur and that both Y. pestis and Y. pseudotuberculosis secrete yersinopine under zinc-limited conditions. Unexpectedly, the operon mediates iron uptake in Y. pseudotuberculosis but supports zinc acquisition in Y. pestis. Moreover, targeted disruption of cntQ in Y. pseudotuberculosis shifts metal specificity from iron to zinc, mimicking the Y. pestis phenotype. Collectively, our results suggest that a single pseudogenization event could rewire metal uptake specificity. Our findings illustrate how evolutionary genome reduction can reshape bacterial physiology.