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Life expectancy is increasing globally, but if people are to age healthily, they must do so with fewer limitations in their daily activities. However, information on either the frequency or risk factors for limitations to walking ability or other key activities across different regions of the world is limited. Our aim was to describe the incidence, trajectories, risk factors, and population-attributable fraction of new-onset walking limitations in 25 countries at all socioeconomic levels. PURE is an ongoing, prospective cohort study. The current analysis included community-dwelling participants who lived in four high-income countries (HICs), 16 middle-income countries (MICs), and five low-income countries (LICs). Individuals aged 35-70 years at baseline who completed a baseline questionnaire about activity limitations between Jan 12, 2001, and May 6, 2019, were included in our analysis. The activity limitation screen included questions on self-reported difficulty with walking, grasping, bending, seeing close-up, seeing distance, and hearing. The primary outcome was incident walking limitation and our analytic sample comprised those with no walking limitation at baseline. We estimated the incidence rates, adjusted for age and sex, per 100 person-years in the overall PURE population, by country income level (and separately for China) and sex. We used multistate modelling to evaluate trajectories across the life course, analysed across continuous age, through three distinct sequential states: no limitation, walking limitation, and death. We used survival models to evaluate the associations of socioeconomic status, vascular and behavioural factors, community walkability, and incident adverse events, with incident walking limitations. We then calculated the population-attributable fraction of selected modifiable factors and compared the risk factors for walking limitation and mortality. 172 889 people from the PURE cohort answered questions on walking limitations at baseline, 150 221 of whom reported no walking limitation and were included in the multistate model. Of these 150 221 individuals, 122 538 had at least one follow-up assessment with walking limitations data (mean age at baseline 49·7 years [SD 9·5]; 71 424 [58·3%] female and 51 114 [41·7%] male). Mean follow-up was 14·5 years (SD 3·3). Incidence of a new walking limitation per 100 person-years was higher in LICs (3·34 [95% CI 3·27-3·41]), and lowest in China (0·58 [0·56-0·60]), compared with other MICs (1·80 [1·77-1·84]) and HICs (1·31 [1·27-1·37]). The incidence of walking limitation was higher in female participants (1·84 [1·81-1·87]) than in male participants (1·25 [1·22-1·28]). In multistate models, state transitions from no walking limitation to walking limitation and death occurred at a higher rate and earlier in LICs, where the age at which the probability of transitioning to a walking limitation was reached by an estimated one-third of people at 64 years compared with age 76 years in HICs. Female participants had a higher probability of incident walking limitation across the age spectrum compared with male participants. Many socioeconomic, vascular, and behavioural risk factors, community walkability, and incident adverse events, especially incident stroke, were associated with incident walking limitations. The population-level risk factors with the highest population-attributable fractions for walking limitation were low education (11·1% [95% CI 9·9-12·4]), obesity (5·2% [4·7-5·8]), hypertension (3·6% [2·2-5·0]), and low recreational physical activity (4·3% [2·3-6·3]), with obesity being the highest in HICs (12·9% [11·2-14·6]) and low education being the highest elsewhere. Potentially modifiable individual-level risk factors explained approximately 32·9% of the population's risk of walking limitations and approximately 47·4% of mortality, and four of the top five factors were shared for both outcomes (low education, low recreational activity, poor diet, and hypertension). Individuals in LICs had an accelerated transition to walking limitation, which was approximately 12 years earlier than those in HICs. Walking limitation and mortality shared a common set of modifiable risk factors, accounting for almost one-third of the population-level risk of walking limitations and highlighting opportunities for integrated prevention strategies in mid-life that simultaneously target disability and premature mortality across socioeconomic settings. Funding sources are listed at the end of the Article.

To conduct a bibliometric analysis of the literature on C-shaped canal systems in mandibular second molars (MSMs) and to review key research themes and evolving trends. A comprehensive search of the Web of Science Core Collection (WoS-CC) was conducted for publications through 31 December 2024. Following study selection and data extraction, bibliometric data such as publication years, authors, citation counts, institutions, countries/regions, journals, and keywords were analyzed using VOSviewer, CiteSpace, SPSS, and Microsoft Excel. A related review was also performed to synthesize key research themes and evolving trends. 166 publications from 1979 to 2024 met the inclusion criteria, with 50.6% published within the past 5 years. The most cited article received 239 citations. Research originated from 52 countries/regions, with China contributing the largest number of publications (n=34), followed by the United States (n=26). Wuhan University, the University of Hong Kong, and Texas A&M University were the leading institutional contributors. Journal of Endodontics (JOE) published the most articles (n=38), while International Endodontic Journal (IEJ) accumulated the highest total citations (n=1 666). James L. Gutmann was the most prolific author (n=12), and Bing Fan was the most cited (n=577). Keyword co-occurrence analysis revealed "C-shaped canal" and "cone-beam computed tomography" as the most frequent terms, while "deep learning" demonstrated a recent and marked citation burst. This study provides an overview of influential studies on C-shaped canal systems in MSMs and identifies key research themes and evolving trends, serving as a reference for future research and clinical practice.

Gastrocnemius flap coverage is a widely used technique for soft-tissue reconstruction in complex revision total knee arthroplasty (rTKA) for periprosthetic joint infection (PJI). However, clinical outcomes following one-stage and two-stage revision strategies in this context are poorly defined. The purpose of this meta-analysis was to synthesize, critically appraise, systematically review and compare reinfection rates and complication profiles between one- and two-stage septic rTKA for PJI using a gastrocnemius flap for reconstruction. A systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. MEDLINE, Embase, Cochrane Library and Web of Science were searched from inception to 6 April 2025 for studies on patients undergoing rTKA for PJI with soft tissue reconstruction using a gastrocnemius flap. Outcomes of interest included reinfection rates, any complications and flap-related complications. A pooled meta-analysis at group level was performed to compare interventions. There were 11 studies reporting on 271 rTKAs involving gastrocnemius flap reconstruction for PJI that met inclusion criteria. Of these, 56 were one-stage rTKAs, while 215 were two-stage rTKAs. PJI eradication rate was 66.1% in the one-stage group versus 54.4% in the two-stage group. There were no statistically significant differences between groups for reinfection (odds ratio [OR]: 0.61; 95% confidence interval [CI]: 0.33-1.13; p = 0.12), any complications (OR: 1.59; 95% CI: 0.71-3.54; p = 0.26) or flap-related complications (OR: 1.03; 95% CI: 0.43-2.47; p = 0.94). It was found that one-stage and two-stage rTKA using a gastrocnemius flap showed comparable rates of reinfection, any complication and flap-related complication with the data available for this meta-analysis. Findings suggest that one-stage revision may be a viable treatment option for suitable patients. However, higher-quality studies are warranted to identify potential true differences within this high-risk group. Level IV.

Late presentation of ovarian cancer continues to pose a major challenge, as the disease typically manifests with vague and misattributed symptoms. Public awareness initiatives have sought to address this through the use of succinct, symptom-based messaging. The BEAT acronym - Bloating, Eating difficulties, Abdominal pain, Toilet changes - has been developed as a public health tool to promote symptom recognition and timely action in ovarian cancer. Its origins are considered in the context of health communication strategies that also employ acronym-based tools, with lessons drawn from the success of the FAST campaign for stroke awareness. International and national approaches to ovarian cancer awareness, including community partnerships, social media campaigns, and visual public engagement, are also discussed herein. Such initiatives reveal the considerable reach and engagement possible through coordinated awareness campaigns, emphasising their potential to catalyse earlier presentation and diagnosis in ovarian cancer.

The extracellular matrix (ECM) critically regulates tumour cell adhesion, mechanotransduction and therapeutic response, yet there is a lack of in vitro models that faithfully reproduce ECM-integrin signalling while remaining compatible with histological and molecular workflows. Here, we present a biomimetic hydrogel platform based on gelatin-tyramine and silk fibroin, engineered to recreate defined vitronectin microenvironments and integrin-targeting conditions, including pharmacological inhibition with the αvβ3-integrin antagonist cilengitide. The platform enables control over matrix composition and bioactivity while preserving tissue-like architecture. We establish robust protocols for hydrogel synthesis under distinct vitronectin conditions, cell embedding, pharmacological treatment and downstream processing, including genomic DNA isolation. In addition, the platform supports standard histological processing and immunostaining, enabling digital pathology-based assessment of morphological features, vitronectin expression patterns, and adhesion-related markers such as vinculin and β3 integrin. Importantly, the system enables recovery of viable cells, allowing subsequent orthotopic implantation in vivo. Together, these workflows provide a reproducible and scalable framework to investigate ECM-mediated regulation of neuroblastoma cell behaviour and drug response, with scope for quantitative image analysis of integrin-associated signals and ECM deposition. This ECM-mimetic hydrogel system offers a versatile and histology-compatible experimental platform for studying integrin-dependent tumour-matrix interactions and developing physiologically relevant in vitro-in vivo translational pipelines.

The World Health Organization recommends the use of balanced energy protein (BEP) supplements during pregnancy in settings with a ≥ 20% prevalence of underweight women of reproductive age to reduce the risk of adverse health outcomes. Several countries are implementing BEP supplementation in varied formats. However, the implementation and monitoring of outcomes remain poor across countries. This qualitative study explores the experiences, opportunities, and challenges related to implementing national and sub-national BEP supplementation programs in nine countries (12 countries originally invited) to inform best practices. Semi-structured interviews were conducted with 15 personnel involved in its implementation in Haiti, India, Malawi, Mexico, Nigeria, Pakistan, Rwanda, Senegal, and Sri Lanka between October 2024 and March 2025. The interviewees in each country were predominantly implementation experts but also government officials involved in the provision of BEP supplementation. The transcripts were analyzed thematically, focusing on acceptability, adoption, appropriateness, cost, feasibility, and sustainability of outcomes. In non-humanitarian settings (five countries), BEP supplementation was commonly integrated into the governmental health system or social protection programs. However, humanitarian contexts (four countries) often relied on partner-led (e.g., UN organizations) implementation. Clear operational protocols, including behavioral change communication strategies, facilitated the implementation. Community-based organization partnerships strengthened adherence; however, implementation costs, stock shortages, and geographic inequities in coverage varied and were limiting factors in scale-up, primarily in humanitarian contexts. In sum, two distinct implementation pathways emerged: government-led models characterized by policy integration, national ownership, and more stable systems, and humanitarian or donor-led models shaped by crisis response, external dependency, and non-committal challenges. Successful implementation of BEP supplements depends on the presence of effective policies, context-adapted design, integration into health systems, consistent funding, and effective monitoring. There is a need for implementation research to generate evidence on best practices when implementing BEP supplementation programs.

Here, we present EMQN Best Practice Guidelines for Genetic Testing and Reporting in RYR1-related disorders. They aim is to aid clinical genetic laboratories in testing, and unequivocal and comprehensive reporting of RYR1 variants for the benefit of patients and their relatives. These guidelines are supported by experts in the field of anaesthesia, (paediatric) neurology, clinical genetics and clinical laboratory genetics. The ryanodine receptor type 1 is a large calcium channel that regulates calcium release from the sarcoplasmic reticulum resulting in muscle contraction. This receptor is encoded by the RYR1 gene and expressed predominantly in skeletal muscle. Pathogenic RYR1 variants are associated with several allelic disorders: malignant hyperthermia, a hypermetabolic reaction to certain anaesthetics in otherwise healthy individuals, exertional rhabdomyolysis and both autosomal dominant and recessive congenital myopathies. In general, RYR1 gain-of-function variants are associated with malignant hyperthermia susceptibility, whereas dominant-negative and loss-of-function variants are associated with dominant and recessive myopathies, respectively. However, a small subset of RYR1 variants is associated with a combination of dominant malignant hyperthermia susceptibility with either a dominant or a recessive myopathy or exertional rhabdomyolysis. The apparent discrepancy between molecular mechanisms and different phenotypes is currently poorly understood. As a consequence, the context-dependent interpretation of RYR1 variants is challenging in diagnostic genetic testing. In particular, it is not trivial to assign a possible associated risk for an allelic disorder for an individual or their relatives, which is especially relevant in family planning.

Randomised controlled trials (RCTs) underpin surgical practice, but external validity depends on transparent reporting of participant characteristics. In gastrointestinal (GI) cancer surgery, socio-demographic factors influence outcomes, yet the extent to which these are reported in surgical RCTs remains unclear. This review evaluated reporting of baseline characteristics and equality, diversity, and inclusion (EDI) considerations in contemporary trials. Systematic searches of MEDLINE, EMBASE, and CENTRAL identified RCTs of surgical interventions for GI malignancies published in journals with an impact factor ≥7.5. Two reviewers independently screened studies and extracted data. Reporting of eligibility criteria, baseline characteristics, and equality, diversity, and inclusion (EDI)-related statements was narratively synthesised. Thirty-two RCTs including 9370 patients were analysed. Age and sex were reported in 93.8% of trials, and body mass index in 65.6%. No trial reported disability status, pregnancy status, ethnicity, socioeconomic status, or sexual orientation. Exclusions relating to older adults (≥80 years) and pregnancy were common, but explanations were infrequently reported. Only 40.6% of trials discussed generalisability. Reporting of participant characteristics in GI cancer surgery RCTs remains limited. Despite journal-level EDI guidance, demographic reporting beyond age and sex is uncommon, constraining assessment of external validity.

We developed a continuous prognostic monitoring tool to predict recovery from disorders of consciousness (DoC) following acute brain injury (ABI), utilizing resting-state EEG recorded during routine clinical care. Predictive models updating every 5 min were developed using serial neurologic assessments and continuous resting-state EEG to predict future consciousness level at 24-, 48-, and 72-hour time horizons. An ensemble of CatBoost classifiers was utilized for multi-class DoC grade prediction, leveraging a comprehensive set of 242 computed EEG features encoding time, frequency, and time-frequency characteristics. Conventional and confound-isolating cross-validation mitigated biases and increased robustness. Performance was compared across multiple ordinal DoC grade cut-points and time horizons. 201 patients met inclusion criteria. Models incorporating EEG outperformed behavioral assessments alone, achieving a mean one-vs-rest AUROC of 0.88-0.89 (EEG + GCS) across 24-72-hour horizons and various trichotomized cut-points, with 95% bootstrap confidence intervals. The most robust features included global field power, theta-band (4-8 Hz) bandpower, beta-band (13-30 Hz) phase-locking value, and spectral entropy. EEG-augmented models enabled continuous prediction of future DoC grade after ABI. Combining EEG with other serial measures during routine clinical care creates a novel paradigm for improved shared decision-making through continuous prognostic monitoring and serial assessment.

To investigate perceived rehabilitation needs and service utilisation amongst people living with and beyond cancer in a large Comprehensive Cancer Centre in Ireland and examine associations between impairment and demographic and clinical parameters. Utilising a prospective, observational design, a consecutive sample of participants attending outpatient clinics was enrolled in June and July 2025. Demographic data, clinical data, and use of allied health professional (AHP) cancer rehabilitation services were self-reported. Unmet needs were captured using the Macmillan Holistic Needs Assessment. Data were analysed using descriptive statistics and multivariate regression models. In total, 660 surveys were analysed. Most participants were female (58.2%) and aged between 56 and 75 years (54%). Haematological cancers (25.6%) and breast cancers (22.9%) were the two largest cohorts, and most patients (57%) were currently on treatment. Prevalence of AHP cancer rehabilitation needs was considerable with an average of 71% of patients reporting at least one specialist need and 49% reporting at least two specialist needs across professions. On treatment status was consistently associated with greater odds of patients reporting specialised needs. However, only 36% of patients with perceived needs reported seeing a relevant AHP since their diagnosis. Results confirm that patient-reported rehabilitation needs are significant across the cancer trajectory, however utilisation of cancer rehabilitation AHPs is suboptimal. Strategic development of the cancer rehabilitation AHP workforce and service models is required to mitigate the impact of cancer and its treatment on functional, nutritional, and psychosocial patient outcomes, and optimise health-related quality of life.

Cancer cachexia is a multifactorial syndrome characterized by involuntary loss of skeletal muscle and adipose tissue that is often resistant to nutritional support. The branched-chain amino acids (BCAA: leucine, isoleucine, and valine) stimulate protein synthesis, yet BCAA-targeted therapies have yielded limited clinical benefit and inconsistent results. This might be related to altered metabolism of BCAA in cachexia. In this study, a C26 tumor allograft mouse model was used to examine how tumor burden alters BCAA metabolism across tumor tissue, liver, kidney, adipose tissue and skeletal muscle. Tumor tissue at 4 weeks exhibited higher BCAA levels and elevated branched-chain α-ketoacid dehydrogenase (BCKD) activity compared to samples collected at 2 weeks. At 4 weeks, skeletal muscles from tumor-bearing mice showed reduced BCAA concentrations relative to control. In contrast, liver and adipose tissue did not demonstrate uniform reductions in BCAA content, indicating tissue-specific metabolic responses. Multiple peripheral tissues also displayed lower expression of the L-type amino acid transporter 1 (LAT1) and alterations in downstream mechanistic target of rapamycin complex 1 (mTORC1) signaling. Notably, the soleus muscle maintained elevated phosphorylated S6 (P-S6) levels despite reduced BCAA availability, suggesting muscle-specific adaptations. These findings demonstrate distinct tumor and peripheral tissue alterations in BCAA handling in C26 tumor bearing mice. The observed changes in BCAA metabolism may underlie the limited success of BCAA-based interventions in cachexia and highlight the need for therapies that address both tumor and host metabolism.

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Within cells, across diverse organisms, macromolecular condensation enables spatial and temporal organization of biochemical reactions by organizing proteins and nucleic acids into compositionally distinct membraneless biomolecular condensates. In the gut bacterium Bacteroides thetaiotaomicron, condensate formation by the transcription termination factor Rho (BtRho) increases its termination activity and promotes B. thetaiotaomicron fitness in the mammalian gut. Here, we elucidate the molecular mechanism governing carbon starvation-induced BtRho phase separation. We establish that short, specific amino acid sequences within BtRho's intrinsically disordered region (IDR) control BtRho condensation via complex coacervation. The identified sequences participate in RNA and intra-IDR regulatory interactions that drive condensate formation in vitro and in vivo. We also report that the signaling molecule ppGpp is essential for BtRho phase separation in vivo, binds to purified BtRho in an IDR-dependent manner, and promotes RNA-dependent BtRho condensation in vitro. Our findings demonstrate how specific short sequences within an IDR dictate phase separation in response to nutritional cues.

A hot and dense state of nuclear matter, known as the quark-gluon plasma, is created in collisions of ultrarelativistic heavy nuclei. Highly energetic quarks and gluons, collectively referred to as partons, lose energy as they travel through this matter, leading to suppressed production of particles with large transverse momenta (p_{T}). Conversely, high-p_{T} particle suppression has not been seen in proton-lead collisions, raising questions regarding the minimum system size required to observe parton energy loss. Oxygen-oxygen (OO) collisions examine a region of effective system size that lies between these two extreme cases. The CMS detector at the CERN LHC has been used to quantify charged-particle production in inclusive OO collisions for the first time via measurements of the nuclear modification factor (R_{AA}). The R_{AA} is derived by comparing particle production to expectations based on proton-proton (pp) data and has a value of unity in the absence of nuclear effects. The data for OO and pp collisions at a nucleon-nucleon center-of-mass energy sqrt[s_{NN}]=5.36  TeV correspond to integrated luminosities of 6.1  nb^{-1} and 1.02  pb^{-1}, respectively. The R_{AA} is below unity with a minimum of 0.69±0.04 around p_{T}=6  GeV. The data exhibit better agreement with theoretical models incorporating parton energy loss as compared to baseline models without energy loss.

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Acute disturbances caused by changing environmental conditions are increasingly affecting the structure and function of coral reef ecosystems. Notably, changing rainfall patterns are leading to increasing incidence of hyposalinity. This study explored interannual changes in the overall cover and composition of hard corals (order Scleractinia) in Pioneer Bay, Orpheus Island, which was subject to hyposalinity during unprecedented high rainfall in February 2025. Hard coral cover declined 66.60%, from 41.66% (±1.22 SE) in September 2024 to 13.92% (±0.92 SE) in October 2025, with coral loss mostly apparent on the reef flat and reef crest. Coral loss was not equally apportioned among different coral taxa (genera), possibly reflecting differential susceptibility to hyposalinity based on specific physiology and habitat associations. The most pronounced declines were recorded among Merulinidae, which were the predominant hard corals on the reef flat in 2024. Soft corals were similarly affected and exhibited major declines in abundance on the reef flat. Hyposalinity is rarely considered among the suite of climatic disturbances that impact on coral assemblages and reef ecosystems, but this research shows that the potential ecological effects are very extensive, adding to the diversity of acute disturbances that will influence the structure coral reef ecosystems in the Anthropocene.

The soil dwelling bacteriaStreptomycesis a prolific producer of bioactive natural products (NPs). The sophisticated cellular machinery required to produce NPs is frequently regulated by quorum-sensing systems, consisting of cluster situated regulators (CSRs), such as TetR-like repressors, and small-molecule autoregulator (AR) ligands. Only a small fraction of bioinformatically predicted quorum-sensing AR circuits have been experimentally determined, and fewer have been engineered as inducible expression systems for synthetic biology. This research details the development of eight CSR-based AR biosensors and the synthetic routes to their AR ligands. Overall, the AR biosensors exhibit a range of maximum activation (101-103 fold), AR affinity (0.03-111 μM), and AR selectivity. We examined crosstalk between noncognate CSRs and ARs, as well as the ability of CSRs to regulate alternative operators. Additionally, we established that these Escherichia coli chassis biosensors can be cocultured with Streptomyces for rapid analysis of AR production. Finally, we demonstrate that the AR biosensors can be combined to create 12 orthogonal signaling systems in E. coli coculturing or multi-input genetic circuits. In the long term, these AR biosensors will contribute to the elucidation of small molecule quorum sensing employed by Streptomyces for NP regulation. Additionally, these autoregulator-based biosensors provide ultrasensitive, robust-output platforms that can be adapted for quorum-sensing-regulated genetic circuits.

Olfactory dysfunction is a hallmark feature of COVID-19, yet the potential for recovery with long-standing COVID-19-related smell loss (CRSL) remains uncertain, particularly when treatment is initiated years later. This study evaluated olfactory outcomes in patients with CRSL compared with non-COVID-19-related smell loss (non-CRSL), with emphasis on delayed treatment initiation. This retrospective cohort study included 104 patients evaluated at a tertiary clinic between January 2023 and February 2025, comprising 47 patients with CRSL and 57 with non-CRSL. All patients completed serial Sniffin' Sticks testing (threshold, discrimination, and identification [TDI]) at &#x2265;2 visits. Minimal clinically important difference (MCID) was defined as a &#x2265;5.5-point increase in TDI score. All patients received olfactory training combined with twice-daily steroid nasal irrigation. Subgroup analyses examined delayed treatment initiation (>2 years), treatment adherence, and COVID-19 vaccination status. Baseline TDI scores were higher in the CRSL group than in the non-CRSL group (19.6&#xa0;&#xb1;&#xa0;6.3 vs. 16.8&#xa0;&#xb1;&#xa0;6.8; p&#xa0;<&#xa0;0.05). The CRSL group demonstrated significant improvement in TDI scores at follow-up (19.6&#xa0;&#xb1;&#xa0;6.3 to 23.9&#xa0;&#xb1;&#xa0;6.5; p&#xa0;<&#xa0;0.001), with 46% achieving MCID, whereas the non-CRSL group showed no significant change. Among CRSL patients initiating therapy >2 years after onset (n&#xa0;=&#xa0;36; mean 30.8&#xa0;&#xb1;&#xa0;5.5 months), 50% achieved MCID. Treatment adherence was strongly associated with improvement, whereas COVID-19 vaccination showed a favorable but attenuated association after adjustment. Clinically meaningful olfactory recovery remains achievable with long-standing CRSL, even when treatment is initiated >2 years after onset. Prospective studies are needed to clarify causal relationships given known spontaneous recovery in post-viral olfactory dysfunction.