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Diversity in CDK structural mechanisms of regulation and drug discovery opportunities
Full text link\ua9 2025 The Author(s)Cyclin-dependent kinases (CDKs) are required for progression through the eukaryotic cell cycle and for gene transcription. The recent determination of structures of CDK-containing complexes by cryogenic electron microscopy has significantly enriched our understanding of the diverse mechanisms by which CDKs can be activated and regulated. Recent studies have also highlighted the importance of short linear motifs within CDK substrates and regulators to CDK activity. Aberrant CDK activity is a hallmark of a number of diseases, including cancers, and selective ATP-competitive inhibitors are in clinical use. Herein, we review recent structural insights into CDK activation and regulation and how these insights suggest alternative ways to modulate CDK activity that may lead to molecules with improved selectivity and/or specificity
An adaptive dual-graph spatial–temporal convolutional network with edge-aware fusion for elderly gait recognition using Kinect-based skeleton data
No full text\ua9 2026 Elsevier Ltd. The accurate recognition of elderly gait patterns can significantly contribute to clinical applications such as elderly health monitoring and fall risk prediction. However, how to develop a high-generalization elderly gait classification model has become a challenging problem in elderly gait quantization analysis. Considering the interaction coupling changes across joints in the kinetic chains of elderly gait, we propose an advanced adaptive edge-aware dual-graph convolutional network (AEDGCN) for high-accuracy elderly gait recognition. Our model integrates a gait-graph and a gait-hypergraph to capture high-order joint interaction coupling, which reflects subtle differences in elderly gait changes. By modeling these fine-grained spatial–temporal dependencies, the proposed model achieves strong generalization in accurately identifying elderly gait patterns. Specifically, the proposed technique employs an Edge-Aware Mechanism (EAM) to simultaneously model local spatial dependencies between joints from the gait-graph and cross-joint correlations from the gait-hypergraph. Additionally, the Hierarchical Deep Fully Convolution (HDFC) module is designed to enhance the modeling of temporal dependencies across multiple scales. Our Kinect-based gait dataset, comprising 45 healthy younger participants and 34 healthy elderly participants, with three walking patterns, is used to evaluate the feasibility of our method. In addition, experiments on the public KINECAL dataset further demonstrate the generalization capability of the proposed model. The experimental results confirm that our model outperforms state-of-the-art methods while keeping a low learning complexity. The proposed method effectively enables modeling of elderly gait dynamics, providing informative feature representations for understanding age-related locomotion changes and supporting downstream clinical assessment
Specialist PrE-hospital rEDirection for ischaemic stroke thrombectomY (SPEEDY): study protocol for a cluster randomised controlled trial with included health economic and process evaluations
Full text link\ua9 Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY. Published by BMJ Group. BACKGROUND: Outcome from large vessel occlusion stroke can be significantly improved by time-critical thrombectomy but treatment is only available in regional comprehensive stroke centres (CSCs). Many patients are first admitted to a local primary stroke centre (PSC) and require transfer to a CSC, which delays treatment and decreases the chance of a good outcome. Access to thrombectomy might be improved if eligible patients could be identified in the prehospital setting and selectively redirected to a CSC. This study is evaluating a new specialist prehospital redirection pathway intended to facilitate access to thrombectomy. METHODS AND ANALYSIS: This study is a multicentre cluster randomised controlled trial with included health economic and process evaluations. Clusters are ambulance stations (or teams) which are work bases for ambulance practitioners. Intervention allocated ambulance practitioners use the Specialist PrE-hospital rEDirection for ischaemic stroke thrombectomY (\u27SPEEDY\u27) pathway which comprises initiation according to specific criteria followed by contact with CSC staff who undertake a remote assessment to select patients for direct CSC admission. Control allocated ambulance practitioners continue to provide standard care which comprises admission to a local PSC and transfer to a CSC for thrombectomy if required. A co-primary outcome of thrombectomy treatment rate and time from stroke symptom onset to thrombectomy treatment will evaluate the impact of the pathway. Secondary outcomes include key aspects of emergency care including prehospital/hospital time intervals, receipt of other treatments including thrombolysis, and performance characteristics of the pathway. A broad population of all ambulance practitioner suspected and confirmed stroke patients across participating regions is being enrolled with a consent waiver. Data about SPEEDY pathway delivery are captured onto a study case record form, but all other data are obtained from routine healthcare records. Powered on a \u27primary analysis population\u27 (ischaemic stroke patients with pathway initiation criteria), 894 participants will detect an 8.4% difference in rate and data from 564 thrombectomy procedures will detect a 30 minute difference in time to treatment. The full study population is estimated to be approximately 80 000. Regression modelling will be used to examine primary and secondary outcomes in several analysis populations. The economic analyses will include cost-effectiveness and cost-utility analyses, and calculation of willingness to pay at a range of accepted threshold values. The process evaluation involves semi-structured interviews with professionals and patient/family members to explore views and experiences about the SPEEDY pathway. ETHICS AND DISSEMINATION: This study has ethical, Health Research Authority and participating NHS Trust approvals.Dissemination of study results will include presentations at national and international conferences and events, publication in peer-reviewed journals, and plain English summaries for patient/public engagement activities. TRIAL REGISTRATION NUMBER: ISRCTN77453332
Comment on “Nivolumab plus ipilimumab for potentially resectable hepatocellular carcinoma: Long-term efficacy and biomarker exploration”
No full textScreening for brain-related comorbidities in Duchenne muscular dystrophy: Construction, reliability, and validity of the BIND screener
Full text link\ua9 2026 The Author(s). Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.Aim: To develop a brief, reliable, and valid screening tool and to provide normative data for the identification of individuals with Duchenne muscular dystrophy (DMD) at risk of brain-related comorbidities. Method: An 18-item proxy/self-report screening tool covering nine comorbidity areas was developed on the basis of existing literature and expert consensus, and translated into 11 languages. In this cross-sectional observational study, data from 835 individuals with DMD (aged 5–42 years) were used to assess reliability, construct validity, and diagnostic accuracy. A subsample of 90 participants completed cognitive and behavioural assessments for concurrent validity analyses. Results: The Brain Involvement iN Dystrophinopathies (BIND) screener showed excellent internal consistency (α = 0.89) and a factor structure aligned with theoretical domains. Age-related patterns were observed across domains. The total score (Duchenne Brain Comorbidity Score) correlated with clinical and cognitive markers in the validation subsample. Receiver operating characteristic analysis in the full sample yielded an area under the curve of 0.78, with a cut-off score of 20/72 providing optimal sensitivity (71.6%) and specificity (72.5%) for identifying parent- or self-reported neurodevelopmental conditions previously diagnosed by professionals. Interpretation: The BIND screener is a brief, psychometrically robust tool that facilitates early identification of brain-related comorbidities in DMD and may be applied in both clinical practice and research
Distributionally Robust Chance-Constrained Unit Commitment for Power Systems Considering Wind Power Curtailment and Load Shedding Levels
No full textWith increasing wind power penetration, the inherent uncertainty of wind power poses significant challenges to dispatch decisions in power systems. To address this issue, this paper proposes a two-stage distributionally robust chance-constrained (TDRC) model for the unit commitment problem with wind power uncertainty. In this model, an ambiguity confidence set is developed to characterise wind power uncertainty with unknown probability distributions, and wind power curtailment and load shedding levels are modelled as chance constraints to balance wind power uncertainty and system security of dispatch decisions. A hybrid parallel solution (HPS) is proposed for efficient computation by integrating Benders decomposition (BD) and column-and-constraint generation (C&CG) methods. Case studies on the IEEE 24- and 118-bus systems demonstrate the rationality of the proposed approach, while experiments on a practical 126-bus system using the cyber-physical power system (CPPS) dispatch platform further validate the effectiveness and practical applicability of the proposed TDRC model
Population attributable fractions of a wide range of peripheral diseases for the burden of dementia
No full text\ua9 The Author(s), under exclusive licence to Springer Nature Limited 2026. Growing evidence suggests that peripheral diseases serve as risk factors for dementia, but the population-level burden of dementia associated with various peripheral diseases has remained unknown. Here, by conducting a systematic review and Bayesian meta-analyses to estimate the relative risks of 26 peripheral diseases across 9 systems with dementia, including 202 articles searched from the PubMed until 6 September 2024, we identified 16 peripheral diseases as associated with increased risk of dementia. With the relative risks estimated from meta-analyses, prevalences extracted from the Global Burden of Disease Study, and communalities among these 16 peripheral diseases derived from the UK Biobank, we analysed the population attributable fractions (PAFs) of these 16 peripheral diseases for dementia, stratified by sex, age, sociodemographic index level, world region and country, and trends from 1990 to 2021. Globally, these peripheral diseases collectively were related to a combined PAF of 33.18% (95% confidence interval (CI) 16.80–48.43) of dementia burden, corresponding to 18.8 million prevalent cases. The leading ten PAF contributors were periodontal diseases (6.10%, 95% CI 0.95–10.28), cirrhosis and other chronic liver diseases (5.51%, 95% CI 1.77–8.86), age-related and other hearing loss (4.70%, 95% CI 3.51–6.06), blindness and vision loss (4.30%, 95% CI 3.43–5.05), type 2 diabetes mellitus (3.80%, 95% CI 3.06–4.53), chronic kidney disease (2.74%, 95% CI 1.53–4.02), osteoarthritis (2.26%, 95% CI 0.41–4.12), stroke (1.01%, 95% CI 0.86–1.17), ischaemic heart disease (0.97%, 95% CI 0.69–1.29) and chronic obstructive pulmonary disease (0.92%, 95% CI 0.34–1.54). This study revealed that a series of peripheral diseases were associated with increased risk of dementia and collectively were related to about one-third of the global dementia burden, highlighting the need for targeted public health strategies
Prioritizing quality of life in the management of hyperthyroidism: an expert clinical perspective
Full text link\ua9 2026 the author(s).Hyperthyroidism adversely affects quality of life (QoL), encompassing physical, mental and social functioning and well-being. Patients with hyperthyroidism often complain of anxiety, physical symptoms and tiredness. Concurrent thyroid eye disease (TED) further reduces QoL. With treatment of hyperthyroidism, QoL improves. Symptoms of hyperthyroidism, overall QoL and tiredness are among the domains that improve with a high effect size. Notwithstanding, the overall reduction in QoL persists compared to a matched general population, which seems to relate to residual tiredness, mental fatigue and concerns about levothyroxine substitution, ophthalmological symptoms and weight gain. Common factors contributing to reduced QoL in the long term have been described and include a high prevalence of thyroid dysfunction, the psychological burden of chronic illness, TED, possible inability of levothyroxine replacement to restore euthyroidism in all tissues, and central nervous system residual damage and/or dysfunction. The aetiology and treatment modality for hyperthyroidism may also play a role. In addition, a recently highlighted contributor and predictor of poor QoL is excessive weight gain, which given the global epidemic of obesity, mandates further attention. Regarding newer therapies for hyperthyroidism, notably radiofrequency ablation and molecular targeted immunotherapies, there is a dearth of objective data on QoL. New or improved tools for assessing QoL may be needed to better capture all concerns of these patients. There is a need for randomized controlled studies to guide practitioners regarding which pharmacological or non-pharmacological interventions offer the best long-term QoL outcomes in hyperthyroidism. Anti-obesity medications to mitigate weight gain could also be considered for such patients
Real-World Performance of FIT Triage for Symptomatic Colonoscopy: Analysis of the UK National Endoscopy Database (NED)
Full text link\ua9 2026 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd. Background: The UK has adopted faecal immunochemical testing (FIT) to triage symptomatic colonoscopy referrals. Objective: Quantify diagnostic yield and independent effects of FIT, age, sex and symptoms on polyp and cancer detection in symptomatic colonoscopy. Design: Nationwide analysis of prospectively collected colonoscopy reports (June 2023–August 2025) from the National Endoscopy Database. Symptomatic procedures, including iron-deficiency anaemia (IDA), were identified and diagnostic yields calculated. Mixed-effects logistic regression estimated adjusted odds ratios (aORs) with age, sex, symptom group and FIT. Post-estimation margins modelled cancer yield by age, FIT and symptoms. Results: Analysis of 447,109 symptomatic colonoscopies, with FIT recorded in 202,219 (45.2%). Overall cancer yield was 1.9% (95% CI, 1.8–1.9). Cancer yield was 3.8% (95% CI, 3.7–3.9) in FIT ≥ 10, including 2.5% (95% CI, 2.3–2.7) at age 40–49 and 0.6% (95% CI, 0.5–0.7) at age 16–39; yield in FIT < 10 was 0.3% (95% CI, 0.2–0.3). FIT concentration showed a strong, graded association with cancer risk, weaker association with large polyps, and minimal association with small polyps. IDA was associated with higher cancer risk versus rectal bleeding (aOR 2.2, 95% CI, 2.0–2.3; p < 0.01). With FIT < 10, cancer yield exceeded 1% only in IDA patients aged > 80 and remained < 0.5% otherwise. A model combining FIT, age, and IDA detected > 94% of cancers while reducing colonoscopy demand by > 40%. Conclusion: This national analysis demonstrates the superiority of FIT-based triage over symptom-based referral, with FIT ≥ 10 identifying high-risk patients, including those aged 40–49, while FIT < 10 indicated very low risk
Flexible MIL-53(Al)/Biochar composite for enhanced norfloxacin Removal: Synergistic effects and adsorption mechanisms
No full text\ua9 2025 The Korean Society of Industrial and Engineering Chemistry. The presence of antibiotic contaminants, particularly norfloxacin (NRFX) in aquatic environments poses a significant threat to ecosystems and public health, due to their persistence, bioaccumulation, and contribution to antimicrobial resistance. In this study, a novel MIL-53(Al)/biochar composite was synthesized and applied for NRFX removal from wastewater. The synthesized composite exhibited a high surface area (806 m2/g) and mesopore structure, promoting to improved dispersion and adsorption efficiency. Under optimal conditions (20 mg/L NRFX, 40 mg/L adsorbent, 30 \ub0C, 120 min), the composite achieved a maximum adsorption capacity of 357 mg/g, surpassing most reported antibiotic sorbents (< 250 mg/g). The superior performance was attributed to the synergistic integration of MIL-53(Al) flexible “wine-rack” framework with the oxygen-functionalized, mesoporous carbon matrix of bamboo-derived biochar, facilitating multiple adsorption mechanisms, including electrostatic attraction, hydrogen bonding, π–π interactions, and pore-filling effects. These findings highlight the potential of MIL-53(Al)/BC as a cost‑effective, sustainable, and high‑performance adsorbent with strong potential for real-world remediation of antibiotic-contaminated wastewater under diverse environmental conditions